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Sample records for basolateral amygdala mediates

  1. Sex-Dependent Regulation of Aromatase-Mediated Synaptic Plasticity in the Basolateral Amygdala.

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    Bender, Roland A; Zhou, Lepu; Vierk, Ricardo; Brandt, Nicola; Keller, Alexander; Gee, Christine E; Schäfer, Michael K E; Rune, Gabriele M

    2017-02-08

    The basolateral amygdala (BLA) integrates sensory input from cortical and subcortical regions, a function that requires marked synaptic plasticity. Here we provide evidence that cytochrome P450 aromatase (AROM), the enzyme converting testosterone to 17β-estradiol (E2), contributes to the regulation of this plasticity in a sex-specific manner. We show that AROM is expressed in the BLA, particularly in the basolateral nucleus (BL), in male and female rodents. Systemic administration of the AROM inhibitor letrozole reduced spine synapse density in the BL of adult female mice but not in the BL of male mice. Similarly, in organotypic corticoamygdalar slice cultures from immature rats, treatment with letrozole significantly reduced spine synapses in the BL only in cultures derived from females. In addition, letrozole sex-specifically altered synaptic properties in the BL: in acute slices from juvenile (prepubertal) female rats, wash-in of letrozole virtually abolished long-term potentiation (LTP), whereas it did not prevent the generation of LTP in the slices from males. Together, these data indicate that neuron-derived E2 modulates synaptic plasticity in rodent BLA sex-dependently. As protein expression levels of AROM, estrogen and androgen receptors did not differ between males and females and were not sex-specifically altered by letrozole, the findings suggest sex-specific mechanisms of E2 signaling. SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) is a key structure of the fear circuit. This research reveals a sexually dimorphic regulation of synaptic plasticity in the BLA involving neuronal aromatase, which produces the neurosteroid 17β-estradiol (E2). As male and female neurons in rodent BLA responded differently to aromatase inhibition both in vivo and in vitro , our findings suggest that E2 signaling in BLA neurons is regulated sex-dependently, presumably via mechanisms that have been established during sexual determination. These findings could be

  2. Basolateral amygdala GABA-A receptors mediate stress-induced memory retrieval impairment in rats.

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    Sardari, Maryam; Rezayof, Ameneh; Khodagholi, Fariba; Zarrindast, Mohammad-Reza

    2014-04-01

    The present study was designed to investigate the involvement of GABA-A receptors of the basolateral amygdala (BLA) in the impairing effect of acute stress on memory retrieval. The BLAs of adult male Wistar rats were bilaterally cannulated and memory retrieval was measured in a step-through type passive avoidance apparatus. Acute stress was evoked by placing the animals on an elevated platform for 10, 20 and 30 min. The results indicated that exposure to 20 and 30 min stress, but not 10 min, before memory retrieval testing (pre-test exposure to stress) decreased the step-through latency, indicating stress-induced memory retrieval impairment. Intra-BLA microinjection of a GABA-A receptor agonist, muscimol (0.005-0.02 μg/rat), 5 min before exposure to an ineffective stress (10 min exposure to stress) induced memory retrieval impairment. It is important to note that pre-test intra-BLA microinjection of the same doses of muscimol had no effect on memory retrieval in the rats unexposed to 10 min stress. The blockade of GABA-A receptors of the BLA by injecting an antagonist, bicuculline (0.4-0.5 μg/rat), 5 min before 20 min exposure to stress, prevented stress-induced memory retrieval. Pre-test intra-BLA microinjection of the same doses of bicuculline (0.4-0.5 μg/rat) in rats unexposed to 20 min stress had no effect on memory retrieval. In addition, pre-treatment with bicuculline (0.1-0.4 μg/rat, intra-BLA) reversed muscimol (0.02 μg/rat, intra-BLA)-induced potentiation on the effect of stress in passive avoidance learning. It can be concluded that pre-test exposure to stress can induce memory retrieval impairment and the BLA GABA-A receptors may be involved in stress-induced memory retrieval impairment.

  3. The Basolateral Amygdala Can Mediate the Effects of Fear Memory on Sleep Independently of Fear Behavior and the Peripheral Stress Response

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    Wellman, Laurie L.; Fitzpatrick, Mairen E.; Hallum, Olga Y.; Sutton, Amy M.; Williams, Brook L.; Sanford, Larry D.

    2016-01-01

    Fear conditioning associated with inescapable shock training (ST) and fearful context re-exposure (CR) alone can produce significant behavioral fear, a stress response and alterations in subsequent REM sleep. These alterations may vary among animals and are mediated by the basolateral nucleus of the amygdala (BLA). Here, we used the GABAA agonist, muscimol (Mus), to inactivate BLA prior to CR and examined the effects on sleep, freezing and stress-induced hyperthermia (SIH). Wistar rats (n=28)...

  4. TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors.

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    Choi, Juli; Kim, Ji-eun; Kim, Tae-Kyung; Park, Jin-Young; Lee, Jung-Eun; Kim, Hannah; Lee, Eun-Hwa; Han, Pyung-Lim

    2015-10-01

    Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up-regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated suppression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Neurofascin Knock Down in the Basolateral Amygdala Mediates Resilience of Memory and Plasticity in the Dorsal Dentate Gyrus Under Stress.

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    Saha, Rinki; Kriebel, Martin; Volkmer, Hansjürgen; Richter-Levin, Gal; Albrecht, Anne

    2018-02-05

    Activation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo-hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of rats. Metaplastic effects of such a BLA modulation on hippocampal synaptic function were assessed using BLA priming prior to the induction of long-term potentiation (LTP) on dentate gyrus synapses in anesthetized rats in vivo. The knock down of neurofascin in the BLA prevented a priming-induced impairment on LTP maintenance in the dentate gyrus. At the behavioral level, a similar effect was observable, with neurofascin knock down preventing the detrimental impact of acute traumatic stress on hippocampus-dependent spatial memory retrieval in a water maze task. These findings suggest that reducing GABAergic inhibition specifically at the AIS synapses of the BLA alters amygdalo-hippocampal interactions such that it attenuates the adverse impact of acute stress exposure on cognition-related hippocampal functions.

  6. Contributions of basolateral amygdala and nucleus accumbens subregions to mediating motivational conflict during punished reward-seeking.

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    Piantadosi, Patrick T; Yeates, Dylan C M; Wilkins, Mathew; Floresco, Stan B

    2017-04-01

    The involvement of different nodes within meso-cortico-limbic-striatal circuitry in mediating reward-seeking has been well described, yet comparatively less is known about how such circuitry may regulate appetitively-motivated behaviors that may be punished. The basolateral amygdala (BLA) is one nucleus that has been implicated in suppressing punished reward-seeking, and this structure can modulate goal-directed behavior via projections to subregions of the nucleus accumbens (NAc). Here, we examined the effects of reversible inactivations of the BLA, NAc Shell (NAcS), and core (NAcC) on performance of a "Conflict" task where rats pressed a lever for sucrose reinforcement during three distinct 5min phases. During the first and last phases of a session, rats lever-pressed for food reward delivered on a VI-15/FR5 schedule. In between these phases was a signaled "Conflict" period, where each lever-press yielded food, but 50% of presses were also punished with foot-shock. Under control conditions, well-trained rats responded vigorously during the two "safe" VI-15/FR5 periods, but reduced responding during the punished Conflict period. Inactivation of either the BLA or the NAcS via infusions of baclofen/muscimol disinhibited punished seeking, increasing lever-pressing during the conflict period, while attenuating pressing during VI-15/FR5 phases. In contrast, NAcC inactivation markedly decreased responding across all three phases. Similar inactivation of the BLA or NAcS did not alter responding in a separate control experiment where rats pressed for food on schedules identical to the Conflict task in the absence of any punishment, while NAcC inactivation again suppressed responding. These results imply that BLA and NAcS are part of a circuit that suppresses reward-seeking in the face of danger, which in turn may have implications for disorders characterized by punishment resistance, including substance abuse and obsessive-compulsive disorder. Copyright © 2017 Elsevier

  7. The basolateral nucleus of the amygdala mediates caloric sugar preference over a non-caloric sweetener in mice.

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    Yasoshima, Y; Yoshizawa, H; Shimura, T; Miyamoto, T

    2015-04-16

    Neurobiological and genetic mechanisms underlying increased intake of and preference for nutritive sugars over non-nutritive sweeteners are not fully understood. We examined the roles of subnuclei of the amygdala in the shift in preference for a nutritive sugar. Food-deprived mice alternately received caloric sucrose (1.0 M) on odd-numbered training days and a non-caloric artificial sweetener (2.5 mM saccharin) on even-numbered training days. During training, mice with sham lesions of the basolateral (BLA) or central (CeA) nucleus of the amygdala increased their intake of 1.0 M sucrose, but not saccharin. Trained mice with sham lesions showed a significant shift in preference toward less concentrated sucrose (0.075 M) over the saccharin in a two-bottle choice test, although the mice showed an equivalent preference for these sweeteners before training. No increased intake of or preference for sucrose before and after the alternating training was observed in non-food-deprived mice. Excitotoxic lesions centered in the BLA impaired the increase in 1.0M sucrose intake and shift in preference toward 0.075 M sucrose over saccharin. Microlesions with iontophoretic excitotoxin injections into the CeA did not block the training-dependent changes. These results suggest that food-deprived animals selectively shift their preference for a caloric sugar over a non-caloric sweetener through the alternate consumption of caloric and non-caloric sweet substances. The present data also suggest that the BLA, but not CeA, plays a role in the selective shift in sweetener preference. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Enhancement of striatum-dependent memory by conditioned fear is mediated by beta-adrenergic receptors in the basolateral amygdala

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    Travis D. Goode

    2016-06-01

    Full Text Available Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs enhance dorsolateral striatum (DLS-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA. Recent work indicates that, like unconditioned emotional stimuli, exposure to an aversive conditioned stimulus (CS (i.e., a tone previously paired with shock can also enhance consolidation of DLS-dependent habit memory. The present experiments examined whether noradrenergic activity, particularly within the BLA, is required for a fear CS to enhance habit memory consolidation. First, rats underwent a fear conditioning procedure in which a tone CS was paired with an aversive unconditioned stimulus. Over the course of the next five days, rats received training in a DLS-dependent water plus-maze task, in which rats were reinforced to make a consistent body-turn response to reach a hidden escape platform. Immediately after training on days 1–3, rats received post-training systemic (Experiment 1 or intra-BLA (Experiment 2 administration of the β-adrenoreceptor antagonist, propranolol. Immediately after drug administration, half of the rats were re-exposed to the tone CS in the conditioning context (without shock. Post-training CS exposure enhanced consolidation of habit memory in vehicle-treated rats, and this effect was blocked by peripheral (Experiment 1 or intra-BLA (Experiment 2 propranolol administration. The present findings reveal that noradrenergic activity within the BLA is critical for the enhancement of DLS-dependent habit memory as a result of exposure to conditioned emotional stimuli.

  9. Identification of a dopamine receptor-mediated opiate reward memory switch in the basolateral amygdala-nucleus accumbens circuit.

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    Lintas, Alessandra; Chi, Ning; Lauzon, Nicole M; Bishop, Stephanie F; Gholizadeh, Shervin; Sun, Ninglei; Tan, Huibing; Laviolette, Steven R

    2011-08-03

    The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single-unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates.

  10. Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

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    Roozendaal, Benno; McReynolds, Jayme R.; Van der Zee, Eddy A.; Lee, Sangkwan; McGaugh, James L.; McIntyre, Christa K.

    2009-01-01

    Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing

  11. Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons.

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    Maroun, Mouna; Ioannides, Pericles J; Bergman, Krista L; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara L

    2013-08-01

    Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non-conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress-related disorders. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

  12. The basolateral amygdala can mediate the effects of fear memory on sleep independently of fear behavior and the peripheral stress response.

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    Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y; Sutton, Amy M; Williams, Brook L; Sanford, Larry D

    2017-01-01

    Fear conditioning associated with inescapable shock training (ST) and fearful context re-exposure (CR) alone can produce significant behavioral fear, a stress response and alterations in subsequent REM sleep. These alterations may vary among animals and are mediated by the basolateral nucleus of the amygdala (BLA). Here, we used the GABA A agonist, muscimol (Mus), to inactivate BLA prior to CR and examined the effects on sleep, freezing and stress-induced hyperthermia (SIH). Wistar rats (n=28) were implanted with electrodes for recording sleep, data loggers for recording core body temperature, and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure and baseline sleep was recorded. On experimental day 1, rats received ST (20 footshocks, 0.8mA, 0.5s duration, 60s interstimulus interval). On experimental day 7, the rats received microinjections (0.5μl) into BLA of either Mus (1.0μM; n=13) or vehicle (Veh; n=15) prior to CR (CR1). On experimental day 21, the animals experienced a second CR (CR2) without Mus. For analysis, the rats were separated into 4 groups: (Veh-vulnerable (Veh-Vul; n=8), Veh-resilient (Veh-Res; n=7), Mus-vulnerable (Mus-Vul; n=7), and Mus-resilient (Mus-Res; n=6)) based on whether or not REM was decreased, compared to baseline, during the first 4h following ST. Pre-CR1 inactivation of BLA did not alter freezing or SIH, but did block the reduction in REM in the Mus-Vul group compared to the Veh-Vul group. These data indicate that BLA is an important region for mediating the effects of fearful memories on sleep. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. The Role of the Basolateral Amygdala in Punishment

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    Dit-Bressel, Philip Jean-Richard; McNally, Gavan P.

    2015-01-01

    Aversive stimuli not only support fear conditioning to their environmental antecedents, they also punish behaviors that cause their occurrence. The amygdala, especially the basolateral nucleus (BLA), has been critically implicated in Pavlovian fear learning but its role in punishment remains poorly understood. Here, we used a within-subjects…

  14. Fear extinction requires infralimbic cortex projections to the basolateral amygdala.

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    Bloodgood, Daniel W; Sugam, Jonathan A; Holmes, Andrew; Kash, Thomas L

    2018-03-06

    Fear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role. To address this outstanding issue, the current study employed a combination of electrophysiological and chemogenetic approaches in mice to interrogate the role of IL-BLA and IL-NAc pathways in extinction. Specifically, we used patch-clamp electrophysiology coupled with retrograde tracing to examine changes in neuronal activity of the IL and prelimbic cortex (PL) projections to both the BLA and NAc following fear extinction. We found that extinction produced a significant increase in the intrinsic excitability of IL-BLA projection neurons, while extinction appeared to reverse fear-induced changes in IL-NAc projection neurons. To establish a causal counterpart to these observations, we then used a pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD) strategy to selectively inhibit PFC-BLA projection neurons during extinction acquisition. Using this approach, we found that DREADD-mediated inhibition of PFC-BLA neurons during extinction acquisition impaired subsequent extinction retrieval. Taken together, our findings provide further evidence for a critical contribution of the IL-BLA neural circuit to fear extinction.

  15. Paradoxical facilitation of working memory after basolateral amygdala damage.

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    Barak Morgan

    Full Text Available Working memory is a vital cognitive capacity without which meaningful thinking and logical reasoning would be impossible. Working memory is integrally dependent upon prefrontal cortex and it has been suggested that voluntary control of working memory, enabling sustained emotion inhibition, was the crucial step in the evolution of modern humans. Consistent with this, recent fMRI studies suggest that working memory performance depends upon the capacity of prefrontal cortex to suppress bottom-up amygdala signals during emotional arousal. However fMRI is not well-suited to definitively resolve questions of causality. Moreover, the amygdala is neither structurally or functionally homogenous and fMRI studies do not resolve which amygdala sub-regions interfere with working memory. Lesion studies on the other hand can contribute unique causal evidence on aspects of brain-behaviour phenomena fMRI cannot "see". To address these questions we investigated working memory performance in three adult female subjects with bilateral basolateral amygdala calcification consequent to Urbach-Wiethe Disease and ten healthy controls. Amygdala lesion extent and functionality was determined by structural and functional MRI methods. Working memory performance was assessed using the Wechsler Adult Intelligence Scale-III digit span forward task. State and trait anxiety measures to control for possible emotional differences between patient and control groups were administered. Structural MRI showed bilateral selective basolateral amygdala damage in the three Urbach-Wiethe Disease subjects and fMRI confirmed intact functionality in the remaining amygdala sub-regions. The three Urbach-Wiethe Disease subjects showed significant working memory facilitation relative to controls. Control measures showed no group anxiety differences. Results are provisionally interpreted in terms of a 'cooperation through competition' networks model that may account for the observed paradoxical

  16. Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala

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    Anna Beyeler

    2018-01-01

    Full Text Available The basolateral amygdala (BLA mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc, medial aspect of the central amygdala (CeM, and ventral hippocampus (vHPC. Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.

  17. Sex- and Estrus-Dependent Differences in Rat Basolateral Amygdala.

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    Blume, Shannon R; Freedberg, Mari; Vantrease, Jaime E; Chan, Ronny; Padival, Mallika; Record, Matthew J; DeJoseph, M Regina; Urban, Janice H; Rosenkranz, J Amiel

    2017-11-01

    Depression and anxiety are diagnosed almost twice as often in women, and the symptomology differs in men and women and is sensitive to sex hormones. The basolateral amygdala (BLA) contributes to emotion-related behaviors that differ between males and females and across the reproductive cycle. This hints at sex- or estrus-dependent features of BLA function, about which very little is known. The purpose of this study was to test whether there are sex differences or estrous cyclicity in rat BLA physiology and to determine their mechanistic correlates. We found substantial sex differences in the activity of neurons in lateral nuclei (LAT) and basal nuclei (BA) of the BLA that were associated with greater excitatory synaptic input in females. We also found strong differences in the activity of LAT and BA neurons across the estrous cycle. These differences were associated with a shift in the inhibition-excitation balance such that LAT had relatively greater inhibition during proestrus which paralleled more rapid cued fear extinction. In contrast, BA had relatively greater inhibition during diestrus that paralleled more rapid contextual fear extinction. These results are the first to demonstrate sex differences in BLA neuronal activity and the impact of estrous cyclicity on these measures. The shift between LAT and BA predominance across the estrous cycle provides a simple construct for understanding the effects of the estrous cycle on BLA-dependent behaviors. These results provide a novel framework to understand the cyclicity of emotional memory and highlight the importance of considering ovarian cycle when studying the BLA of females. SIGNIFICANCE STATEMENT There are differences in emotional responses and many psychiatric symptoms between males and females. This may point to sex differences in limbic brain regions. Here we demonstrate sex differences in neuronal activity in one key limbic region, the basolateral amygdala (BLA), whose activity fluctuates across the

  18. Extinction of relapsed fear does not require the basolateral amygdala.

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    Lingawi, Nura W; Westbrook, R Frederick; Laurent, Vincent

    2017-03-01

    It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The role of human basolateral amygdala in ambiguous social threat perception

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    De Gelder, B.; Terburg, D.|info:eu-repo/dai/nl/32304087X; Morgan, B.; Hortensius, R.; Stein, D.J.; van Honk, J.|info:eu-repo/dai/nl/188602801

    2014-01-01

    Previous studies have shown that the amygdala (AMG) plays a role in how affective signals are processed. Animal research has allowed this role to be better understood and has assigned to the basolateral amygdala (BLA) an important role in threat perception. Here we show that, when passively exposed

  20. Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons

    OpenAIRE

    Maroun, Mouna; Ioannides, Pericles J.; Bergman, Krista L.; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara L.

    2013-01-01

    Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retrac...

  1. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

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    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress

  2. Glutamate Receptor Antagonist Infusions into the Basolateral and Medial Amygdala Reveal Differential Contributions to Olfactory vs. Context Fear Conditioning and Expression

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    Walker, David L.; Paschall, Gayla Y.; Davis, Michael

    2005-01-01

    The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and…

  3. The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex

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    Chavez, Candice M.; McGaugh, James L.; Weinberger, Norman M.

    2008-01-01

    Stress hormones released by an experience can modulate memory strength via the basolateral amygdala, which in turn acts on sites of memory storage such as the cerebral cortex [McGaugh, J. L. (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience, 27, 1–28]. Stimuli that acquire behavioral importance gain increased representation in the cortex. For example, learning shifts the tuning of neurons in the primary auditory cor...

  4. The Basolateral Amygdala Is Necessary for the Encoding and the Expression of Odor Memory

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    Sevelinges, Yannick; Desgranges, Bertrand; Ferreira, Guillaume

    2009-01-01

    Conditioned odor avoidance (COA) results from the association between a novel odor and a delayed visceral illness. The present experiments investigated the role of the basolateral amygdala (BLA) in acquisition and retrieval of COA memory. To address this, we used the GABAA agonist muscimol to temporarily inactivate the BLA during COA acquisition…

  5. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation

    NARCIS (Netherlands)

    Atsak, P.; Hauer, D.; Campolongo, P.; Schelling, G.; Fornari, R.V.; Roozendaal, B.

    2015-01-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory

  6. Noradrenergic activation of the basolateral amygdala modulates the consolidation of object-in-context recognition memory

    NARCIS (Netherlands)

    Barsegyan, Areg; McGaugh, James L.; Roozendaal, Benno

    2014-01-01

    Noradrenergic activation of the basolateral complex of the amygdala (BLA) is well known to enhance the consolidation of long-term memory of highly emotionally arousing training experiences. The present study investigated whether such noradrenergic activation of the BLA also influences the

  7. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    NARCIS (Netherlands)

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors,

  8. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior.

    Science.gov (United States)

    McCall, Jordan G; Siuda, Edward R; Bhatti, Dionnet L; Lawson, Lamley A; McElligott, Zoe A; Stuber, Garret D; Bruchas, Michael R

    2017-07-14

    Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.

  9. Phencyclidine affects firing activity of basolateral amygdala neurons related to social behavior in rats.

    Science.gov (United States)

    Katayama, T; Jodo, E; Suzuki, Y; Hoshino, K-Y; Takeuchi, S; Kayama, Y

    2009-03-03

    Negative symptoms of schizophrenia, such as social withdrawal and blunted affect, usually persist for a long period, making rehabilitation difficult. Many studies have demonstrated a close relationship between function of the amygdala and social behavior. Normal social behavior is disturbed in animals administered phencyclidine (PCP), which is now considered a reliable pharmacological model of schizophrenia. Recent studies have reported that disruption of social behavior in PCP-treated rats involved dysfunction of the amygdala. Disturbance of function of the amygdala has also been reported in schizophrenic patients. However, no study has yet examined the effects of PCP on the firing activity of amygdala neurons. In the present study, we recorded the unit activity of basolateral amygdala neurons while rats engaged in socially interactive behavior. After identifying the response properties of recorded neurons, we then recorded the same neurons with systemic PCP administration. Approximately half of the neurons recorded from exhibited an increase in spontaneous discharge rate during social interaction. Only a few neurons exhibited suppression of discharge rate during social interaction. Systemic administration of PCP induced long-lasting activation in half of the neurons that exhibited an increase in firing rate during social interaction. PCP activated half of basolateral amygdala neurons related to socially interactive behavior, and might in this fashion produce dysfunction of social behavior.

  10. A neuroplasticity hypothesis of chronic stress in the basolateral amygdala.

    Science.gov (United States)

    Boyle, Lara M

    2013-06-01

    Chronic stress plays a role in the etiology of several affective and anxiety-related disorders. Despite this, its mechanistic effects on the brain are still unclear. Of particular interest is the effect of chronic stress on the amygdala, which plays a key role in the regulation of emotional responses and memory consolidation. This review proposes a neuroplasticity model for the effects of chronic stress in this region, emphasizing the roles of glutamate and BDNF signaling. This model provides a review of recent discoveries of the effects of chronic stress in the amygdala and reveals pathways for future research.

  11. Progressively Disrupted Intrinsic Functional Connectivity of Basolateral Amygdala in Very Early Alzheimer’s Disease

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    Marion Ortner

    2016-09-01

    Full Text Available Abstract:Very early Alzheimer’s disease (AD - i.e., AD at stages of mild cognitive impairment (MCI and mild dementia - is characterized by progressive structural and neuropathologic changes such as atrophy or tangle deposition in medial temporal lobes, including hippocampus and entorhinal cortex but also adjacent amygdala. While progressively disrupted intrinsic connectivity of hippocampus with other brain areas has been demonstrated by many studies, amygdala connectivity was rarely investigated in AD, notwithstanding its known relevance for emotion processing and mood disturbances, which are both important in early AD. Intrinsic functional connectivity (iFC patterns of hippocampus and amygdala overlap in healthy persons. Thus, we hypothesized that increased alteration of iFC patterns along AD is not limited to the hippocampus but also concerns the amygdala, independent from atrophy. To address this hypothesis, we applied structural and functional resting-state MRI in healthy controls (CON, n=33 and patients with AD in the stages of MCI (AD-MCI, n=38 and mild dementia (AD-D, n=36. Outcome measures were voxel-based morphometry (VBM values and region of interest-based intrinsic functional connectivity maps (iFC of basolateral amygdala, which has extended cortical connectivity. Amygdala VBM values were progressively reduced in patients (CON > AD-MCI and AD-D. Amygdala iFC was progressively reduced along impairment severity (CON > AD-MCI > AD-D, particularly for hippocampus, temporal lobes, and fronto-parietal areas. Notably, decreased iFC was independent of amygdala atrophy. Results demonstrate progressively impaired amygdala intrinsic connectivity in temporal and fronto-parietal lobes independent from increasing amygdala atrophy in very early AD. Data suggest that early AD disrupts intrinsic connectivity of medial temporal lobe key regions including that of amygdala.

  12. Stress impairs reconsolidation of drug memory via glucocorticoid receptors in the basolateral amygdala.

    Science.gov (United States)

    Wang, Xiao-Yi; Zhao, Mei; Ghitza, Udi E; Li, Yan-Qin; Lu, Lin

    2008-05-21

    Relapse to drug taking induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Previous studies indicate that drug seeking can be inhibited by disrupting the reconsolidation of a drug-related memory. Stress plays an important role in modulating different stages of memory including reconsolidation, but its role in the reconsolidation of a drug-related memory has not been investigated. Here, we examined the effects of stress and corticosterone on reconsolidation of a drug-related memory using a conditioned place preference (CPP) procedure. We also determined the role of glucocorticoid receptors (GRs) in the basolateral amygdala (BLA) in modulating the effects of stress on reconsolidation of this memory. We found that rats acquired morphine CPP after conditioning, and that this CPP was inhibited by stress given immediately after re-exposure to a previously morphine-paired chamber (a reconsolidation procedure). The disruptive effect of stress on reconsolidation of morphine related memory was prevented by inhibition of corticosterone synthesis with metyrapone or BLA, but not central amygdala (CeA), injections of the glucocorticoid (GR) antagonist RU38486 [(11,17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one]. Finally, the effect of stress on drug related memory reconsolidation was mimicked by systemic injections of corticosterone or injections of RU28362 [11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one] (a GR agonist) into BLA, but not the CeA. These results show that stress blocks reconsolidation of a drug-related memory, and this effect is mediated by activation of GRs in the BLA.

  13. Noradrenergic activation of the basolateral amygdala modulates the consolidation of object-in-context recognition memory

    OpenAIRE

    Barsegyan, Areg; McGaugh, James L.; Roozendaal, Benno

    2014-01-01

    Noradrenergic activation of the basolateral complex of the amygdala (BLA) is well known to enhance the consolidation of long-term memory of highly emotionally arousing training experiences. The present study investigated whether such noradrenergic activation of the BLA also influences the consolidation of object-in-context recognition memory, a low-arousing training task assessing episodic-like memory. Male Sprague-Dawley rats were exposed to two identical objects in one context for either 3 ...

  14. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    OpenAIRE

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN5...

  15. Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion

    Directory of Open Access Journals (Sweden)

    Rupshi Mitra

    2013-03-01

    Pathological anxiety is thought to reflect a maladaptive state characterized by exaggerated fear. Naturally occurring perturbations that reduce fear can be crucial in the search for new treatments. The protozoan parasite Toxoplasma gondii invades rat brain and removes the fear that rats have of cat odors, a change believed to be parasitic manipulation of host behavior aimed at increasing parasite transmission. It is likely that mechanisms employed by T. gondii can be used as a heuristic tool to understand possible means of fear reduction in clinical settings. Male Long-Evans rats were infected with T. gondii and compared with sham-infected animals 8 weeks after infection. The amount of circulating plasma corticosterone and dendritic arborization of basolateral amygdala principal neurons were quantified. Previous studies have shown that corticosterone, acting within the basolateral amygdala, enhances the fear response to environmental stimuli. Here we show that T. gondii infection causes a dendritic retraction in basolateral amygdala neurons. Such dendritic retraction is accompanied by lower amounts of circulating corticosterone, both at baseline and when induced by an aversive cat odor. The concerted effects of parasitism on two pivotal physiological nodes of the fear response provide an animal model relevant to interactions between stress hormones and amygdalar plasticity.

  16. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; Fornari, Raquel V; Roozendaal, Benno

    2015-05-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

  17. Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala.

    Science.gov (United States)

    Shi, Hai-Shui; Luo, Yi-Xiao; Yin, Xi; Wu, Hong-Hai; Xue, Gai; Geng, Xu-Hong; Hou, Yan-Ning

    2015-08-20

    Drug addiction is considered an aberrant form of learning, and drug-associated memories evoked by the presence of associated stimuli (drug context or drug-related cues) contribute to recurrent craving and reinstatement. Epigenetic changes mediated by DNA methyltransferase (DNMT) have been implicated in the reconsolidation of fear memory. Here, we investigated the role of DNMT activity in the reconsolidation of cocaine-associated memories. Rats were trained over 10 days to intravenously self-administer cocaine by nosepokes. Each injection was paired with a light/tone conditioned stimulus (CS). After acquisition of stable self-administration behaviour, rats underwent nosepoke extinction (10 d) followed by cue-induced reactivation and subsequent cue-induced and cocaine-priming + cue-induced reinstatement tests or subsequently tested to assess the strength of the cocaine-associated cue as a conditioned reinforcer to drive cocaine seeking behaviour. Bilateral intra-basolateral amygdala (BLA) infusion of the DNMT inhibitor5-azacytidine (5-AZA, 1 μg per side) immediately following reactivation decreased subsequent reinstatement induced by cues or cocaine priming as well as cue-maintained cocaine-seeking behaviour. In contrast, delayed intra-BLA infusion of 5-AZA 6 h after reactivation or 5-AZA infusion without reactivation had no effect on subsequent cue-induced reinstatement. These findings indicate that memory reconsolidation for a cocaine-paired stimulus depends critically on DNMT activity in the BLA.

  18. Glycogen synthase kinase 3β in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory.

    Science.gov (United States)

    Wu, Ping; Xue, Yan-Xue; Ding, Zeng-Bo; Xue, Li-Fen; Xu, Chun-Mei; Lu, Lin

    2011-07-01

    Exposure to cocaine-associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3β (GSK-3β) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK-3β in the BLA in the reconsolidation of cocaine cue memories. GSK-3β activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)-induced conditioned place preference increased after re-exposure to a previously cocaine-paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK-3β inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue-induced GSK-3β activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK-3β, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue-induced increases in GSK-3β activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK-3β activity in the BLA mediates the reconsolidation of cocaine cue memories. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  19. Glutamate receptor antagonist infusions into the basolateral and medial amygdala reveal differential contributions to olfactory vs. context fear conditioning and expression

    OpenAIRE

    Walker, David L.; Paschall, Gayla Y.; Davis, Michael

    2005-01-01

    The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and to context fear and fear conditioning by infusing into these areas the NMDA receptor antagonist AP5, the AMPA/kainate receptor antagonist NBQX, or v...

  20. Post-training depletions of basolateral amygdala serotonin fail to disrupt discrimination, retention, or reversal learning

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    G. Jesus eOchoa

    2015-05-01

    Full Text Available In goal-directed pursuits, the basolateral amygdala (BLA is critical in learning about changes in the value of rewards. BLA-lesioned rats show enhanced reversal learning, a task employed to measure the flexibility of response to changes in reward. Similarly, there is a trend for enhanced discrimination learning, suggesting that BLA may modulate formation of stimulus-reward associations. There is a parallel literature on the importance of serotonin (5HT in new stimulus-reward and reversal learning. Recent postulations implicate 5HT in learning from punishment. Whereas dopaminergic involvement is critical in behavioral activation and reinforcement, 5HT may be most critical for aversive processing and behavioral inhibition, complementary cognitive processes. Given these findings, a 5HT-mediated mechanism in BLA may mediate the facilitated learning observed previously. The present study investigated the effects of selective 5HT lesions in BLA using 5,7-dihydroxytryptamine (5,7-DHT versus infusions of saline (Sham on discrimination, retention, and deterministic reversal learning. Rats were required to reach an 85% correct pairwise discrimination and single reversal criterion prior to surgery. Postoperatively, rats were then tested on the 1 retention of the pretreatment discrimination pair 2 discrimination of a novel pair and 3 reversal learning performance. We found statistically comparable preoperative learning rates between groups, intact postoperative retention, and unaltered novel discrimination and reversal learning in 5,7-DHT rats. These findings suggest that 5HT in BLA is not required for formation and flexible adjustment of new stimulus-reward associations when the strategy to efficiently solve the task has already been learned. Given the complementary role of orbitofrontal cortex in reward learning and its interconnectivity with BLA, these findings add to the list of dissociable mechanisms for BLA and orbitofrontal cortex in reward learning.

  1. The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala.

    Science.gov (United States)

    Ratano, Patrizia; Everitt, Barry J; Milton, Amy L

    2014-10-01

    We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.

  2. Deep Brain Stimulation of the Basolateral Amygdala: Targeting Technique and Electrodiagnostic Findings

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    Jean-Philippe Langevin

    2016-08-01

    Full Text Available The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG. MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety.

  3. Stimulus Intensity-dependent Modulations of Hippocampal Long-term Potentiation by Basolateral Amygdala Priming

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    Zexuan eLi

    2012-05-01

    Full Text Available There is growing realization that the relationship between memory and stress/emotionality is complicated, and may include both memory enhancing and memory impairing aspects. It has been suggested that the underlying mechanisms involve amygdalar modulation of hippocampal synaptic plasticity, such as long-term potentiation (LTP. We recently reported that while in CA1 basolateral amygdala (BLA priming impaired theta stimulation induced LTP, it enhanced LTP in the dentate gyrus (DG. However, emotional and stressfull experiences were found to activate synaptic plasticity within the BLA, rasing the possibility that BLA modulation of other brain regions may be altered as well, as it may depend on the way the BLA is activated or is responding. In previous studies BLA priming stimulation was relatively weak (1V, 50 µs pulse duration. In the present study we assessed the effects of two stronger levels of BLA priming stimulation (1V or 2V, 100 µs pulse duration on LTP induction in hippocampal DG and CA1, in anesthetized rats. Results show that 1V-BLA priming stimulation enhanced but 2V-BLA priming stimulation impaired DG LTP; however, both levels of BLA priming stimulation impaired CA1 LTP, suggesting that modulation of hippocampal synaptic plasticity by amygdala is dependent on the degree of amygdala activation. These findings suggest that plasticity induced within the amygdala, by stressful experiences induces a form of metaplasticity that would alter the way the amygdala may modulate memory-related processes in other brain areas, such as the hippocampus.

  4. The Effect of Injection of Pilocarpine Intra Basolateral Amygdala on the Dexamethasone Induced Memory Deficiency in Male Rat

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    Sana Mollahoseini

    2012-09-01

    Full Text Available Background & Objectives: Several studies have shown that Glucocorticoids affect learning and memory processes by influences on limbic structures such as amygdala. The amygdala is an important region for memory formation. Considering the existence of the muscarinic acetylcholine receptors in the basolateral amygdala (BLA, the aim of the present study was to investigate the effect of intra-BLA microinjection of pilocarpine on the effect of dexamethasone on memory retrieval .   Methods: As a model of learning, using a step-through apparatus , inhibitory avoidance was used for assessment of long-term memory in 80 adult male Wistar rats . All animals were bilaterally implanted with cannulas into the BLA and were trained and tested (with 24 h interval 7 days after surgery. Memory retrieval was evaluated by recording of the step-through latencies and the time spent in dark chamber of apparatus in the testing day.   Results: Pre-test subcutaneous (s.c administration of dexamethasone (2 mg/kg impaired memory retrieval in animals when trained 24 h in advance. Co-pretest microinjection of different doses of pilocarpine (1 , 2 μg/rat, intra-BLA , a muscarinic acetylcholine receptor agonist, with the dexamethasone (2 mg/kg, s.c caused enhancement of memory retrieval.   Conclusion: Results of this research indicate that impairment effect of dexamethasone on memory processes may be mediates by decrease of mechanisms of BLA muscarinic cholinergic.

  5. Neuropeptide S in the basolateral amygdala mediates an adaptive behavioral stress response in a rat model of posttraumatic stress disorder by increasing the expression of BDNF and the neuropeptide YY1 receptor.

    Science.gov (United States)

    Cohen, Hagit; Vainer, Ella; Zeev, Kaplan; Zohar, Joseph; Mathé, Aleksander A

    2018-01-01

    Neuropeptide S (NPS) is a regulatory peptide that has anxiolytic and arousal-promoting effects in rodents. We used an animal model of posttraumatic stress disorder (PTSD) to assess long-term behavioral effects of a single dose of NPS, microinjected into the basolateral amygdala (BLA) 1h following exposure to predator-scent stress (PSS). To elucidate the molecular mechanism by which NPS attenuates behavioral stress responses, expression levels of neuropeptide Y (NPY), NPY-Y1 receptor (NPY-Y1R), and brain-derived neurotrophic factor (BDNF) were evaluated in the hippocampus. The behavioral and molecular effects of NPS receptor antagonist (NPS-RA), NPY-Y1R antagonist (NPY-Y1RA), or both administered centrally were evaluated in the same manner. Circulating corticosterone levels were measured at different time points following PSS-exposure. Immediate post-exposure treatment with NPS had a marked protective effect; BLA microinfusion of NPS completely abolished the extreme behavioral response to PSS, restored the decreased expression of BDNF and, unexpectedly, PY-Y1R, but didn't affect the decreased expression of NPY. BLA microinfusion of both NPY-Y1RA and NPS-RA together had an additive effect, which completely prevented the anxiolytic effects of NPS in rats exposed to PSS and disrupted the expression of NPY-Y1R in the hippocampus following NPS infusion. It may therefore be hypothesized that NPS acts, directly or indirectly, on both the NPY-Y1R and NPS receptors and that the cross-talk between NPS and NPY-Y1R may be necessary for the anxiolytic effects of NPS post-exposure. The NPS system might thus contribute to a potential endogenous mechanism underlying the shift towards adaptive behavioral response and thereby might be relevant as a pharmacological target for attenuating stress-related sequelae. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  6. Prefrontal cortex, hippocampus, and basolateral amygdala plasticity in a rat model of autism spectrum.

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    Sosa-Díaz, Nuvia; Bringas, Maria Elena; Atzori, Marco; Flores, Gonzalo

    2014-10-01

    We aimed to investigate the effect of prenatal administration of valproic acid (VPA) (500 mg/kg) at embryonic day 12.5 on the anatomical properties of the prefrontal cortex, hippocampus, and basolateral amygdala, at three different ages: immediately after weaning (postnatal day 21 [PD21]), prepubertal (PD35), and postpubertal (PD70) ages in a rat model of autistic spectrum disorder. Quantitative analysis of the thickness of the prefrontal cortex revealed a reduced size at all study ages in the cingulate 1 area of the prefrontal cortex and CA1 of the dorsal hippocampus in prenatally exposed animals compared to controls. At the level of the basolateral amygdala, a reduction in the size was observed at PD35 and PD70 in the VPA group. In addition, a reduced thickness was observed in the prelimbic region of the prefrontal cortex in VPA animals at PD35. Interestingly, no differences in cortical thickness were observed between control and VPA animals in the infralimbic region of the prefrontal at any age. Our results suggest that prenatal exposure to VPA differentially alters cortical limbic regions anatomical parameters, with implication in the autistic spectrum disorder. © 2014 Wiley Periodicals, Inc.

  7. Preferential recruitment of the basolateral amygdala during memory encoding of negative scenes in posttraumatic stress disorder.

    Science.gov (United States)

    Patel, Ronak; Girard, Todd A; Pukay-Martin, Nicole; Monson, Candice

    2016-04-01

    The vast majority of functional neuroimaging studies in posttraumatic stress disorder (PTSD) have examined the amygdala as a unitary structure. However, an emerging body of studies indicates that separable functions are subserved by discrete amygdala subregions. The basolateral subdivision (BLA), as compared with the centromedial amygdala (CMA), plays a unique role in learning and memory-based processes for threatening events, and alterations to the BLA have been implicated in the pathogenesis of PTSD. We assessed whether PTSD is associated with differential involvement of the BLA versus the CMA during successful encoding of emotionally charged events. Participants with PTSD (n=11) and a trauma-exposed comparison (TEC) group (n=11) viewed a series of photos that varied in valence (negative versus positive) and arousal (high versus low) while undergoing functional magnetic resonance imaging (fMRI). Subsequently, participants completed an old/new recognition memory test. Using analytic methods based on probabilistic cytoarchitectonic mapping, PTSD was associated with greater activation of the BLA, as compared to the CMA, during successful encoding of negative scenes, a finding which was not observed in the TEC group. Moreover, this memory-related activity in the BLA independently predicted PTSD status. Contrary to hypotheses, there was no evidence of altered BLA activity during memory encoding of high arousing relative to low arousing scenes. Task-related brain activation in PTSD does not appear to be consistent across the entire amygdala. Importantly, memory-related processing of negative information in PTSD is associated with preferential recruitment of the BLA. Copyright © 2016. Published by Elsevier Inc.

  8. Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

    Science.gov (United States)

    Wells, Audrey Marie

    The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U

  9. Inactivation of basolateral amygdala prevents chronic immobilization stress-induced memory impairment and associated changes in corticosterone levels.

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    Tripathi, Sunil Jamuna; Chakraborty, Suwarna; Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S

    2017-07-01

    Chronic stress causes detrimental effects on various forms of learning and memory. The basolateral amygdala (BLA) not only plays a crucial role in mediating certain forms of memory, but also in the modulation of the effects of stress. Chronic immobilization stress (CIS) results in hypertrophy of the BLA, which is believed to be one of the underlying causes for stress' effects on learning. Thus, it is plausible that preventing the effects of CIS on amygdala would preclude its deleterious cognitive effects. Accordingly, in the first part, we evaluated the effect of excitotoxic lesion of the BLA on chronic stress-induced hippocampal-dependent spatial learning using a partially baited radial arm maze task. The BLA was ablated bilaterally using ibotenic acid prior to CIS. Chronically stressed rats showed impairment in spatial learning with decreased percentage correct choice and increased reference memory errors. Excitotoxic lesion of the BLA prevented the impairment in spatial learning and reference memory. In the retention test, lesion of the BLA was able to rescue the chronic stress-induced impairment. Interestingly, stress-induced enhanced plasma corticosterone levels were partially prevented by the lesion of BLA. These results motivated us to evaluate if the same effects can be observed with temporary inactivation of BLA, only during stress. We found that chronic stress-induced spatial learning deficits were also prevented by temporary inactivation of the BLA. Additionally, temporary inactivation of BLA partially precluded the stress-induced increase in plasma corticosterone levels. Thus, inactivation of BLA precludes stress-induced spatial learning deficits, and enhanced plasma corticosterone levels. It is speculated that BLA inactivation-induced reduction in corticosterone levels during stress, might be crucial in restoring spatial learning impairments. Our study provides evidence that amygdalar modulation during stress might be beneficial for strategic

  10. The Basolateral Amygdala Determines the Effects of Fear Memory on Sleep in an Animal Model of PTSD

    OpenAIRE

    Wellman, Laurie L.; Fitzpatrick, Mairen E.; Machida, Mayumi; Sanford, Larry D.

    2014-01-01

    Fear conditioning (inescapable shock training (ST)) and fearful context re-exposure (CR) alone can produce significant fear indicated by increased freezing and reductions in subsequent REM sleep. Damage to or inactivation of the basolateral nucleus of the amygdala (BLA) prior to or after ST or prior to CR generally has been found to attenuate freezing in the shock training context. However, no one has examined the impact of BLA inactivation on fear-induced changes in sleep. Here, we used the ...

  11. Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear

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    Dennis R. Sparta

    2014-05-01

    Full Text Available The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD. The basolateral amygdala (BLA has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC. Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning.

  12. CRF1 receptor activation increases the response of neurons in the basolateral nucleus of the amygdala to afferent stimulation

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    2008-07-01

    Full Text Available The basolateral nucleus (BLA of the amygdala contributes to the consolidation of memories for emotional or stressful events. The nucleus contains a high density of CRF1 receptors that are activated by corticotropin-releasing factor (CRF. Modulation of the excitability of neurons in the BLA by CRF may regulate the immediate response to stressful events and the formation of associated memories. In the present study, CRF was found to increase the amplitude of field potentials recorded in the BLA following excitatory afferent stimulation, in vitro. The increase was mediated by CRF1 receptors, since it could be blocked by the selective, non-peptide antagonists, NBI30775 and NBI35583, but not by the CRF2-selective antagonist, astressin 2B. Furthermore, the CRF2-selective agonist, urocortin II had no effect on field potential amplitude. The increase induced by CRF was long-lasting, could not be reversed by subsequent administration of NBI35583, and required the activation of protein kinase C. This effect of CRF in the BLA may be important for increasing the salience of aversive stimuli under stressful conditions, and for enhancing the consolidation of associated memories. The results provide further justification for studying the efficacy of selective antagonists of the CRF1 receptor to reduce memory formation linked to emotional or traumatic events, and suggest that these compounds might be useful as prophylactic treatment for stress-related illness such as post-traumatic stress disorder.

  13. Angiotensin-(1-7) in the basolateral amygdala attenuates the cardiovascular response evoked by acute emotional stress.

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    Oscar, Charles Gonzaga; Müller-Ribeiro, Flávia Camargos de Figueirêdo; de Castro, Lidiane Gonzaga; Martins Lima, Augusto; Campagnole-Santos, Maria José; Santos, Robson Augusto Souza; Xavier, Carlos Henrique; Fontes, Marco Antônio Peliky

    2015-01-12

    The basolateral amygdala (BLA) plays a critical role in mediating physiological responses to emotional stress. Recent data suggest that angiotensin-(1-7) [Ang-(1-7)] can act centrally attenuating the cardiovascular response to acute stress. We investigated whether Ang-(1-7) in the BLA plays a role in the cardiovascular response to emotional stress. Under anesthesia, guide cannulas were implanted into the BLA of Wistar rats. Five days later, the femoral artery was cannulated for mean arterial pressure (MAP) and heart rate (HR) recordings. Microinjections of Ang-(1-7) (5 or 50 pmol), the Mas receptor antagonist A-779 (100 pmol), Ang-(1-7)+A-779 (50 + 100 pmol, respectively), or vehicle (NaCl 0.9%, control) were performed after 24h and rats were then submitted to stress trials. Injection of Ang-(1-7) into the BLA blocked the tachycardia (ΔHR: vehicle 135 ± 23 vs. Ang-(1-7) 9 ± 12 bpm; Presponse (ΔMAP: vehicle 28 ± 3 mmHg vs. Ang-(1-7) 6 ± 2 mmHg; Presponse evoked by cage-switch stress paradigm. These findings indicate that Ang-(1-7) can act in the BLA through the Mas receptors modulating the cardiovascular response evoked by emotional stress. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Involvement of CRFR1 in the Basolateral Amygdala in the Immediate Fear Extinction Deficit.

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    Hollis, Fiona; Sevelinges, Yannick; Grosse, Jocelyn; Zanoletti, Olivia; Sandi, Carmen

    2016-01-01

    Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR 1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF 6-33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser 845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR 1 antagonist indicates their dependence on CRFR 1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.

  15. Differential calcium dependence in basal and forskolin-potentiated spontaneous transmitter release in basolateral amygdala neurons.

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    Miura, Yuki; Naka, Masamitsu; Matsuki, Norio; Nomura, Hiroshi

    2012-10-31

    Action potential-independent transmitter release, or spontaneous release, is postulated to produce multiple postsynaptic effects (e.g., maintenance of dendritic spines and suppression of local dendritic protein synthesis). Potentiation of spontaneous release may contribute to the precise modulation of synaptic function. However, the expression mechanism underlying potentiated spontaneous release remains unclear. In this study, we investigated the involvement of extracellular and intracellular calcium in basal and potentiated spontaneous release. Miniature excitatory postsynaptic currents (mEPSCs) of the basolateral amygdala neurons in acute brain slices were recorded. Forskolin, an adenylate cyclase activator, increased mEPSC frequency, and the increase lasted at least 25 min after washout. Removal of the extracellular calcium decreased mEPSC frequency in both naïve and forskolin-treated slices. On the other hand, chelation of intracellular calcium by BAPTA-AM decreased mEPSC frequency in naïve, but not in forskolin-treated slices. A blockade of the calcium-sensing receptor (CaSR) resulted in an increase in mEPSC frequency in forskolin-treated, but not in naïve slices. These findings indicate that forskolin-induced potentiation is accompanied by changes in the mechanisms underlying Ca(2+)-dependent spontaneous release. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury.

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    Camila P Almeida-Suhett

    Full Text Available Traumatic brain injury (TBI is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA; hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified. We assessed the functional alterations in inhibitory synaptic transmission in the BLA and one mechanism that modulates excitatory synaptic transmission, the α7 containing nicotinic acetylcholine receptor (α7-nAChR, after mTBI, to shed light on the mechanisms that contribute to increased anxiety-like behaviors. Seven and 30 days after a mild controlled cortical impact (CCI injury, animals displayed significantly greater anxiety-like behavior. This was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs. Decreases in the mIPSC amplitude were associated with reduced surface expression of α1, β2, and γ2 GABAA receptor subunits. However, significant increases in the surface expression and current mediated by α7-nAChR, were observed, signifying increases in the excitability of principal neurons within the BLA. These results suggest that mTBI causes not only a significant reduction in inhibition in the BLA, but also an increase in neuronal excitability, which may contribute to hyperexcitability and the development of anxiety disorders.

  17. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory retrieval pattern in mice.

    Science.gov (United States)

    Chauveau, F; Piérard, C; Coutan, M; Drouet, I; Liscia, P; Béracochéa, D

    2008-09-01

    Previous data from our team have shown that pre-test stress in mice reversed the pattern of memory retrieval in a contextual serial spatial task (CSD; Celerier, A., Pierard, C., Rachbauer, D., Sarrieau, A., & Beracochea, D. (2004). Contextual and serial discriminations: A new learning paradigm to assess simultaneously the effects of acute stress on retrieval of flexible or stable information in mice. Learning and Memory, 11, 196-204). The present study is aimed at determining brain areas which might be critically involved in mediating the stress effect on memory retrieval in the CSD task. For that purpose, we studied hereby the effects of ibotenic acid lesions of either the prefrontal cortex (PFC) or the basolateral amygdala (BLA) in Stressed or Non-Stressed Balb/c mice on memory retrieval in the CSD task. In that task, mice learned two successive spatial discriminations (D1 and D2) within two different internal contexts in a four-hole board. The stressor (electric footshocks) was delivered 5 min before test, occurring 24 h after acquisition. During test, mice were relocated either on the floor of the first or of the second discrimination. Results showed that (i) spatial memory was substantial and remained unaffected both by lesions and stress; (ii) Non-Stressed controls as well as Non-Stressed or Stressed PFC and BLA-lesioned mice remembered accurately D1 but not D2; and (iii) in contrast, Stressed controls accurately remembered D2 but not D1. In parallel to behavioral experiments, we also showed that PFC and BLA lesions did not affect the stress-induced increase of plasma corticosterone levels. All together, PFC and BLA integrity are not necessary for retrieval processes per se; in contrast, the PFC and BLA are critically involved in the mediation of the deleterious stress effects on serial order memory retrieval.

  18. Histamine acting on the basolateral amygdala reverts the impairment of aversive memory of rats submitted to neonatal maternal deprivation.

    Science.gov (United States)

    Benetti, Fernando; da Silveira, Clarice Kras Borges; Rosa, Jessica; Izquierdo, Ivan

    2015-02-01

    Recent findings suggest a role of brain histamine in the regulation of memory consolidation, particularly in one-trial inhibitory avoidance (IA) learning and that disruption in the mother infant relationship i.e. maternal deprivation induces cognitive deficits. We investigate whether histamine itself, and histaminergic compounds given into the basolateral amygdala (BLA) immediately post-training can affect retention (24 h after training) of one-trial (IA) in rats submitted to early postnatal maternal deprivation. In all cases, deprived (Dep) animals had lower retention scores than non-deprived controls (N-dep). Histamine induced memory enhancement on its own in N-dep animals and was able to overcome the deleterious effect of Dep. The effects by SKF-91488 is similar to histamine. The H3 agonist, imetit mimetized the enhancing effects of histamine; neither agonist H1 pyridylethylamine nor the H2 dimaprit had any effect. Ranitidine and thioperamide (50 nmol) co-infused with histamine (10 nmol) fully blocked the restorative effect of histamine on retention in Dep animals. Thioperamide, in addition, blocked the enhancing effect of histamine on memory of the N-dep animals as well. None of the drugs used given into BLA had any effect on open-field or elevated plus-maze behavior in N-dep or Dep rats. Our results are limited to experimental design in rats. Extrapolation i.e. in humans requires further experimentations. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may at least in part be due to an impairment of histamine H3 receptor-mediated mediated mechanisms in the BLA. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex.

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    Chavez, Candice M; McGaugh, James L; Weinberger, Norman M

    2009-05-01

    Stress hormones released by an experience can modulate memory strength via the basolateral amygdala, which in turn acts on sites of memory storage such as the cerebral cortex [McGaugh, J. L. (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience, 27, 1-28]. Stimuli that acquire behavioral importance gain increased representation in the cortex. For example, learning shifts the tuning of neurons in the primary auditory cortex (A1) to the frequency of a conditioned stimulus (CS), and the greater the level of CS importance, the larger the area of representational gain [Weinberger, N. M. (2007). Associative representational plasticity in the auditory cortex: A synthesis of two disciplines. Learning & Memory, 14(1-2), 1-16]. The two lines of research suggest that BLA strengthening of memory might be accomplished in part by increasing the representation of an environmental stimulus. The present study investigated whether stimulation of the BLA can affect cortical memory representations. In male Sprague-Dawley rats studied under urethane general anesthesia, frequency receptive fields were obtained from A1 before and up to 75min after the pairing of a tone with BLA stimulation (BLAstm: 100 trials, 400ms, 100Hz, 400microA [+/-16.54]). Tone started before and continued after BLAstm. Group BLA/1.0 (n=16) had a 1s CS-BLAstm interval while Group BLA/1.6 (n=5) has a 1.6s interval. The BLA/1.0 group did develop specific tuning shifts toward and to the CS, which could change frequency tuning by as much as two octaves. Moreover, its shifts increased over time and were enduring, lasting 75min. However, group BLA/1.6 did not develop tuning shifts, indicating that precise CS-BLAstm timing is important in the anesthetized animal. Further, training in the BLA/1.0 paradigm but stimulating outside of the BLA did not produce tuning shifts. These findings demonstrate that the BLA is capable of exerting highly specific

  20. Synaptic Organization of Perisomatic GABAergic Inputs onto the Principal Cells of the Mouse Basolateral Amygdala

    Science.gov (United States)

    Vereczki, Viktória K.; Veres, Judit M.; Müller, Kinga; Nagy, Gergö A.; Rácz, Bence; Barsy, Boglárka; Hájos, Norbert

    2016-01-01

    Spike generation is most effectively controlled by inhibitory inputs that target the perisomatic region of neurons. Despite the critical importance of this functional domain, very little is known about the organization of the GABAergic inputs contacting the perisomatic region of principal cells (PCs) in the basolateral amygdala. Using immunocytochemistry combined with in vitro single-cell labeling we determined the number and sources of GABAergic inputs of PCs at light and electron microscopic levels in mice. We found that the soma and proximal dendrites of PCs were innervated primarily by two neurochemically distinct basket cell types expressing parvalbumin (PVBC) or cholecystokinin and CB1 cannabinoid receptors (CCK/CB1BC). The innervation of the initial segment of PC axons was found to be parceled out by PVBCs and axo-axonic cells (AAC), as the majority of GABAergic inputs onto the region nearest to the soma (between 0 and 10 μm) originated from PVBCs, while the largest portion of the axon initial segment was innervated by AACs. Detailed morphological investigations revealed that the three perisomatic region-targeting interneuron types significantly differed in dendritic and axonal arborization properties. We found that, although individual PVBCs targeted PCs via more terminals than CCK/CB1BCs, similar numbers (15–17) of the two BC types converge onto single PCs, whereas fewer (6–7) AACs innervate the axon initial segment of single PCs. Furthermore, we estimated that a PVBC and a CCK/CB1BC may target 800–900 and 700–800 PCs, respectively, while an AAC can innervate 600–650 PCs. Thus, BCs and AACs innervate ~10 and 20% of PC population, respectively, within their axonal cloud. Our results collectively suggest, that these interneuron types may be differently affiliated within the local amygdalar microcircuits in order to fulfill specific functions in network operation during various brain states. PMID:27013983

  1. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

    Science.gov (United States)

    Heinrichs, Stephen C; Leite-Morris, Kimberly A; Guy, Marsha D; Goldberg, Lisa R; Young, Angela J; Kaplan, Gary B

    2013-07-01

    Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi-Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders. Published by Elsevier B.V.

  2. Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

    Science.gov (United States)

    Skelly, M J; Ariwodola, O J; Weiner, J L

    2017-02-01

    Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline

  3. Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning.

    Science.gov (United States)

    Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha

    2015-11-01

    The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. The role of basolateral amygdala adrenergic receptors in hippocampus dependent spatial memory in rat

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    Vafaei A.L.

    2008-03-01

    Full Text Available Background and the purpose of the study: There are extensive evidences indicating that the noradrenergic system of the basolateral nucleus of the amygdala (BLA is involved in memory processes. The present study investigated the role of the BLA adrenergic receptors (ARs in hippocampus dependent spatial memory in place avoidance task in male rat. Material and Methods: Long Evans rats (n=150 were trained to avoid footshock in a 60° segment while foraging for scattered food on a circular (80-cm diameter arena. The rats were injected bilaterally in the BLA specific ARS (Adrenergic receptors agonist norepinephrine (NE, 0.5 and 1 µg/µl and specific β-ARs antagonist propranolol (PRO, 0.5 and 1 µg/µl before acquisition, after training or before retrieval of the place avoidance task. Control rats received vehicle at the same volume. The learning in a single 30-min session was assessed 24h later by a 30-min extinction trial in which the time to first entrance and the number of entrances to the shocked area measured the avoidance memory. Results: Acquisition and consolidation were enhanced and impaired significantly by NE and PRO when the drugs were injected 10 min before or immediately after training, respectively. In contrast, neither NE nor PRO influenced animal performances when injected before retention testing. Conclusion: Findings of this study indicates that adrenergic system of the BLA plays an important role in regulation of memory storage and show further evidences for the opinion that the BLA plays an important role in integrating hormonal and neurotransmitter influences on memory storage.

  5. Noradrenergic activation of the basolateral amygdala modulates the consolidation of object-in-context recognition memory

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    Areg eBarsegyan

    2014-05-01

    Full Text Available Noradrenergic activation of the basolateral complex of the amygdala (BLA is well known to enhance the consolidation of long-term memory of highly emotionally arousing training experiences. The present study investigated whether such noradrenergic activation of the BLA also influences the consolidation of object-in-context recognition memory, a low-arousing training task assessing episodic-like memory. Male Sprague–Dawley rats were exposed to two identical objects in one context for either 3 or 10 min, immediately followed by exposure to two other identical objects in a distinctly different context. Immediately after the training they received bilateral intra-BLA infusions of norepinephrine (0.3, 1.0 or 3.0 μg or the β-adrenoceptor antagonist propranolol (0.1, 0.3 or 1.0 μg. On the 24-h retention test, rats were placed back into one of the training contexts with one copy of each of the two training objects. Thus, although both objects were familiar, one of the objects had not previously been encountered in this particular test context. Hence, if the animal generated a long-term memory for the association between an object and its context, it would spend significantly more time exploring the object that was not previously experienced in this context. Saline-infused control rats exhibited poor 24-h retention when given 3 min of training and good retention when given 10 min of training. Norepinephrine administered after 3 min of object-in-context training induced a dose-dependent memory enhancement, whereas propranolol administered after 10 min of training produced memory impairment. These findings provide evidence that posttraining noradrenergic activation of the BLA also enhances the consolidation of memory of object-in-context recognition training, enabling accuracy of episodic-like memories.

  6. Contribution of the basolateral amygdala NMDA and muscarinic receptors in rat's memory retrieval.

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    Nazarinia, Efat; Rezayof, Ameneh; Sardari, Maryam; Yazdanbakhsh, Nima

    2017-03-01

    The present study was designed to investigate the involvement of the muscarinic cholinergic receptors in the basolateral amygdala (BLA) in memory retrieval. Also, the possible relationship between the BLA muscarinic cholinergic and the NMDA receptor systems was evaluated in the inhibitory avoidance learning. Male Wistar rats were bilaterally cannulated into the BLAs and memory retrieval was measured in a step-through type inhibitory avoidance apparatus. Intra-BLA microinjection of different doses of a non-selective muscarinic receptor antagonist, scopolamine (0.5-1μg/rat, intra-BLA), 5min before the testing phase dose-dependently induced amnesia. Pre-test intra-BLA microinjection of different doses of NMDA (0.005-0.05μg/rat) reversed scopolamine-induced amnesia and improved memory retrieval. In addition, different doses of a selective NMDA receptor antagonist, D-AP5 (0.001-0.005μg/rat, intra-BLA) potentiated the response of an ineffective dose of scopolamine (0.5μg/rat) to inhibit memory retrieval. It should be considered that pre-test intra-BLA microinjection of the same doses of NMDA or D-AP5 by themselves had no effect on memory retrieval. Similar to ANOVA analysis, our cubic interpolation analysis also predicted that the activation or inactivation of the NMDA receptors by different doses of drugs can affect the scopolamine response. On the other hand, pre-test intra-BLA microinjection of D-AP5 inhibited the reversal effect of NMDA on scopolamine-induced amnesia. It can be concluded that the BLA cholinergic system, via muscarinic receptors, has a critical role in memory retrieval. Our results also suggest that a cooperative interaction between the BLA NMDA and muscarinic acetylcholine receptors modulates memory formation of inhibitory avoidance task in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The Dissociative Subtype of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes.

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    Nicholson, Andrew A; Densmore, Maria; Frewen, Paul A; Théberge, Jean; Neufeld, Richard Wj; McKinnon, Margaret C; Lanius, Ruth A

    2015-09-01

    Previous studies point towards differential connectivity patterns among basolateral (BLA) and centromedial (CMA) amygdala regions in patients with posttraumatic stress disorder (PTSD) as compared with controls. Here we describe the first study to compare directly connectivity patterns of the BLA and CMA complexes between PTSD patients with and without the dissociative subtype (PTSD+DS and PTSD-DS, respectively). Amygdala connectivity to regulatory prefrontal regions and parietal regions involved in consciousness and proprioception were expected to differ between these two groups based on differential limbic regulation and behavioral symptoms. PTSD patients (n=49) with (n=13) and without (n=36) the dissociative subtype and age-matched healthy controls (n=40) underwent resting-state fMRI. Bilateral BLA and CMA connectivity patterns were compared using a seed-based approach via SPM Anatomy Toolbox. Among patients with PTSD, the PTSD+DS group exhibited greater amygdala functional connectivity to prefrontal regions involved in emotion regulation (bilateral BLA and left CMA to the middle frontal gyrus and bilateral CMA to the medial frontal gyrus) as compared with the PTSD-DS group. In addition, the PTSD+DS group showed greater amygdala connectivity to regions involved in consciousness, awareness, and proprioception-implicated in depersonalization and derealization (left BLA to superior parietal lobe and cerebellar culmen; left CMA to dorsal posterior cingulate and precuneus). Differences in amygdala complex connectivity to specific brain regions parallel the unique symptom profiles of the PTSD subgroups and point towards unique biological markers of the dissociative subtype of PTSD.

  8. Activation of NF-κB in basolateral amygdala is required for memory reconsolidation in auditory fear conditioning.

    Science.gov (United States)

    Si, Jijian; Yang, Jianli; Xue, Lifen; Yang, Chenhao; Luo, Yixiao; Shi, Haishui; Lu, Lin

    2012-01-01

    Posttraumatic stress disorder (PTSD) is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA), but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC). We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.

  9. Activation of NF-κB in basolateral amygdala is required for memory reconsolidation in auditory fear conditioning.

    Directory of Open Access Journals (Sweden)

    Jijian Si

    Full Text Available Posttraumatic stress disorder (PTSD is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA, but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC. We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.

  10. [Interneuronal relationships in the basolateral amygdala of cats trained for choice in the quality of food reinforcement].

    Science.gov (United States)

    Merzhanova, G Kh; Dolbakian, E E; Partev, A Z

    1997-01-01

    The alimentary instrumental conditioned bar-pressing reflex was elaborated in cats by the method of "active choice" of either short-delayed reinforcement with bread-meat mixture of delayed more valuable reinforcement with meat. The animals differed in behavior strategy: some animals preferred bar-pressing with the long delay (the so-called "self-control" group), other animals pressed the bar with short delay (the so-called "impulsive" group). The multiunit activity in the basolateral amygdala was recorded with chronically implanted nichrome microelectrodes. The interactions between the spike trains of the neighbouring neurons selected from the multiunit activity were evaluated by means of statistical crosscorrelation analysis. It was shown that the number of correlations between the discharges of neurons was significantly higher in the "impulsive" cats. In both groups the number of cross-correlations was maximal in cases of a difficult choice, i.e., during the omission of the conditioned bar-pressing response. In "impulsive" cats the number of interneuronal correlations was highest with the latencies in the range of 0-30 msec. We suggest that the basolateral amygdala is involved in the system of structures which determine the individual-typological characteristics of animals.

  11. Fear extinction learning can be impaired or enhanced by modulation of the CRF system in the basolateral nucleus of the amygdala

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    Abiri, Dina; Douglas, Christina E.; Calakos, Katina C.; Barbayannis, Georgia; Roberts, Andrea; Bauer, Elizabeth P.

    2014-01-01

    The neuropeptide corticotropin-releasing factor (CRF) is released during periods of anxiety and modulates learning and memory formation. One region with particularly dense concentrations of CRF receptors is the basolateral nucleus of the amygdala (BLA), a critical structure for both Pavlovian fear conditioning and fear extinction. While CRF has the potential to modify amygdala-dependent learning, its effect on fear extinction has not yet been assessed. In the present study, we examined the mo...

  12. Exposure to predator odor influences the relative use of multiple memory systems: role of basolateral amygdala.

    Science.gov (United States)

    Leong, Kah-Chung; Packard, Mark G

    2014-03-01

    In a dual-solution plus-maze task in which both hippocampus-dependent place learning and dorsolateral striatal-dependent response learning provide an adequate solution, the relative use of multiple memory systems can be influenced by emotional state. Specifically, pre-training peripheral or intra-basolateral (BLA) administration of anxiogenic drugs result in the predominant use of response learning. The present experiments were designed to extend these findings by examining whether exposure to a putatively ethologically valid stressor would also produce a predominant use of response learning. In experiment 1, adult male Long-Evans rats were exposed to either a predator odor (trimethylthiazoline [TMT], a component of fox feces) or distilled water prior to training in a dual-solution water plus maze task. On a probe trial 24h following task acquisition, rats previously exposed to TMT predominantly displayed response learning relative to control animals. In experiment 2, rats trained on a single-solution plus maze task that required the use of response learning displayed enhanced acquisition following pre-training TMT exposure. In experiment 3, rats exposed to TMT or distilled water were trained in the dual-solution task and received post-training intra-BLA injections of the sodium channel blocker bupivacaine (1.0% solution, 0.5 μl) or saline. Relative to control animals, rats exposed to TMT predominantly displayed response learning on the probe trial, and this effect was blocked by neural inactivation of the BLA. The findings indicate that (1) the use of dorsal striatal-dependent habit memory produced by emotional arousal generalizes from anxiogenic drug administration to a putatively ecologically valid stressor (i.e. predator odor), and (2) the BLA mediates the modulatory effect of exposure to predator odor on the relative use of multiple memory systems. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Infusions of AP5 into the basolateral amygdala impair the formation, but not the expression, of step-down inhibitory avoidance

    Directory of Open Access Journals (Sweden)

    R. Roesler

    2000-07-01

    Full Text Available We evaluated the effects of infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5 into the basolateral nucleus of the amygdala (BLA on the formation and expression of memory for inhibitory avoidance. Adult male Wistar rats (215-300 g were implanted under thionembutal anesthesia (30 mg/kg, ip with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Bilateral infusions of AP5 (5.0 µg were given 10 min prior to training, immediately after training, or 10 min prior to testing in a step-down inhibitory avoidance task (0.3 mA footshock, 24-h interval between training and the retention test session. Both pre- and post-training infusions of AP5 blocked retention test performance. When given prior to the test, AP5 did not affect retention. AP5 did not affect training performance, and a control experiment showed that the impairing effects were not due to alterations in footshock sensitivity. The results suggest that NMDA receptor activation in the BLA is involved in the formation, but not the expression, of memory for inhibitory avoidance in rats. However, the results do not necessarily imply that the role of NMDA receptors in the BLA is to mediate long-term storage of fear-motivated memory within the amygdala.

  14. Proteolytic Cleavage of ProBDNF into Mature BDNF in the Basolateral Amygdala Is Necessary for Defeat-Induced Social Avoidance

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    Dulka, Brooke N.; Ford, Ellen C.; Lee, Melissa A.; Donnell, Nathaniel J.; Goode, Travis D.; Prosser, Rebecca; Cooper, Matthew A.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is essential for memory processes. The present study tested whether proteolytic cleavage of proBDNF into mature BDNF (mBDNF) within the basolateral amygdala (BLA) regulates the consolidation of defeat-related memories. We found that acute social defeat increases the expression of mBDNF, but not proBDNF, in…

  15. Oxytocin Signaling in Basolateral and Central Amygdala Nuclei Differentially Regulates the Acquisition, Expression, and Extinction of Context-Conditioned Fear in Rats

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    Campbell-Smith, Emma J.; Holmes, Nathan M.; Lingawi, Nura W.; Panayi, Marios C.; Westbrook, R. Frederick

    2015-01-01

    The present study investigated how oxytocin (OT) signaling in the central (CeA) and basolateral (BLA) amygdala affects acquisition, expression, and extinction of context-conditioned fear (freezing) in rats. In the first set of experiments, acquisition of fear to a shocked context was impaired by a preconditioning infusion of synthetic OT into the…

  16. Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

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    Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

    2011-01-01

    Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

  17. Cooperative interaction between the basolateral amygdala and ventral tegmental area modulates the consolidation of inhibitory avoidance memory.

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    Nazari-Serenjeh, Farzaneh; Rezayof, Ameneh

    2013-01-10

    The aim of the current study was to examine the existence of a cooperative interaction between the basolateral nucleus of amygdala (BLA) and the ventral tegmental area (VTA) in inhibitory avoidance task. The BLA and the VTA regions of adult male Wistar rats were simultaneously cannulated and memory consolidation was measured in a step-through type inhibitory avoidance apparatus. Post-training microinjection of muscimol, a potent GABA-A receptor agonist (0.01-0.02 μg/rat), into the VTA impaired memory in a dose-dependent manner. Post-training intra-BLA microinjection of NMDA (0.02-0.04 μg/rat), 5 min before the intra-VTA injection of muscimol (0.02 μg/rat), attenuated muscimol-induced memory impairment. Microinjection of a NMDA receptor antagonist, D-AP5 (0.02-0.06 μg/rat) into the BLA inhibited NMDA effect on the memory impairment induced by intra-VTA microinjection of muscimol. On the other hand, post-training intra-BLA microinjection of muscimol (0.02-0.04 μg/rat) dose-dependently decreased step-through latency, indicating an impairing effect on memory. This impairing effect was however significantly attenuated by intra-VTA microinjection of NMDA (0.01-0.03 μg/rat). Intra-VTA microinjection of D-AP5 (0.02-0.08 μg/rat), 5 min prior to NMDA injection, inhibited NMDA response on the impairing effect induced by intra-BLA microinjection of muscimol. It should be considered that post-training microinjection of the same doses of NMDA or D-AP5 into the BLA or the VTA alone had no effect on memory consolidation. The data suggest that the relationship between the BLA and the VTA in mediating memory consolidation in inhibitory avoidance learning may be dependent on a cooperative interaction between the glutamatergic and GABAergic systems via NMDA and GABA-A receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Basolateral amygdala CB1 cannabinoid receptors are involved in cross state-dependent memory retrieval between morphine and ethanol.

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    Ofogh, Sattar Norouzi; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

    2016-09-01

    Ethanol and morphine are largely co-abused and affect memory formation. The present study intended to investigate the involvement of cannabinoid CB1 receptors of the basolateral amygdala (BLA) in cross state-dependent memory retrieval between morphine and ethanol. Adult male Wistar rats received bilateral cannulation of the BLA, and memory retrieval was measured in step-through type passive avoidance apparatus. Our results showed that post-training intraperitoneal (i.p.) administration of morphine (6mg/kg) induced amnesia. Pre-test administration of ethanol (0.5g/kg, i.p.) significantly improved morphine-induced memory impairment, suggesting that there is cross state-dependent memory retrieval between morphine and ethanol. It should be considered that pre-test administration of ethanol (0.1 and 0.5g/kg, i.p.) by itself had no effect on memory retrieval in the passive avoidance task. Interestingly, pre-test intra-BLA microinjection of different doses of WIN55,212-2 (0.1, 0.2 and 0.3μg/rat), a non-selective CB1/CB2 receptor agonist, plus an ineffective dose of ethanol (0.1g/kg, i.p.) improved morphine-induced memory impairment. Intra-BLA microinjection of AM251 (0.4-0.6ng/rat), a selective CB1 receptor antagonist, inhibited the improved effect of ethanol (0.5g/kg, i.p.) on morphine response. Pre-test intra-BLA microinjection of WIN55,212-2 or AM251 had no effect on memory retrieval or morphine-induced amnesia. Taken together, it can be concluded that morphine and ethanol can induce state-dependent memory retrieval. In addition, the BLA endocannabinoid system mediates via CB1 receptors the functional interaction of morphine and ethanol state-dependent memory retrieval which may depend on the rewarding effects of the drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized.

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    Tremblay, Melanie; Cocker, Paul J; Hosking, Jay G; Zeeb, Fiona D; Rogers, Robert D; Winstanley, Catharine A

    2014-12-01

    Individuals switch from risk seeking to risk aversion when mathematically identical options are described in terms of loss versus gains, as exemplified in the reflection and framing effects. Determining the neurobiology underlying such cognitive biases could inform our understanding of decision making in health and disease. Although reports vary, data using human subjects have implicated the amygdala in such biases. Animal models enable more detailed investigation of neurobiological mechanisms. We therefore tested whether basolateral amygdala (BLA) lesions would affect risk preference for gains or losses in rats. Choices in both paradigms were always between options of equal expected value-a guaranteed outcome, or the 50:50 chance of double or nothing. In the loss-chasing task, most rats exhibited strong risk seeking preferences, gambling at the risk of incurring double the penalty, regardless of the size of the guaranteed loss. In the betting task, the majority of animals were equivocal in their choice, irrespective of bet size; however, a wager-sensitive subgroup progressively shifted away from the uncertain option as the bet size increased, which is reminiscent of risk aversion. BLA lesions increased preference for the smaller guaranteed loss in the loss-chasing task, without affecting choice on the betting task, which is indicative of reduced risk seeking for losses, but intact risk aversion for gains. These data support the hypothesis that the amygdala plays a more prominent role in choice biases related to losses. Given the importance of the amygdala in representing negative affect, the aversive emotional reaction to loss, rather than aberrant estimations of probability or loss magnitude, may underlie risk seeking for losses.

  20. Effects of Optogenetic inhibition of BLA on Sleep Brief Optogenetic Inhibition of the Basolateral Amygdala in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep.

    Science.gov (United States)

    Machida, Mayumi; Wellman, Laurie L; Fitzpatrick Bs, Mairen E; Hallum Bs, Olga; Sutton Bs, Amy M; Lonart, György; Sanford, Larry D

    2017-04-01

    Stressful events can directly produce significant alterations in subsequent sleep, in particular rapid eye movement sleep (REM); however, the neural mechanisms underlying the process are not fully known. Here, we investigated the role of the basolateral nuclei of the amygdala (BLA) in regulating the effects of stressful experience on sleep. We used optogenetics to briefly inhibit glutamatergic cells in BLA during the presentation of inescapable footshock (IS) and assessed effects on sleep, the acute stress response, and fear memory. c-Fos expression was also assessed in the amygdala and the medial prefrontal cortex (mPFC), both regions involved in coping with stress, and in brain stem regions implicated in the regulation of REM. Compared to control mice, peri-shock inhibition of BLA attenuated an immediate reduction in REM after IS and produced a significant overall increase in REM. Moreover, upon exposure to the shock context alone, mice receiving peri-shock inhibition of BLA during training showed increased REM without altered freezing (an index of fear memory) or stress-induced hyperthermia (an index of acute stress response). Inhibition of BLA during REM under freely sleeping conditions enhanced REM only when body temperature was high, suggesting the effect was influenced by stress. Peri-shock inhibition of BLA also led to elevated c-Fos expression in the central nucleus of the amygdala and mPFC and differentially altered c-Fos activity in the selected brain stem regions. Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  1. Dorsal Periaqueductal gray simultaneously modulates ventral Subiculum induced-plasticity in the Basolateral Amygdala and the Nucleus Accumbens

    Directory of Open Access Journals (Sweden)

    Omer eHorovitz

    2015-03-01

    Full Text Available The ventral subiculum of the hippocampus projects both to the basolateral amygdala, which is typically, associated with a response to aversive stimuli, as well as to the nucleus accumbens, which is typically associated with a response to appetitive stimuli. Traditionally, studies of the responses to emotional events focus on either negative or positive affect-related processes, however, emotional experiences often affect both. The ability of high-level processing brain regions (e.g. medial prefrontal cortex to modulate the balance between negative and positive affect-related regions was examined extensively. In contrast, the ability of low-level processing areas (e.g. periaqueductal grey - PAG to do so, has not been sufficiently studied. To address whether midbrain structures have the ability to modulate limbic regions, we first examined the ventral subiculum stimulation’s (vSub ability to induce plasticity in the basolateral amygdala (BLA and nucleus accumbens (NAcc simultaneously in rats. Further, dorsal PAG (dPAG priming ability to differentially modulate vSub stimulation induced plasticity in the BLA and the NAcc was subsequently examined. vSub stimulation resulted in plasticity in both the BLA and the NAcc simultaneously. Moreover, depending on stimulus intensity, differential dPAG priming effects on LTP in these two regions were observed. The results demonstrate that negative and positive affect-related processes may be simultaneously modulated. Furthermore, under some conditions lower-level processing areas, such as the dPAG, may differentially modulate plasticity in these regions and thus affect the long-term emotional outcome of the experience.

  2. Higher-Order Sensory Cortex Drives Basolateral Amygdala Activity during the Recall of Remote, but Not Recently Learned Fearful Memories.

    Science.gov (United States)

    Cambiaghi, Marco; Grosso, Anna; Likhtik, Ekaterina; Mazziotti, Raffaele; Concina, Giulia; Renna, Annamaria; Sacco, Tiziana; Gordon, Joshua A; Sacchetti, Benedetto

    2016-02-03

    Negative experiences are quickly learned and long remembered. Key unresolved issues in the field of emotional memory include identifying the loci and dynamics of memory storage and retrieval. The present study examined neural activity in the higher-order auditory cortex Te2 and basolateral amygdala (BLA) and their crosstalk during the recall of recent and remote fear memories. To this end, we obtained local field potentials and multiunit activity recordings in Te2 and BLA of rats that underwent recall at 24 h and 30 d after the association of an acoustic conditioned (CS, tone) and an aversive unconditioned stimulus (US, electric shock). Here we show that, during the recall of remote auditory threat memories in rats, the activity of the Te2 and BLA is highly synchronized in the theta frequency range. This functional connectivity stems from memory consolidation processes because it is present during remote, but not recent, memory retrieval. Moreover, the observed increase in synchrony is cue and region specific. A preponderant Te2-to-BLA directionality characterizes this dialogue, and the percentage of time Te2 theta leads the BLA during remote memory recall correlates with a faster latency to freeze to the auditory conditioned stimulus. The blockade of this information transfer via Te2 inhibition with muscimol prevents any retrieval-evoked neuronal activity in the BLA and animals are unable to retrieve remote memories. We conclude that memories stored in higher-order sensory cortices drive BLA activity when distinguishing between learned threatening and neutral stimuli. How and where in the brain do we store the affective/motivational significance of sensory stimuli acquired through life experiences? Scientists have long investigated how "limbic" structures, such as the amygdala, process affective stimuli. Here we show that retrieval of well-established threat memories requires the functional interplay between higher-order components of the auditory cortex and the

  3. Rapid corticosteroid actions on synaptic plasticity in the mouse basolateral amygdala: relevance of recent stress history and β-adrenergic signaling.

    Science.gov (United States)

    Sarabdjitsingh, R A; Joëls, M

    2014-07-01

    The rodent stress hormone corticosterone rapidly enhances long-term potentiation in the CA1 hippocampal area, but leads to a suppression when acting in a more delayed fashion. Both actions are thought to contribute to stress effects on emotional memory. Emotional memory formation also involves the basolateral amygdala, an important target area for corticosteroid actions. We here (1) investigated the rapid effects of corticosterone on amygdalar synaptic potentiation, (2) determined to what extent these effects depend on the mouse's recent stress history or (3) on prior β-adrenoceptor activation; earlier studies at the single cell level showed that especially a recent history of stress changes the responsiveness of basolateral amygdala neurons to corticosterone. We report that, unlike the hippocampus, stress enhances amygdalar synaptic potentiation in a slow manner. In vitro exposure to 100 nM corticosterone quickly decreases synaptic potentiation, and causes only transient potentiation in tissue from stressed mice. This transient type of potentiation is also seen when β-adrenoceptors are blocked during stress and this is further exacerbated by subsequent in vitro administered corticosterone. We conclude that stress and corticosterone change synaptic potentiation in the basolateral amygdala in a manner opposite to that seen in the hippocampus and that renewed exposure to corticosterone only allows induction of non-persistent forms of synaptic potentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. PKMζ maintains drug reward and aversion memory in the basolateral amygdala and extinction memory in the infralimbic cortex.

    Science.gov (United States)

    He, Ying-Ying; Xue, Yan-Xue; Wang, Ji-Shi; Fang, Qin; Liu, Jian-Feng; Xue, Li-Fen; Lu, Lin

    2011-09-01

    The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories, but how this mechanism is maintained is unknown. Protein kinase M ζ (PKMζ) was recently shown to be necessary and sufficient for long-term potentiation maintenance and memory storage. In the present study, we used conditioned place preference (CPP) and aversion (CPA) to examine whether PKMζ maintains both morphine-associated reward memory and morphine withdrawal-associated aversive memory in the basolateral amygdala (BLA). We also investigate the role of PKMζ in the infralimbic cortex in the extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. We found that intra-BLA but not central nucleus of the amygdala injection of the selective PKMζ inhibitor ZIP 1 day after CPP and CPA training impaired the expression of CPP and CPA 1 day later, and the effect of ZIP on memory lasted at least 2 weeks. Inhibiting PKMζ activity in the infralimbic cortex, but not prelimbic cortex, disrupted the expression of the extinction memory of CPP and CPA. These results indicate that PKMζ in the BLA is required for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory, and PKMζ in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues.

  5. Fear Conditioning Downregulates Rac1 Activity in the Basolateral Amygdala Astrocytes to Facilitate the Formation of Fear Memory.

    Science.gov (United States)

    Liao, Zhaohui; Tao, Yezheng; Guo, Xiaomu; Cheng, Deqin; Wang, Feifei; Liu, Xing; Ma, Lan

    2017-01-01

    Astrocytes are well known to scale synaptic structural and functional plasticity, while the role in learning and memory, such as conditioned fear memory, is poorly elucidated. Here, using pharmacological approach, we find that fluorocitrate (FC) significantly inhibits the acquisition of fear memory, suggesting that astrocyte activity is required for fear memory formation. We further demonstrate that fear conditioning downregulates astrocytic Rac1 activity in basolateral amygdala (BLA) in mice and promotes astrocyte structural plasticity. Ablation of astrocytic Rac1 in BLA promotes fear memory acquisition, while overexpression or constitutive activation of astrocytic Rac1 attenuates fear memory acquisition. Furthermore, temporal activation of Rac1 by photoactivatable Rac1 (Rac1-PA) induces structural alterations in astrocytes and in vivo activation of Rac1 in BLA astrocytes during fear conditioning attenuates the formation of fear memory. Taken together, our study demonstrates that fear conditioning-induced suppression of BLA astrocytic Rac1 activity, associated with astrocyte structural plasticity, is required for the formation of conditioned fear memory.

  6. Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway.

    Science.gov (United States)

    Rei, Damien; Mason, Xenos; Seo, Jinsoo; Gräff, Johannes; Rudenko, Andrii; Wang, Jun; Rueda, Richard; Siegert, Sandra; Cho, Sukhee; Canter, Rebecca G; Mungenast, Alison E; Deisseroth, Karl; Tsai, Li-Huei

    2015-06-09

    Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation.

  7. Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala.

    Science.gov (United States)

    Stehberg, Jimmy; Moraga-Amaro, Rodrigo; Salazar, Christian; Becerra, Alvaro; Echeverría, Cesar; Orellana, Juan A; Bultynck, Geert; Ponsaerts, Raf; Leybaert, Luc; Simon, Felipe; Sáez, Juan C; Retamal, Mauricio A

    2012-09-01

    Recent in vitro evidence indicates that astrocytes can modulate synaptic plasticity by releasing neuroactive substances (gliotransmitters). However, whether gliotransmitter release from astrocytes is necessary for higher brain function in vivo, particularly for memory, as well as the contribution of connexin (Cx) hemichannels to gliotransmitter release, remain elusive. Here, we microinfused into the rat basolateral amygdala (BLA) TAT-Cx43L2, a peptide that selectively inhibits Cx43-hemichannel opening while maintaining synaptic transmission or interastrocyte gap junctional communication. In vivo blockade of Cx43 hemichannels during memory consolidation induced amnesia for auditory fear conditioning, as assessed 24 h after training, without affecting short-term memory, locomotion, or shock reactivity. The amnesic effect was transitory, specific for memory consolidation, and was confirmed after microinfusion of Gap27, another Cx43-hemichannel blocker. Learning capacity was recovered after coinfusion of TAT-Cx43L2 and a mixture of putative gliotransmitters (glutamate, glutamine, lactate, d-serine, glycine, and ATP). We propose that gliotransmitter release from astrocytes through Cx43 hemichannels is necessary for fear memory consolidation at the BLA. Thus, the present study is the first to demonstrate a physiological role for astroglial Cx43 hemichannels in brain function, making these channels a novel pharmacological target for the treatment of psychiatric disorders, including post-traumatic stress disorder.

  8. The effect of basolateral amygdala nucleus lesion on memory under acute,mid and chronic stress in male rats.

    Science.gov (United States)

    Ranjbar, Hoda; Radahmadi, Maryam; Alaei, Hojjatallah; Reisi, Parham; Karimi, Sara

    2016-12-20

    The basolateral amygdala (BLA) modulates memory for emotional events and is involved in both stress and memory. This study investigated different durations of stress and the role of BLA on serum corticosterone level and spatial and cognitive memory. Different durations of stress (acute, mid, and chronic stress), with and without BLA lesion were induced in rats by 6 h/day restraint stress for 1, 7, and 21 days. Memory functions were evaluated by novel object recognition (NOR) and object location test (OLT). The OLT findings showed locomotor activity and spatial memory slightly decreased with different durations of stress. The NOR findings significantly showed locomotor activity impairment in different durations of stress. Cognitive memory deficit was observed in mid stress. The corticosterone level significantly increased in the mid and chronic stress groups. Moreover, the mid stress was the strongest stress condition. There is a possibility that different stress durations act by different mechanisms. The recognition of a novel location decreased in all lesion groups. It was more severe in the NOR. The BLA lesion significantly decreased corticosterone level in the mid and chronic stress groups compared to similar groups without lesion. The BLA lesion caused more damage to cognitive than spatial memory in stressed groups.

  9. Hippocampal dendritic spines remodeling and fear memory are modulated by GABAergic signaling within the basolateral amygdala complex.

    Science.gov (United States)

    Giachero, Marcelo; Calfa, Gaston D; Molina, Victor A

    2015-05-01

    GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long-term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra-BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress-induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory. © 2015 Wiley Periodicals, Inc.

  10. Role of basolateral amygdala dopamine D2 receptors in impulsive choice in acute cocaine-treated rats.

    Science.gov (United States)

    Li, Yijing; Zuo, Yanfang; Yu, Peng; Ping, Xingjie; Cui, Cailian

    2015-01-01

    Psychostimulant substances have been found to either increase or inhibit impulsive choice (preference to choose small immediate reward over large delayed reward) in laboratory animals. Although central dopamine transmission has been demonstrated to be involved in impulsivity and drug addiction, little is known regarding dopaminergic neurotransmission in addictive drug-induced alteration of impulse control. In this study, we used a delay discounting model to measure impulsive choice in rats and found that acute cocaine dose-dependently decreased impulsive choice in rats. Intraperitoneal injection (i.p.) of D1 receptor antagonist SCH23390 (0.02 mg/kg) could increase the impulsive choice but had no effect on the inhibition of impulsive choice induced by acute cocaine exposure. D2 receptor antagonist eticlopride (0.06 mg/kg) had no effect on the choice behavior itself, but it reversed acute cocaine-induced impulse inhibition. Moreover, bilateral microinjection of eticlopride (1 μg/side) into the basolateral amygdala (BLA) but not the nucleus accumbens (NAc) core reversed the inhibitory effect of acute cocaine on impulsive choice. These data suggest important but dissociable roles of dopamine D1 and D2 receptors in impulse control. The preference of delayed rewards depends on D1 receptors, whereas acute cocaine inhibited impulsive choice by activating D2 receptors in the BLA. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway

    Science.gov (United States)

    Rei, Damien; Mason, Xenos; Seo, Jinsoo; Gräff, Johannes; Rudenko, Andrii; Wang, Jun; Rueda, Richard; Siegert, Sandra; Cho, Sukhee; Canter, Rebecca G.; Mungenast, Alison E.; Deisseroth, Karl; Tsai, Li-Huei

    2015-01-01

    Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation. PMID:25995364

  12. Fear Conditioning Downregulates Rac1 Activity in the Basolateral Amygdala Astrocytes to Facilitate the Formation of Fear Memory

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    Zhaohui Liao

    2017-11-01

    Full Text Available Astrocytes are well known to scale synaptic structural and functional plasticity, while the role in learning and memory, such as conditioned fear memory, is poorly elucidated. Here, using pharmacological approach, we find that fluorocitrate (FC significantly inhibits the acquisition of fear memory, suggesting that astrocyte activity is required for fear memory formation. We further demonstrate that fear conditioning downregulates astrocytic Rac1 activity in basolateral amygdala (BLA in mice and promotes astrocyte structural plasticity. Ablation of astrocytic Rac1 in BLA promotes fear memory acquisition, while overexpression or constitutive activation of astrocytic Rac1 attenuates fear memory acquisition. Furthermore, temporal activation of Rac1 by photoactivatable Rac1 (Rac1-PA induces structural alterations in astrocytes and in vivo activation of Rac1 in BLA astrocytes during fear conditioning attenuates the formation of fear memory. Taken together, our study demonstrates that fear conditioning-induced suppression of BLA astrocytic Rac1 activity, associated with astrocyte structural plasticity, is required for the formation of conditioned fear memory.

  13. Reversible Inactivation of the Higher Order Auditory Cortex during Fear Memory Consolidation Prevents Memory-Related Activity in the Basolateral Amygdala during Remote Memory Retrieval

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    Marco Cambiaghi

    2017-07-01

    Full Text Available Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. Here, we tested whether the reversible blockade of Te2 during memory consolidation may affect the activity changes occurring in the amygdala during the retrieval of fearful memories. To address this issue, we blocked Te2 in a reversible manner during memory consolidation processes. After 4 weeks, we assessed the activity of Te2 and individual nuclei of the amygdala during the retrieval of long-term memories. Rats in which Te2 was inactivated upon memory encoding showed a decreased freezing and failed to show Te2-to-basolateral amygdala (BLA synchrony during memory retrieval. In addition, the expression of the immediate early gene zif268 in the lateral, basal and central amygdala nuclei did not show memory-related enhancement. As all sites were intact upon memory retrieval, we propose that the auditory cortex represents a key node in the consolidation of fear memories and it is essential for amygdala nuclei to support memory retrieval process.

  14. Reversible Inactivation of the Higher Order Auditory Cortex during Fear Memory Consolidation Prevents Memory-Related Activity in the Basolateral Amygdala during Remote Memory Retrieval.

    Science.gov (United States)

    Cambiaghi, Marco; Renna, Annamaria; Milano, Luisella; Sacchetti, Benedetto

    2017-01-01

    Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. Here, we tested whether the reversible blockade of Te2 during memory consolidation may affect the activity changes occurring in the amygdala during the retrieval of fearful memories. To address this issue, we blocked Te2 in a reversible manner during memory consolidation processes. After 4 weeks, we assessed the activity of Te2 and individual nuclei of the amygdala during the retrieval of long-term memories. Rats in which Te2 was inactivated upon memory encoding showed a decreased freezing and failed to show Te2-to-basolateral amygdala (BLA) synchrony during memory retrieval. In addition, the expression of the immediate early gene zif268 in the lateral, basal and central amygdala nuclei did not show memory-related enhancement. As all sites were intact upon memory retrieval, we propose that the auditory cortex represents a key node in the consolidation of fear memories and it is essential for amygdala nuclei to support memory retrieval process.

  15. Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala.

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    Keistler, Colby R; Hammarlund, Emma; Barker, Jacqueline M; Bond, Colin W; DiLeone, Ralph J; Pittenger, Christopher; Taylor, Jane R

    2017-04-26

    The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections. SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic

  16. Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice.

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    Qin, M; Xia, Z; Huang, T; Smith, C B

    2011-10-27

    Several lines of clinical evidence support the idea that fragile X syndrome (FXS) may involve a dysregulation of hypothalamic-pituitary-adrenal axis function [Wisbeck et al. (2000) J Dev Behav Pediatr 21:278-282; Hessl et al. (2002) Psychoneuroendocrinology 27:855-872]. We had tested this idea in a mouse model of FXS (Fmr1 KO) and found that the hormonal response to acute stress was similar to that of wild-type (WT) mice [Qin and Smith (2008) Psychoneuroendocrinology 33:883-889]. We report here responses to chronic stress (CS) in Fmr1 KO mice. Following restraint for 120 min/d, 10 consecutive days, we assessed dendrite and spine morphology in basolateral amygdala (BLA). We also monitored behavior in an elevated plus maze (EPM) and the hormonal response to this novel spatial environment. After CS, mice of both genotypes underwent adrenal hypertrophy, but effects were greater in WT mice. Behavior in the EPM indicated that only WT mice had the expected increase in anxiety following CS. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels were both increased following the spatial novelty of EPM, and there were no differences between genotypes in the hormonal responses. BLA dendritic branching increased proximal to the soma in WT, but in Fmr1 KO mice branching was unaffected close to the soma and slightly decreased at one point distal to the soma. Similarly, spine density on apical and basal dendrites increased in WT but decreased in Fmr1 KO mice. Spine length on apical and basal dendrites increased in WT but was unaffected in Fmr1 KO mice. These differences in behavioral response and effects on neuron morphology in BLA suggest a diminished adaptive response of Fmr1 KO mice. Published by Elsevier Ltd.

  17. Interaction of basolateral amygdala, ventral hippocampus and medial prefrontal cortex regulates the consolidation and extinction of social fear.

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    Qi, Chu-Chu; Wang, Qing-Jun; Ma, Xue-Zhu; Chen, Hai-Chao; Gao, Li-Ping; Yin, Jie; Jing, Yu-Hong

    2018-03-19

    Following a social defeat, the balanced establishment and extinction of aversive information is a beneficial strategy for individual survival. Abnormal establishment or extinction is implicated in the development of mental disorders. This study investigated the time course of the establishment and extinction of aversive information from acute social defeat and the temporal responsiveness of the basolateral amygdala (BLA), ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) in this process. Mouse models of acute social defeat were established by using the resident-intruder paradigm. To evaluate the engram of social defeat, the intruder mice were placed into the novel context at designated time to test the social behavior. Furthermore, responses of BLA, vHIP and mPFC were investigated by analyzing the expression of immediate early genes, such as zif268, arc, and c-fos. The results showed after an aggressive attack, aversive memory was maintained for approximately 7 days before gradually diminishing. The establishment and maintenance of aversive stimulation were consistently accompanied by BLA activity. By contrast, vHIP and mPFC response was inhibited from this process. Additionally, injecting muscimol (Mus), a GABA receptor agonist, into the BLA alleviated the freezing behavior and social fear and avoidance. Simultaneously, Mus treatment decreased the zif268 and arc expression in BLA, but it increased their expression in vHIP. Our data support and extend earlier findings that implicate BLA, vHIP and mPFC in social defeat. The time courses of the establishment and extinction of social defeat are particularly consistent with the contrasting BLA and vHIP responses involved in this process.

  18. LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety.

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    Prager, Eric M; Figueiredo, Taiza H; Long, Robert P; Aroniadou-Anderjaska, Vassiliki; Apland, James P; Braga, Maria F M

    2015-02-01

    Exposure to nerve agents can cause brain damage due to prolonged seizure activity, producing long-term behavioral deficits. We have previously shown that LY293558, a GluK1/AMPA receptor antagonist, is a very effective anticonvulsant and neuroprotectant against nerve agent exposure. In the present study, we examined whether the protection against nerve agent-induced seizures and neuropathology conferred by LY293558 translates into protection against pathophysiological alterations in the basolateral amygdala (BLA) and the development of anxiety, which is the most prevalent behavioral deficit resulting from exposure. LY293558 (15 mg/kg) was administered to rats, along with atropine and HI-6, at 20 min after exposure to soman (1.2 × LD50). At 24 h, 7 days, and 30 days after exposure, soman-exposed rats who did not receive LY293558 had reduced but prolonged evoked field potentials in the BLA, as well as increased paired-pulse ratio, suggesting neuronal damage and impaired synaptic inhibition; rats who received LY293558 did not differ from controls in these parameters. Long-term potentiation of synaptic transmission was impaired at 7 days after exposure in the soman-exposed rats who did not receive anticonvulsant treatment, but not in the LY293558-treated rats. Anxiety-like behavior assessed by the open field and acoustic startle response tests was increased in the soman-exposed rats at 30 and 90 days after exposure, while rats treated with LY293558 did not differ from controls. Along with our previous findings, the present data demonstrate the remarkable efficacy of LY293558 in counteracting nerve agent-induced seizures, neuropathology, pathophysiological alterations in the BLA, and anxiety-related behavioral deficits. Published by Elsevier Ltd.

  19. Stress-induced resistance to the fear memory labilization/reconsolidation process. Involvement of the basolateral amygdala complex.

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    Espejo, Pablo Javier; Ortiz, Vanesa; Martijena, Irene Delia; Molina, Victor Alejandro

    2016-10-01

    Consolidated memories can enter into a labile state after reactivation followed by a restabilization process defined as reconsolidation. This process can be interfered with Midazolam (MDZ), a positive allosteric modulator of the GABA-A receptor. The present study has evaluated the influence of prior stress on MDZ's interfering effect. We also assessed the influence of both systemic and intra-basolateral amygdala (BLA) infusion of d-cycloserine (DCS), a partial agonist of the NMDA receptors, on the MDZ effect in previously stressed rats. Furthermore, we analyzed the effect of stress on the expression of Zif-268 and the GluN2B sites, two molecular markers of the labilization/reconsolidation process, following reactivation. The results revealed that prior stress resulted into a memory trace that was insensitive to the MDZ impairing effect. Both systemic and intra-BLA DCS administration previous to reactivation restored MDZ's disruptive effect on memory reconsolidation in stressed animals. Further, reactivation enhanced Zif-268 expression in the BLA in control unstressed rats, whereas no elevation was observed in stressed animals. In agreement with the behavioral findings, DCS restored the increased level of Zif-268 expression in the BLA in stressed animals. Moreover, memory reactivation in unstressed animals elevated GluN2B expression in the BLA, thus suggesting that this effect is involved in memory destabilization, whereas stressed animals did not reveal any changes. These findings are consistent with resistance to the MDZ effect in these rats, indicating that stress exposure prevents the onset of destabilization following reactivation. In summary, prior stress limited both the occurrence of the reactivation-induced destabilization and restabilization. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Noradrenergic Activation of the Basolateral Amygdala Enhances Object Recognition Memory and Induces Chromatin Remodeling in the Insular Cortex

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    Hassiba eBeldjoud

    2015-04-01

    Full Text Available It is well established that arousal-induced memory enhancement requires noradrenergic activation of the basolateral complex of the amygdala (BLA and modulatory influences on information storage processes in its many target regions. While this concept is well accepted, the molecular basis of such BLA effects on neural plasticity changes within other brain regions remains to be elucidated. The present study investigated whether noradrenergic activation of the BLA after object recognition training induces chromatin remodeling through histone post-translational modifications in the insular cortex (IC, a brain region that is importantly involved in object recognition memory. Male Sprague–Dawley rats were trained on an object recognition task, followed immediately by bilateral microinfusions of norepinephrine (1.0 µg or saline administered into the BLA. Saline-treated control rats exhibited poor 24-h retention, whereas norepinephrine treatment induced robust 24-h object recognition memory. Most importantly, this memory-enhancing dose of norepinephrine induced a global reduction in the acetylation levels of histone H3 at lysine 14, H2B and H4 in the IC 1 h later, whereas it had no effect on the phosphorylation of histone H3 at serine 10 or tri-methylation of histone H3 at lysine 27. Norepinephrine administered into the BLA of non-trained control rats did not induce any changes in the histone marks investigated in this study. These findings indicate that noradrenergic activation of the BLA induces training-specific effects on chromatin remodeling mechanisms, and presumably gene transcription, in its target regions, which may contribute to the understanding of the molecular mechanisms of stress and emotional arousal effects on memory consolidation.

  1. Prior stress promotes the generalization of contextual fear memories: Involvement of the gabaergic signaling within the basolateral amygdala complex.

    Science.gov (United States)

    Bender, C L; Otamendi, A; Calfa, G D; Molina, V A

    2018-04-20

    Fear generalization occurs when a response, previously acquired with a threatening stimulus, is transferred to a similar one. However, it could be maladaptive when stimuli that do not represent a real threat are appraised as dangerous, which is a hallmark of several anxiety disorders. Stress exposure is a major risk factor for the occurrence of anxiety disorders and it is well established that it influences different phases of fear memory; nevertheless, its impact on the generalization of contextual fear memories has been less studied. In the present work, we have characterized the impact of acute restraint stress prior to contextual fear conditioning on the generalization of this fear memory, and the role of the GABAergic signaling within the basolateral amygdala complex (BLA) on the stress modulatory effects. We have found that a single stress exposure promoted the generalization of this memory trace to a different context that was well discriminated in unstressed conditioned animals. Moreover, this effect was dependent on the formation of a contextual associative memory and on the testing order (i.e., conditioning context first vs generalization context first). Furthermore, we observed that increasing GABA-A signaling by intra-BLA midazolam administration prior to the stressful session exposure prevented the generalization of fear memory, whereas intra-BLA administration of the GABA-A antagonist (Bicuculline), prior to fear conditioning, induced the generalization of fear memory in unstressed rats. We concluded that stress exposure, prior to contextual fear conditioning, promotes the generalization of fear memory and that the GABAergic transmission within the BLA has a critical role in this phenomenon. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Dissociable roles for the basolateral amygdala and orbitofrontal cortex in decision-making under risk of punishment.

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    Orsini, Caitlin A; Trotta, Rose T; Bizon, Jennifer L; Setlow, Barry

    2015-01-28

    Several neuropsychiatric disorders are associated with abnormal decision-making involving risk of punishment, but the neural basis of this association remains poorly understood. Altered activity in brain systems including the basolateral amygdala (BLA) and orbitofrontal cortex (OFC) can accompany these same disorders, and these structures are implicated in some forms of decision-making. The current study investigated the role of the BLA and OFC in decision-making under risk of explicit punishment. Rats were trained in the risky decision-making task (RDT), in which they chose between two levers, one that delivered a small safe reward, and the other that delivered a large reward accompanied by varying risks of footshock punishment. Following training, they received sham or neurotoxic lesions of BLA or OFC, followed by RDT retesting. BLA lesions increased choice of the large risky reward (greater risk-taking) compared to both prelesion performance and sham controls. When reward magnitudes were equated, both BLA lesion and control groups shifted their choice to the safe (no shock) reward lever, indicating that the lesions did not impair punishment sensitivity. In contrast to BLA lesions, OFC lesions significantly decreased risk-taking compared with sham controls, but did not impair discrimination between different reward magnitudes or alter baseline levels of anxiety. Finally, neither lesion significantly affected food-motivated lever pressing under various fixed ratio schedules, indicating that lesion-induced alterations in risk-taking were not secondary to changes in appetitive motivation. Together, these findings indicate distinct roles for the BLA and OFC in decision-making under risk of explicit punishment. Copyright © 2015 the authors 0270-6474/15/351368-12$15.00/0.

  3. Activation of exchange protein activated by cAMP in the rat basolateral amygdala impairs reconsolidation of a memory associated with self-administered cocaine.

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    Xun Wan

    Full Text Available The intracellular mechanisms underlying memory reconsolidation critically involve cAMP signaling. These events were originally attributed to PKA activation by cAMP, but the identification of Exchange Protein Activated by cAMP (Epac, as a distinct mediator of cAMP signaling, suggests that cAMP-regulated processes that subserve memory reconsolidation are more complex. Here we investigated how activation of Epac with 8-pCPT-cAMP (8-CPT impacts reconsolidation of a memory that had been associated with cocaine self-administration. Rats were trained to lever press for cocaine on an FR-1 schedule, in which each cocaine delivery was paired with a tone+light cue. Lever pressing was then extinguished in the absence of cue presentations and cocaine delivery. Following the last day of extinction, rats were put in a novel context, in which the conditioned cue was presented to reactivate the cocaine-associated memory. Immediate bilateral infusions of 8-CPT into the basolateral amygdala (BLA following reactivation disrupted subsequent cue-induced reinstatement in a dose-dependent manner, and modestly reduced responding for conditioned reinforcement. When 8-CPT infusions were delayed for 3 hours after the cue reactivation session or were given after a cue extinction session, no effect on cue-induced reinstatement was observed. Co-administration of 8-CPT and the PKA activator 6-Bnz-cAMP (10 nmol/side rescued memory reconsolidation while 6-Bnz alone had no effect, suggesting an antagonizing interaction between the two cAMP signaling substrates. Taken together, these studies suggest that activation of Epac represents a parallel cAMP-dependent pathway that can inhibit reconsolidation of cocaine-cue memories and reduce the ability of the cue to produce reinstatement of cocaine-seeking behavior.

  4. Lateral/Basolateral Amygdala Serotonin Type-2 Receptors Modulate Operant Self-administration of a Sweetened Ethanol Solution via Inhibition of Principal Neuron Activity

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    Brian eMccool

    2014-01-01

    Full Text Available The lateral/basolateral amygdala (BLA forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration behaviors suggests a much broader role in the regulation of reward evaluation. To test this, we employed a self-administration paradigm that procedurally segregates ‘seeking’ (exemplified as lever-press behaviors from consumption (drinking directed at a sweetened ethanol solution. Microinjection of the nonselective serotonin type-2 receptor agonist, alpha-methyl-5-hydroxytryptamine (-m5HT into the BLA reduced lever pressing behaviors in a dose-dependent fashion. This was associated with a significant reduction in the number of response-bouts expressed during non-reinforced sessions without altering the size of a bout or the rate of responding. Conversely, intra-BLA -m5HT only modestly effected consumption-related behaviors; the highest dose reduced the total time spent consuming a sweetened ethanol solution but did not inhibit the total number of licks, number of lick bouts, or amount of solution consumed during a session. In vitro neurophysiological characterization of BLA synaptic responses showed that -m5HT significantly reduced extracellular field potentials. This was blocked by the 5-HT2A/C antagonist ketanserin suggesting that 5-HT2-like receptors mediate the behavioral effect of -m5HT. During whole-cell patch current-clamp recordings, we subsequently found that -m5HT increased action potential threshold and hyperpolarized the resting membrane potential of BLA pyramidal neurons. Together, our findings show that the activation of BLA 5-HT2A/C receptors inhibits behaviors related to reward-seeking by suppressing BLA principal neuron activity. These data are consistent with the hypothesis that the BLA modulates reward-related behaviors and provides specific insight into BLA contributions during operant self-administration of a

  5. Angiotensin II's role in sodium lactate-induced panic-like responses in rats with repeated urocortin 1 injections into the basolateral amygdala

    DEFF Research Database (Denmark)

    Johnson, Philip L; Sajdyk, Tammy J; Fitz, Stephanie D

    2013-01-01

    Rats treated with three daily urocortin 1 (UCN) injections into the basolateral amygdala (BLA; i.e., UCN/BLA-primed rats) develop prolonged anxiety-associated behavior and vulnerability to panic-like physiological responses (i.e., tachycardia, hypertension and tachypnea) following intravenous......-injected with saralasin, but not PD123319 or vehicle, had reduced NaLac-induced anxiety-associated behavior and panic-associated tachycardia and tachypnea responses. We then confirmed the presence of AT1rs in the BLA using immunohistochemistry which, combined with the previous data, suggest that A-II's panicogenic...

  6. Activation of the basolateral amygdala induces long-term enhancement of specific memory representations in the cerebral cortex.

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    Chavez, Candice M; McGaugh, James L; Weinberger, Norman M

    2013-03-01

    The basolateral amygdala (BLA) modulates memory, particularly for arousing or emotional events, during post-training periods of consolidation. It strengthens memories whose substrates in part or whole are stored remotely, in structures such as the hippocampus, striatum and cerebral cortex. However, the mechanisms by which the BLA influences distant memory traces are unknown, largely because of the need for identifiable target mnemonic representations. Associative tuning plasticity in the primary auditory cortex (A1) constitutes a well-characterized candidate specific memory substrate that is ubiquitous across species, tasks and motivational states. When tone predicts reinforcement, the tuning of cells in A1 shifts toward or to the signal frequency within its tonotopic map, producing an over-representation of behaviorally important sounds. Tuning shifts have the cardinal attributes of forms of memory, including associativity, specificity, rapid induction, consolidation and long-term retention and are therefore likely memory representations. We hypothesized that the BLA strengthens memories by increasing their cortical representations. We recorded multiple unit activity from A1 of rats that received a single discrimination training session in which two tones (2.0 s) separated by 1.25 octaves were either paired with brief electrical stimulation (400 ms) of the BLA (CS+) or not (CS-). Frequency response areas generated by presenting a matrix of test tones (0.5-53.82 kHz, 0-70 dB) were obtained before training and daily for 3 weeks post-training. Tuning both at threshold and above threshold shifted predominantly toward the CS+ beginning on day 1. Tuning shifts were maintained for the entire 3 weeks. Absolute threshold and bandwidth decreased, producing less enduring increases in sensitivity and selectivity. BLA-induced tuning shifts were associative, highly specific and long-lasting. We propose that the BLA strengthens memory for important experiences by increasing the

  7. The basolateral amygdala determines the effects of fear memory on sleep in an animal model of PTSD.

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    Wellman, Laurie L; Fitzpatrick, Mairen E; Machida, Mayumi; Sanford, Larry D

    2014-05-01

    Fear conditioning [inescapable shock training (ST)] and fearful context re-exposure (CR) alone can produce significant fear indicated by increased freezing and reductions in subsequent rapid eye movement (REM) sleep. Damage to or inactivation of the basolateral nucleus of the amygdala (BLA) prior to or after ST or prior to CR generally has been found to attenuate freezing in the shock training context. However, no one has examined the impact of BLA inactivation on fear-induced changes in sleep. Here, we used the GABAA agonist, muscimol (MUS), to inactivate BLA prior to ST, the period when fear is learned, and assessed sleep after ST and sleep and freezing after two CR sessions. Wistar rats (n = 14) were implanted with electrodes for recording sleep and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure (handling) over 2 consecutive days and baseline sleep following handling was recorded. On experimental day 1, the rats were injected (0.5 μl) into BLA with either MUS (1.0 μM; n = 7) or vehicle (distilled water, n = 7) 30 min prior to ST (20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval). On experimental days 7 and 21, the animals experienced CR (CR1 and CR2, respectively) alone. Electroencephalogram and electromyogram were recorded for 8 h on each day, and the recording was scored for non-rapid eye movement sleep, REM sleep, and wakefulness. Freezing was examined during CR1 and CR2. MUS microinjections into BLA prior to ST blocked the post-training reduction in REM sleep seen in vehicle-treated rats. Furthermore, in MUS-treated rats, REM sleep after CR1 and CR2 was at baseline levels and freezing was significantly attenuated. Thus, BLA inactivation prior to ST blocks the effects of footshock stress on sleep and reduces fear memory, as indicated by the lack of freezing and changes in sleep after CR. These data indicate that BLA is an important regulator of stress-induced alterations in

  8. Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala Activity at Discrete Time Points during Risky Decision Making.

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    Orsini, Caitlin A; Hernandez, Caesar M; Singhal, Sarthak; Kelly, Kyle B; Frazier, Charles J; Bizon, Jennifer L; Setlow, Barry

    2017-11-29

    Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (risky decision-making task) in which rats choose between a small, "safe" reward and a large reward accompanied by varying probabilities of footshock punishment. Male Long-Evans rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the risky decision-making task. Laser delivery during the task occurred during intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did laser delivery affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active. SIGNIFICANCE STATEMENT To date, most behavioral neuroscience research on neural mechanisms of decision making has used techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the BLA has opposite effects on choice behavior in a rat model of risky decision making, depending on the phase

  9. Effects of Chronic Ethanol Consumption on Rat GABAA and Strychnine-sensitive Glycine Receptors Expressed by Lateral/Basolateral Amygdala Neurons

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    McCool, Brian A.; Frye, Gerald D.; Pulido, Marisa D.; Botting, Shaleen K.

    2010-01-01

    It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABAA and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABAA receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptor’s response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABAA receptors composed of unique α subunits were differentially sensitive to acute ethanol. Likewise, the presence of the β subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the α2 subunit. Our results suggest that the facilitation of GABAA receptors during chronic ethanol exposure may help explain the maintenance of ethanol’s anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABAA and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure. PMID:12560122

  10. Activation of ERK2 in basolateral amygdala underlies the promoting influence of stress on fear memory and anxiety: influence of midazolam pretreatment.

    Science.gov (United States)

    Maldonado, N M; Espejo, P J; Martijena, I D; Molina, V A

    2014-02-01

    Exposure to emotionally arousing experiences elicits a robust and persistent memory and enhances anxiety. The amygdala complex plays a key role in stress-induced emotional processing and in the fear memory formation. It is well known that ERK activation in the amygdala is a prerequisite for fear memory consolidation. Moreover, stress elevates p-ERK2 levels in several areas of the brain stress circuitry. Therefore, given that the ERK1/2 cascade is activated following stress and that the role of this cascade is critical in the formation of fear memory, the present study investigated the potential involvement of p-ERK2 in amygdala subnuclei in the promoting influence of stress on fear memory formation and on anxiety-like behavior. A robust and persistent ERK2 activation was noted in the Basolateral amygdala (BLA), which was evident at 5min after restraint and lasted at least one day after the stressful experience. Midazolam, a short-acting benzodiazepine ligand, administered prior to stress prevented the increase in the p-ERK2 level in the BLA. Pretreatment with intra-BLA infusion of U0126 (MEK inhibitor), but not into the adjacent central nucleus of the amygdala, attenuated the stress-induced promoting influence on fear memory formation. Finally, U0126 intra-BLA infusion prevented the enhancement of anxiety-like behavior in stressed animals. These findings suggest that the selective ERK2 activation in BLA following stress exposure is an important mechanism for the occurrence of the promoting influence of stress on fear memory and on anxiety-like behavior. © 2013 Published by Elsevier B.V. and ECNP.

  11. Capsaicin-induced changes in LTP in the lateral amygdala are mediated by TRPV1.

    Directory of Open Access Journals (Sweden)

    Carsten Zschenderlein

    2011-01-01

    Full Text Available The transient receptor potential vanilloid type 1 (TRPV1 channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA. Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was found within the nuclei of the basolateral complex of the amygdala. Capsaicin specifically changed the magnitude of long-term potentiation (LTP in the LA in brain slices of mice depending on the anesthetic (ether, isoflurane used before euthanasia. After ether anesthesia, capsaicin had a suppressive effect on LA-LTP both in patch clamp and in extracellular recordings. The capsaicin-induced reduction of LTP was completely blocked by the nitric oxide synthase (NOS inhibitor L-NAME and was absent in neuronal NOS as well as in TRPV1 deficient mice. The specific antagonist of cannabinoid receptor type 1 (CB1, AM 251, was also able to reduce the inhibitory effect of capsaicin on LA-LTP, suggesting that stimulation of TRPV1 provokes the generation of anandamide in the brain which seems to inhibit NO synthesis. After isoflurane anesthesia before euthanasia capsaicin caused a TRPV1-mediated increase in the magnitude of LA-LTP. Therefore, our results also indicate that the appropriate choice of the anesthetics used is an important consideration when brain plasticity and the action of endovanilloids will be evaluated. In summary, our results demonstrate that TRPV1 may be involved in the amygdala control of learning mechanisms.

  12. Differential role of Rac in the basolateral amygdala and cornu ammonis 1 in the reconsolidation of auditory and contextual Pavlovian fear memory in rats.

    Science.gov (United States)

    Wu, Ping; Ding, Zeng-Bo; Meng, Shi-Qiu; Shen, Hao-Wei; Sun, Shi-Chao; Luo, Yi-Xiao; Liu, Jian-Feng; Lu, Lin; Zhu, Wei-Li; Shi, Jie

    2014-08-01

    A conditioned stimulus (CS) is associated with a fearful unconditioned stimulus (US) in the traditional fear conditioning model. After fear conditioning, the CS-US association memory undergoes the consolidation process to become stable. Consolidated memory enters an unstable state after retrieval and requires the reconsolidation process to stabilize again. Evidence indicates the important role of Rac (Ras-related C3 botulinum toxin substrate) in the acquisition and extinction of fear memory. In the present study, we hypothesized that Rac in the amygdala is crucial for the reconsolidation of auditory and contextual Pavlovian fear memory. Auditory and contextual fear conditioning and microinjections of the Rac inhibitor NSC23766 were used to explore the role of Rac in the reconsolidation of auditory and contextual Pavlovian fear memory in rats. A microinjection of NSC23766 into the basolateral amygdala (BLA) but not central amygdala (CeA) or cornu ammonis 1 (CA1) immediately after memory retrieval disrupted the reconsolidation of auditory Pavlovian fear memory. A microinjection of NSC23766 into the CA1 but not BLA or CeA after memory retrieval disrupted the reconsolidation of contextual Pavlovian fear memory. Our experiments demonstrate that Rac in the BLA is crucial for the reconsolidation of auditory Pavlovian fear memory, whereas Rac in the CA1 is critical for the reconsolidation of contextual Pavlovian fear memory.

  13. Infusion of the NMDA Receptor Antagonist, DL-APV, into the Basolateral Amygdala Disrupts Learning to Fear a Novel and a Familiar Context as Well as Relearning to Fear an Extinguished Context

    Science.gov (United States)

    Laurent, Vincent; Westbrook, R. Frederick

    2009-01-01

    Ample evidence suggests that activation of NMDA receptors (NMDAr) in the basolateral complex of the amygdala (BLA) is necessary for context fear conditioning. The present series of experiments examined whether this activation was still required when the to-be-shocked context had a history. We found that BLA infusion of the selective NMDAr…

  14. The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice.

    Science.gov (United States)

    Valero, E; Gómez-Milanés, I; Almela, P; Ribeiro Do Couto, B; Laorden, M L; Milanés, M V; Núñez, C

    2018-06-08

    Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse

  15. Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala

    DEFF Research Database (Denmark)

    Maigaard, Katrine; Pedersen, Ida Hageman; Jørgensen, Anders

    2012-01-01

    in the brain. We find that stress tended to upregulate Ca(v)1.2 and Ca(v)1.3 channels in a brain region specific manner, while ECS tended to normalise this effect. This was more pronounced for Ca(v)1.2 channels, where stress clearly increased expression in both the basolateral amygdala, dentate gyrus and CA3......, while stress only upregulated Ca(v)1.3 channel expression significantly in the dentate gyrus. ECS effects on Ca(v)1.2 channel expression were generally specific to stressed animals. Our findings are consistent with and extent previous studies on the involvement of intracellular calcium ion dysfunction...

  16. The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

    Science.gov (United States)

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Pidoplichko, Volodymyr I.; Figueiredo, Taiza H.; Apland, James P.; Krishnan, Jishnu K. S.

    2017-01-01

    Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon—namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ih in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M1 antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive. PMID:27799295

  17. The MARVEL transmembrane motif of occludin mediates oligomerization and targeting to the basolateral surface in epithelia.

    Science.gov (United States)

    Yaffe, Yakey; Shepshelovitch, Jeanne; Nevo-Yassaf, Inbar; Yeheskel, Adva; Shmerling, Hedva; Kwiatek, Joanna M; Gaus, Katharina; Pasmanik-Chor, Metsada; Hirschberg, Koret

    2012-08-01

    Occludin (Ocln), a MARVEL-motif-containing protein, is found in all tight junctions. MARVEL motifs are comprised of four transmembrane helices associated with the localization to or formation of diverse membrane subdomains by interacting with the proximal lipid environment. The functions of the Ocln MARVEL motif are unknown. Bioinformatics sequence- and structure-based analyses demonstrated that the MARVEL domain of Ocln family proteins has distinct evolutionarily conserved sequence features that are consistent with its basolateral membrane localization. Live-cell microscopy, fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) were used to analyze the intracellular distribution and self-association of fluorescent-protein-tagged full-length human Ocln or the Ocln MARVEL motif excluding the cytosolic C- and N-termini (amino acids 60-269, FP-MARVEL-Ocln). FP-MARVEL-Ocln efficiently arrived at the plasma membrane (PM) and was sorted to the basolateral PM in filter-grown polarized MDCK cells. A series of conserved aromatic amino acids within the MARVEL domain were found to be associated with Ocln dimerization using BiFC. FP-MARVEL-Ocln inhibited membrane pore growth during Triton-X-100-induced solubilization and was shown to increase the membrane-ordered state using Laurdan, a lipid dye. These data demonstrate that the Ocln MARVEL domain mediates self-association and correct sorting to the basolateral membrane.

  18. Optogenetic dissection of amygdala functioning

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    Ryan eLalumiere

    2014-03-01

    Full Text Available Studies of amygdala functioning have occupied a significant place in the history of understanding how the brain controls behavior and cognition. Early work on the amygdala placed this small structure as a key component in the regulation of emotion and affective behavior. Over time, our understanding of its role in brain processes has expanded, as we have uncovered amygdala influences on memory, reward behavior, and overall functioning in many other brain regions. Studies have indicated that the amygdala has widespread connections with a variety of brain structures, from the prefrontal cortex to regions of the brainstem, that explain its powerful influence on other parts of the brain and behaviors mediated by those regions. Thus, many optogenetic studies have focused on harnessing the powers of this technique to elucidate the functioning of the amygdala in relation to motivation, fear, and memory as well as to determine how the amygdala regulates activity in other structures. For example, studies using optogenetics have examined how specific circuits within amygdala nuclei regulate anxiety. Other work has provided insight into how the basolateral and central amygdala nuclei regulate memory processing underlying aversive learning. Many experiments have taken advantage of optogenetics’ ability to target either genetically distinct subpopulations of neurons or the specific projections from the amygdala to other brain regions. Findings from such studies have provided evidence that particular patterns of activity in basolateral amygdala glutamatergic neurons are related to memory consolidation processes, while other work has indicated the critical nature of amygdala inputs to the prefrontal cortex and nucleus accumbens in regulating behavior dependent on those downstream structures. This review will examine the recent discoveries on amygdala functioning made through experiments using optogenetics, placing these findings in the context of the major

  19. 15. Amygdala pain mechanisms

    Science.gov (United States)

    Neugebauer, Volker

    2015-01-01

    A limbic brain area the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety and depression. The amygdala has also emerged as an important brain center for the emotional-affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the “nociceptive amygdala”) accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral-basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms. PMID:25846623

  20. Memory-enhancing intra-basolateral amygdala clenbuterol infusion reduces post-burst afterhyperpolarizations in hippocampal CA1 pyramidal neurons following inhibitory avoidance learning.

    Science.gov (United States)

    Lovitz, E S; Thompson, L T

    2015-03-01

    Activation of the basolateral amygdala can modulate the strength of fear memories, including those in single-trial inhibitory avoidance (IA) tasks. Memory retention, measured by the latency to re-enter a dark-compartment paired 24h earlier with a footshock, varies with intensity of this aversive stimulus. When higher intensity footshocks were used, hippocampal CA1 pyramidal neurons exhibited reduced afterhyperpolarizations (AHPs) 24h post-trial, an effect blocked by immediate post-trial inactivation of the basolateral complex of the amygdala (BLA). Similar AHP reductions in CA1 have been observed in a number of learning tasks, with time courses appropriate to support memory consolidation. When less intense footshocks were used for IA training of Sprague-Dawley rats, immediate post-trial infusion of the β-adrenergic agonist clenbuterol into BLA was required to enhance hippocampal Arc protein expression 45 min later and to enhance memory retention tested 48 h later. Here, using Long-Evans rats and low-intensity footshocks, we confirmed that bilateral immediate post-trial infusion of 15 ng/0.5 μl of the β-adrenergic agonist clenbuterol into BLA significantly enhances memory for an IA task. Next, clenbuterol was infused into one BLA immediately post-training, with vehicle infused into the contralateral BLA, then hippocampal CA1 neuron AHPs were assessed 24 h later. Only CA1 neurons from hemispheres ipsilateral to post-trial clenbuterol infusion showed learning-dependent AHP reductions. Excitability of CA1 neurons from the same trained rats, but from the vehicle-infused hemispheres, was identical to that from untrained rats receiving unilateral clenbuterol or vehicle infusions. Peak AHPs, medium and slow AHPs, and accommodation were reduced only with the combination of IA training and unilateral BLA β-receptor activation. Similar to previous observations of BLA adrenergic memory-related enhancement of Arc protein expression in hippocampus, increased CA1 neuronal

  1. Microinjection of naltrexone into the central, but not the basolateral, amygdala blocks the anxiolytic effects of diazepam in the plus maze

    Science.gov (United States)

    Burghardt, Paul R.; Wilson, Marlene A.

    2009-01-01

    The amygdala is involved in behavioral and physiological responses to fear, and the anxiolytic properties of several drugs are localized to this region. Activation of endogenous opioid systems is known to occur in response to stress and a growing body of literature suggests that opioid systems regulate the properties of anxiolytic drugs. These experiments sought to elucidate the role of opioid receptors in the central (CeA) and basolateral (BLA) nuclei of the amygdala in regulating the anxiolytic properties of ethanol and diazepam. Male rats fitted with cannula received bilateral microinjections of the non-selective opioid receptor antagonist naltrexone (NAL) immediately followed by systemic delivery of either ethanol (1 g/kg) or diazepam (2 mg/kg) in the elevated plus maze. Both diazepam and ethanol decreased anxiety-like behavior. Delivery of NAL into the CeA blocked the anxiolytic properties of diazepam. Delivery of NAL into the BLA slightly increased open arm avoidance, but had no effect on the anxiolytic properties of diazepam. Microinjection of NAL into either nucleus failed to block the effects of ethanol. These results were specific to the anxiolytic properties of diazepam, since baseline behaviors were unaffected by microinjection of naltrexone. Microinjection of lidocaine produced results distinct from NAL and failed to block the anxiolytic actions of diazepam. These studies indicate distinct roles for opioid receptor systems in the CeA and BLA in regulating the anxiolytic properties of diazepam in the elevated plus maze. Further, opioid receptor systems in the CeA and BLA do not regulate the anxiolytic properties of ethanol in this test. PMID:16123750

  2. Cue-induced food seeking after punishment is associated with increased Fos expression in the lateral hypothalamus and basolateral and medial amygdala.

    Science.gov (United States)

    Campbell, Erin J; Barker, David J; Nasser, Helen M; Kaganovsky, Konstantin; Dayas, Christopher V; Marchant, Nathan J

    2017-04-01

    In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  3. Evidence for carrier-mediated Cl-SO4 exchange in rabbit ileal basolateral membrane vesicles

    International Nuclear Information System (INIS)

    Schron, C.M.; Knickelbein, R.G.; Aronson, P.S.; Dobbins, J.W.

    1987-01-01

    In rabbit ileal basolateral membrane (BLM) vesicles, an outwardly directed Cl gradient ([Cl] in/out = 60/6 mM) stimulated the initial velocity of 35 SO 4 uptake compared with uptake in the absence of Cl. Under Cl gradient conditions, 35 SO 4 was transiently accumulated at a concentration twice that found at equilibrium (overshoot). Chloride gradient-stimulated SO 4 uptake was markedly reduced by inhibitors of anion exchange and was saturable. SO 4 uptake by BLM vesicles was not stimulated by imposition of an inside-positive electrical potential, suggesting that the stimulation by a Cl gradient was not due to an induced electrical potential. Oxalate, nitrate, iodide, and bromide inhibited the initial velocity of Cl gradient-stimulated SO 4 uptake, whereas phosphate, β-hydroxybutyrate, lactate, and p-aminohippurate had not effect. When 35 SO 4 uptake by BLM vesicles was compared with that of brush-border membrane vesicles, Cl gradient-stimulated SO 4 uptake was found predominantly in the BLM preparation. In conclusion, these findings provide evidence for a carrier on the ileal basolateral membrane that mediates Cl-SO 4 exchange

  4. Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex–Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices

    Science.gov (United States)

    Song, Chenghui; Ehlers, Vanessa L.

    2015-01-01

    Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC–BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted fear conditioning. SIGNIFICANCE STATEMENT Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change

  5. Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory

    Directory of Open Access Journals (Sweden)

    Cora eHübner

    2014-03-01

    Full Text Available Many lines of evidence suggest that a reciprocally interconnected network comprising the amygdala, ventral hippocampus (vHC, and medial prefrontal cortex (mPFC participates in different aspects of the acquisition and extinction of conditioned fear responses and fear behavior. This could at least in part be mediated by direct connections from mPFC or vHC to amygdala to control amygdala activity and output. However, currently the interactions between mPFC and vHC afferents and their specific targets in the amygdala are still poorly understood. Here, we use an ex-vivo optogenetic approach to dissect synaptic properties of inputs from mPFC and vHC to defined neuronal populations in the basal amygdala (BA, the area that we identify as a major target of these projections. We find that BA principal neurons (PNs and local BA interneurons (INs receive monosynaptic excitatory inputs from mPFC and vHC. In addition, both these inputs also recruit GABAergic feedforward inhibition in a substantial fraction of PNs, in some neurons this also comprises a slow GABAB-component. Amongst the innervated PNs we identify neurons that project back to subregions of the mPFC, indicating a loop between neurons in mPFC and BA, and a pathway from vHC to mPFC via BA. Interestingly, mPFC inputs also recruit feedforward inhibition in a fraction of INs, suggesting that these inputs can activate dis-inhibitory circuits in the BA. A general feature of both mPFC and vHC inputs to local INs is that excitatory inputs display faster rise and decay kinetics than in PNs, which would enable temporally precise signaling. However, mPFC and vHC inputs to both PNs and INs differ in their presynaptic release properties, in that vHC inputs are more depressing. In summary, our data describe novel wiring, and features of synaptic connections from mPFC and vHC to amygdala that could help to interpret functions of these interconnected brain areas at the network level.

  6. Morphological, structural, and functional alterations of the prefrontal cortex and the basolateral amygdala after early lesion of the rat mediodorsal thalamus.

    Science.gov (United States)

    Ouhaz, Zakaria; Ba-M'hamed, Saadia; Bennis, Mohamed

    2017-08-01

    Early postnatal damage to the mediodorsal thalamus (MD) produces deficits in cognition and behavior believed to be associated with early prefrontal cortical maldevelopment. We assessed the role of MD afferents during development on the morphological and functional maturation of the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Sprague-Dawley rat pups (n = 56) received a bilateral electrolytic lesion of the MD or a MD Sham lesion on postnatal day 4. 7 weeks later, all rats were tested in anxiety-related and cognitive paradigms using the elevated plus maze and novel object recognition tests. Following behavioral testing (P70), rats were killed and the baseline expression of C-Fos protein and the number of GABAergic neurons were evaluated in the PFC and the BLA. The dendritic morphology and spine density in the PFC using Golgi-Cox staining was also evaluated. Adult rats with early postnatal bilateral MD damage exhibited disrupted recognition memory and increased anxiety-like behaviors. The lesion also caused a significant diminution of C-Fos immunolabeling and an increase of the number of GABAergic neurons in the PFC. In the BLA, the number of GABAergic neurons was significantly reduced, associated with an increase in C-Fos immunolabeling. Furthermore, in the PFC the lesion induced a significant reduction in dendritic branching and spine density. Our data are consistent with the hypothesis that the MD plays a role in the development of the PFC and, therefore, may be a good animal model to investigate cognitive symptoms associated with schizophrenia.

  7. Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex.

    Science.gov (United States)

    Song, Jiaojiao; Chen, Ming; Dong, Yi; Lai, Bin; Zheng, Ping

    2018-05-01

    Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation.

    Science.gov (United States)

    Rosen, Laura G; Rushlow, Walter J; Laviolette, Steven R

    2017-10-03

    The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate-related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms. Using conditioned place preference (CPP) and withdrawal aversion (conditioned place aversion; CPA) procedures in rats, combined with molecular analyses of BLA protein expression, we examined the effects of chronic opiate exposure on the functional role of intra-BLA D3R transmission during the acquisition of opiate reward or withdrawal aversion memories. Remarkably, we report that the state of opiate exposure during behavioural conditioning (opiate-naïve/non-dependent vs. chronically exposed and in withdrawal) controlled the functional role of intra-BLA D3R transmission during the acquisition of both opiate reward memories and withdrawal-aversion associative memories. Thus, whereas intra-BLA D3R blockade had no effect on opiate reward memory formation in the non-dependent state, blockade of intra-BLA D3R transmission prevented the formation of opiate reward and withdrawal aversion memory in the chronically exposed state. This switch in the functional role of D3R transmission corresponded to significant increases in Cdk5 phosphorylation and total expression levels of calcineurin, and a corresponding decrease in intra-BLA D3R expression. Inhibition of either intra-BLA Cdk5 or calcineurin reversed these effects, switching intra-BLA associative memory formation back to a D3R-independent mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat-induced anxiety and the acquisition of conditioned defeat in Syrian hamsters.

    Science.gov (United States)

    Clinard, Catherine T; Bader, Lauren R; Sullivan, Molly A; Cooper, Matthew A

    2015-03-01

    Conditioned defeat is a model in Syrian hamsters (Mesocricetus auratus) in which normal territorial aggression is replaced by increased submissive and defensive behavior following acute social defeat. The conditioned defeat response involves both a fear-related memory for a specific opponent as well as anxiety-like behavior indicated by avoidance of novel conspecifics. We have previously shown that systemic injection of a 5-HT2a receptor antagonist reduces the acquisition of conditioned defeat. Because neural activity in the basolateral amygdala (BLA) is critical for the acquisition of conditioned defeat and BLA 5-HT2a receptors can modulate anxiety but have a limited effect on emotional memories, we investigated whether 5-HT2a receptor modulation alters defeat-induced anxiety but not defeat-related memories. We injected the 5-HT2a receptor antagonist MDL 11,939 (0 mM, 1.7 mM or 17 mM) or the 5-HT2a receptor agonist TCB-2 (0 mM, 8 mM or 80 mM) into the BLA prior to social defeat. We found that injection of MDL 11,939 into the BLA impaired acquisition of the conditioned defeat response and blocked defeat-induced anxiety in the open field, but did not significantly impair avoidance of former opponents in the Y-maze. Furthermore, we found that injection of TCB-2 into the BLA increased the acquisition of conditioned defeat and increased anxiety-like behavior in the open field, but did not alter avoidance of former opponents. Our data suggest that 5-HT2a receptor signaling in the BLA is both necessary and sufficient for the development of conditioned defeat, likely via modulation of defeat-induced anxiety. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task.

    Science.gov (United States)

    Ardeshiri, Motahareh Rouhi; Hosseinmardi, Narges; Akbari, Esmaeil

    2017-05-15

    There is an extensive evidence concerning basolateral amygdala (BLA) function to hippocampal memory processing. However, few researches have addressed the orexinergic system roles in this modulation. Then, the present study aims at investigating the action of orexin 1 and 2 receptors in BLA on passive avoidance (PA) learning. Wistar male rats (n=79) were trained to avoid foot shock in one type of PA task. The rats were injected bilaterally into BLA, a selective orexin 1 receptor antagonist, SB-334867-A (3, 6, 12μg/0.5μl), and an orexin 2 receptor antagonist, TCS-OX2-29 (2.5, 5, 10μg/0.5μl), after training or before retrieval of the inhibitory avoidance task. Control rats received dimethyl sulfoxide at the same volume. The amount of learning was assessed 24h later. The time of the first entrance to the dark compartment and the total time spending in the light compartment were measured as criteria for the avoidance memory. The results showed that consolidation and retrieval were significantly impaired by SB-334867-A administration into BLA in 3, 6 and 12μg/0.5μl. However, TCS-OX2-29 in 2.5μg/0.5μl could not influence neither consolidation nor retrieval. The TCS-OX2-29 administration into BLA impaired memory retrieval in 5 and 10μg/0/5μl but not the consolidation. It gives the impression that orexinergic system of the BLA plays an important role in regulation of memory processing and learning in the rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Noradrenergic actions in the basolateral complex of the amygdala modulate Arc expression in hippocampal synapses and consolidation of aversive and non-aversive memory

    Science.gov (United States)

    McReynolds, Jayme R.; Anderson, Kelly M.; Donowho, Kyle M.; McIntyre, Christa K.

    2014-01-01

    The basolateral complex of the amygdala (BLA) plays a role in the modulation of emotional memory consolidation through its interactions with other brain regions. In rats, memory enhancing infusions of the β-adrenergic receptor agonist clenbuterol into the BLA immediately after training enhances expression of the protein product of the immediate early gene Arc in the dorsal hippocampus and memory-impairing intra-BLA treatments reduce hippocampal Arc expression. We have proposed that the BLA may modulate memory consolidation through an influence on the local translation of synaptic plasticity proteins, like Arc, in recently active synapses in efferent brain regions. To date, all work related to this hypothesis is based on aversive memory tasks such as inhibitory avoidance (IA). To determine whether BLA modulation of hippocampal Arc protein expression is specific to plasticity associated with inhibitory avoidance memory, or a common mechanism for multiple types of memory, we tested the effect of intra-BLA infusions of clenbuterol on memory and hippocampal synaptic Arc expression following IA or object recognition training. Results indicate that intra-BLA infusions of clenbuterol enhance memory for both tasks; however, Arc expression in hippocampal synaptoneurosomes was significantly elevated only in rats trained on the aversive IA task. These findings suggest that regulation of Arc expression in hippocampal synapses may depend on co-activation of arousal systems. To test this hypothesis, a “high arousal” version of the OR task was used where rats were not habituated to the testing conditions. Posttraining intra-BLA infusions of clenbuterol enhanced consolidation of the high-arousing version of the task and significantly increased Arc protein levels in dorsal hippocampus synaptic fractions. These findings suggest that the BLA modulates multiple forms of memory and affects the synaptic plasticity-associated protein Arc in synapses of the dorsal hippocampus when

  12. Alterations of emotion, cognition and firing activity of the basolateral nucleus of the amygdala after partial bilateral lesions of the nigrostriatal pathway in rats.

    Science.gov (United States)

    Chen, Li; Liu, Jian; Zhang, Qiao Jun; Feng, Jian Jun; Gui, Zhen Hua; Ali, Umar; Wang, Yong; Fan, Ling Ling; Hou, Chen; Wang, Tao

    2011-07-15

    Although increasing evidence indicates that psychiatric symptoms are crucial characteristic of the early stage of Parkinson's disease (PD) and precede motor impairments, the neuronal firing activity of the basolateral nucleus of the amygdala (BLA) in the psychiatric symptom of PD and the involved mechanism are still unclear. In the present study, we examined the changes in emotional and cognitive tests not focused on motor fluency and firing activity of projection neurons in the BLA rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum, and the effects of apomorphine and the medial prefrontal cortex (mPFC) on these changes. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 18-22% and 26-30% loss of tyrosine hydroxylase immunoreactive neurons in the ventral tegmental area and substantia nigra pars compacta of rats, respectively. The striatal lesions induced anxiety-like responses in the rats but did not result in depressive-like behavior or cognitive impairments. In the lesioned rats, the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and the firing pattern of BLA projection neurons was not changed. No significant differences were observed either in behaviors or firing activity of BLA projection neurons by further ibotenic acid lesions of the mPFC in the lesioned rats. Systemic administration of cumulative apomorphine (10-160 μg/kg) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA-lesioned and combined 6-OHDA- and mPFC-lesioned rats, but the latter needed more apomorphine stimulation. These data suggest that the anxiety in early stage of PD is possibly related to the decrease in firing activity of BLA projection neurons, which may be regulated by the activation of dopamine receptor in the mPFC. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. The Basolateral Amygdala and Nucleus Accumbens Core Mediate Dissociable Aspects of Drug Memory Reconsolidation

    Science.gov (United States)

    Theberge, Florence R. M.; Milton, Amy L.; Belin, David; Lee, Jonathan L. C.; Everitt, Barry J.

    2010-01-01

    A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim…

  14. The basolateral amygdala mediates the effects of cues associated with meal interruption on feeding behavior

    OpenAIRE

    Galarce, Ezequiel M.; McDannald, Michael A.; Holland, Peter C.

    2010-01-01

    Considerable evidence shows that environmental cues that signal food delivery when rats are food-deprived can substantially potentiate feeding later when rats are food-sated. Similarly, cues associated with meal interruption, food removal or impending food scarcity may also induce increased eating. For example, after learning the association between a discrete “interruption” stimulus and the unexpected termination of food trials, sated rats show enhanced food consumption when exposed to that ...

  15. Accumbens Shell AMPA Receptors Mediate Expression of Extinguished Reward Seeking through Interactions with Basolateral Amygdala

    Science.gov (United States)

    Millan, E. Zayra; McNally, Gavan P.

    2011-01-01

    Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B).…

  16. Memory-enhancing intra-basolateral amygdala infusions of clenbuterol increase Arc and CaMKII-alpha protein expression in the rostral anterior cingulate cortex

    Directory of Open Access Journals (Sweden)

    Crystal M Holloway-Erickson

    2012-04-01

    Full Text Available Activation of β-adrenoceptors in the basolateral complex of the amygdala (BLA modulates memory through interactions with multiple memory systems. The cellular mechanisms for this interaction remain unresolved. Memory-modulating BLA manipulations influence expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc in the dorsal hippocampus, and hippocampal expression of Arc protein is critically involved in memory consolidation and long-term potentiation. The present studies examined whether this influence of the BLA is specific to the hippocampus and to Arc protein. Like the hippocampus, the rostral portion of the anterior cingulate cortex (rACC is involved in the consolidation of inhibitory avoidance (IA memory, and IA training increases Arc protein in the rACC. Because the BLA interacts with the rACC in the consolidation of IA memory, the rACC is a potential candidate for further studies of BLA modulation of synaptic plasticity. The alpha isoform of the Calcium/Calmodulin-dependent protein kinase II (CaMKIIα and the immediate early gene c-Fos are involved in long-term potentiation and memory. Both Arc and CaMKIIα proteins can be translated in isolated synapses, where the mRNA is localized, but c-Fos protein remains in the soma. To examine the influence of memory-modulating manipulations of the BLA on expression of these memory and plasticity-associated proteins in the rACC, male Sprague-Dawley rats were trained on an IA task and given intra-BLA infusions of either clenbuterol or lidocaine immediately after training. Findings suggest that noradrenergic stimulation of the BLA may modulate memory consolidation through effects on both synaptic proteins Arc and CaMKIIα, but not the somatic protein c-Fos. Furthermore, protein changes observed in the rACC following BLA manipulations suggest that the influence of the BLA on synaptic proteins is not limited to those in the dorsal

  17. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation.

    Science.gov (United States)

    Roozendaal, Benno; Schelling, Gustav; McGaugh, James L

    2008-06-25

    Extensive evidence indicates that stress hormone effects on the consolidation of emotionally influenced memory involve noradrenergic activation of the basolateral complex of the amygdala (BLA). The present experiments examined whether corticotropin-releasing factor (CRF) modulates memory consolidation via an interaction with the beta-adrenoceptor-cAMP system in the BLA. In a first experiment, male Sprague Dawley rats received bilateral infusions of the CRF-binding protein ligand inhibitor CRF(6-33) into the BLA either alone or together with the CRF receptor antagonist alpha-helical CRF(9-41) immediately after inhibitory avoidance training. CRF(6-33) induced dose-dependent enhancement of 48 h retention latencies, which was blocked by coadministration of alpha-helical CRF(9-41), suggesting that CRF(6-33) enhances memory consolidation by displacing CRF from its binding protein, thereby increasing "free" endogenous CRF concentrations. In a second experiment, intra-BLA infusions of atenolol (beta-adrenoceptor antagonist) and Rp-cAMPS (cAMP inhibitor), but not prazosin (alpha(1)-adrenoceptor antagonist), blocked CRF(6-33)-induced retention enhancement. In a third experiment, the CRF receptor antagonist alpha-helical CRF(9-41) administered into the BLA immediately after training attenuated the dose-response effects of concurrent intra-BLA infusions of clenbuterol (beta-adrenoceptor agonist). In contrast, alpha-helical CRF(9-41) did not alter retention enhancement induced by posttraining intra-BLA infusions of either cirazoline (alpha(1)-adrenoceptor agonist) or 8-br-cAMP (cAMP analog). These findings suggest that CRF facilitates the memory-modulatory effects of noradrenergic stimulation in the BLA via an interaction with the beta-adrenoceptor-cAMP cascade, at a locus between the membrane-bound beta-adrenoceptor and the intracellular cAMP formation site. Moreover, consistent with evidence that glucocorticoids enhance memory consolidation via a similar interaction with the

  18. 5-HT1A receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats.

    Science.gov (United States)

    Sardari, M; Rezayof, A; Zarrindast, M-R

    2015-08-06

    The aim of the present study was to investigate the possible role of basolateral amygdala (BLA) 5-HT1A receptors in memory formation under stress. We also examined whether the blockade of these receptors is involved in stress-induced state-dependent memory. Adult male Wistar rats received cannula implants that bilaterally targeted the BLA. Long-term memory was examined using the step-through type of passive avoidance task. Behavioral stress was evoked by exposure to an elevated platform (EP) for 10, 20 and 30min. Post-training exposure to acute stress (30min) impaired the memory consolidation. In addition, pre-test exposure to acute stress-(20 and 30min) induced the impairment of memory retrieval. Interestingly, the memory impairment induced by post-training exposure to stress was restored in the animals that received 20- or 30-min pre-test stress exposure, suggesting stress-induced state-dependent memory retrieval. Post-training BLA-targeted injection of a selective 5-HT1A receptor antagonist, (S)-WAY-100135 (2μg/rat), prevented the impairing effect of stress on memory consolidation. Pre-test injection of the same doses of (S)-WAY-100135 that was targeted to the BLA also reversed stress-induced memory retrieval impairment. It should be considered that post-training or pre-test BLA-targeted injection of (S)-WAY-100135 (0.5-2μg/rat) by itself had no effect on the memory formation. Moreover, pre-test injection of (S)-WAY-100135 (2μg/rat) that targeted the BLA inhibited the stress-induced state-dependent memory retrieval. Taken together, our findings suggest that post-training or pre-test exposure to acute stress induced the impairment of memory consolidation, retrieval and state-dependent learning. The BLA 5-HT1A receptors have a critical role in learning and memory under stress. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats

    Science.gov (United States)

    Trezza, Viviana; Damsteegt, Ruth; Manduca, Antonia; Petrosino, Stefania; Van Kerkhof, Linda W.M.; Pasterkamp, R. Jeroen; Zhou, Yeping; Campolongo, Patrizia; Cuomo, Vincenzo; Di Marzo, Vincenzo; Vanderschuren, Louk J.M.J.

    2012-01-01

    The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4–5 week old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signalling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats. PMID:23100412

  20. Exposure to an open-field arena increases c-Fos expression in a distributed anxiety-related system projecting to the basolateral amygdaloid complex

    DEFF Research Database (Denmark)

    Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.

    2008-01-01

    Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of brain structures including the basolateral amygdala. Our previous studies demonstrate that exposure of rats to an open-field in high- and low-light conditions results in a marked...... of specific afferent input to this region of the amygdala. In order to identify candidate brain regions mediating anxiety-induced activation of the basolateral amygdaloid complex in rats, we used cholera toxin B subunit (CTb) as a retrograde tracer to identify neurons with direct afferent projections...

  1. Antidepressant effects of exercise are produced via suppression of hypocretin/orexin and melanin-concentrating hormone in the basolateral amygdala.

    Science.gov (United States)

    Kim, Tae-Kyung; Kim, Ji-Eun; Park, Jin-Young; Lee, Jung-Eun; Choi, Juli; Kim, Hannah; Lee, Eun-Hwa; Kim, Seung-Woo; Lee, Ja-Kyeong; Kang, Hyun-Sik; Han, Pyung-Lim

    2015-07-01

    Physical exercise is considered beneficial in the treatment of depression, but the underlying mechanism is not clearly understood. In the present study, we investigated the mechanism regulating antidepressant effects of exercise by focusing on the role of the amygdala using a well-defined animal model of depression. C57BL/6 mice treated with repeated restraint showed depression-like behaviors, which was counteracted by post-stress treatment with physical exercise. The two neuropeptides hypocretin/orexin (Hcrt/Orx) and melanin-concentrating hormone (MCH) were transcriptionally upregulated in the BLA after repeated stress, and their enhanced expression was downregulated by treatment with exercise, mirroring stress-induced depression-like behaviors and their reversal by exercise. Stereotaxic injection of either Hcrt/Orx peptide or MCH peptide within the BLA commonly increased phospho-CaMKIIα level and produced depression-like behaviors, mimicking the neural states in the BLA of mice subjected to repeated stress. In contrast, siRNA-mediated suppression of Hcrt/Orx or MCH in the BLA blocked stress-induced depression-like behaviors. Furthermore, siRNA-mediated inhibition of CaMKIIα in the BLA also counteracted stress-induced depression-like behaviors. Local injection of Hcrt/Orx peptide or MCH peptide within the BLA in exercise-treated animals blocked antidepressant-like effects of exercise. Together these results suggest that exercise produces antidepressant effects via suppression of Hcrt/Orx and MCH neural systems in the BLA. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Basolateral Endocytic Recycling Requires RAB-10 and AMPH-1 Mediated Recruitment of RAB-5 GAP TBC-2 to Endosomes.

    Directory of Open Access Journals (Sweden)

    Ou Liu

    Full Text Available The small GTPase RAB-5/Rab5 is a master regulator of the early endosome, required for a myriad of coordinated activities, including the degradation and recycling of internalized cargo. Here we focused on the recycling function of the early endosome and the regulation of RAB-5 by GAP protein TBC-2 in the basolateral C. elegans intestine. We demonstrate that downstream basolateral recycling regulators, GTPase RAB-10/Rab10 and BAR domain protein AMPH-1/Amphiphysin, bind to TBC-2 and help to recruit it to endosomes. In the absence of RAB-10 or AMPH-1 binding to TBC-2, RAB-5 membrane association is abnormally high and recycling cargo is trapped in early endosomes. Furthermore, the loss of TBC-2 or AMPH-1 leads to abnormally high spatial overlap of RAB-5 and RAB-10. Taken together our results indicate that RAB-10 and AMPH-1 mediated down-regulation of RAB-5 is an important step in recycling, required for cargo exit from early endosomes and regulation of early endosome-recycling endosome interactions.

  3. Basolateral Endocytic Recycling Requires RAB-10 and AMPH-1 Mediated Recruitment of RAB-5 GAP TBC-2 to Endosomes

    Science.gov (United States)

    Liu, Ou; Grant, Barth D.

    2015-01-01

    The small GTPase RAB-5/Rab5 is a master regulator of the early endosome, required for a myriad of coordinated activities, including the degradation and recycling of internalized cargo. Here we focused on the recycling function of the early endosome and the regulation of RAB-5 by GAP protein TBC-2 in the basolateral C. elegans intestine. We demonstrate that downstream basolateral recycling regulators, GTPase RAB-10/Rab10 and BAR domain protein AMPH-1/Amphiphysin, bind to TBC-2 and help to recruit it to endosomes. In the absence of RAB-10 or AMPH-1 binding to TBC-2, RAB-5 membrane association is abnormally high and recycling cargo is trapped in early endosomes. Furthermore, the loss of TBC-2 or AMPH-1 leads to abnormally high spatial overlap of RAB-5 and RAB-10. Taken together our results indicate that RAB-10 and AMPH-1 mediated down-regulation of RAB-5 is an important step in recycling, required for cargo exit from early endosomes and regulation of early endosome–recycling endosome interactions. PMID:26393361

  4. Carrier-mediated ¿-aminobutyric acid transport across the basolateral membrane of human intestinal Caco-2 cell monolayers

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Carstensen, Mette; Brodin, Birger

    2012-01-01

    and the anticancer prodrug d-aminolevulinic acid across the apical membrane of small intestinal enterocytes. Little is however known about the basolateral transport of these substances. We investigated basolateral transport of GABA in mature Caco-2 cell monolayers using isotope studies. Here we report that, at least...

  5. Dorsal hippocampal NMDA receptor blockade impairs extinction of naloxone-precipitated conditioned place aversion in acute morphine-treated rats by suppressing ERK and CREB phosphorylation in the basolateral amygdala.

    Science.gov (United States)

    Wang, Wei-Sheng; Chen, Zhong-Guo; Liu, Wen-Tao; Chi, Zhi-Qiang; He, Ling; Liu, Jing-Gen

    2015-01-01

    Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying the loss (extinction) of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction. Naloxone-induced conditioned place aversion (CPA) of Sprague-Dawley rats was used to measure conditioned aversion. An NMDA receptor antagonist and MAPK kinase inhibitor were applied through intracranial injections. The phosphorylation of ERK and cAMP response element-binding protein (CREB) was detected using Western blot. The extinction of CPA behaviour increased the phosphorylation of ERK and CREB in the dorsal hippocampus (DH) and basolateral amygdala (BLA), but not in the central amygdala (CeA). Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuated ERK and CREB phosphorylation in the BLA and impaired the extinction of CPA behaviour. Although intra-DH injections of AP-5 attenuated extinction training-induced activation of the ERK-CREB pathway in the BLA, intra-BLA injection of AP5 had no effect on extinction training-induced activation of the ERK-CREB pathway in the DH. These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behaviour and that the DH, via a direct or indirect pathway, modulates the activity of ERK and CREB in the BLA through activation of NMDA receptors after extinction training. Understanding the mechanisms underlying the extinction of conditioned aversion could facilitate the treatment of drug addiction. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  6. Exposure to an open-field arena increases c-Fos expression in a distributed anxiety-related system projecting to the basolateral amygdaloid complex

    DEFF Research Database (Denmark)

    Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.

    2008-01-01

    Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of brain structures including the basolateral amygdala. Our previous studies demonstrate that exposure of rats to an open-field in high- and low-light conditions results in a marked...... of specific afferent input to this region of the amygdala. In order to identify candidate brain regions mediating anxiety-induced activation of the basolateral amygdaloid complex in rats, we used cholera toxin B subunit (CTb) as a retrograde tracer to identify neurons with direct afferent projections....... These data are consistent with the hypothesis that exposure to the open-field arena activates an anxiety-related neuronal system with convergent input to the basolateral amygdaloid complex Udgivelsesdato: 2008/8/26...

  7. GABAA receptor endocytosis in the basolateral amygdala is critical to the reinstatement of fear memory measured by fear-potentiated startle.

    Science.gov (United States)

    Lin, Hui-Ching; Tseng, Yu-Chou; Mao, Sheng-Chun; Chen, Po-See; Gean, Po-Wu

    2011-06-15

    Reinstatement represents a phenomenon that may be used to model the effects of retraumatization observed in patients with posttraumatic stress disorder (PTSD). In this study, we found intraperitoneal injection of the β-adrenergic receptor antagonist propranolol (10 mg/kg) 1 h before reinstatement training attenuated reinstatement of fear memory in rats. Conversely, reinstatement was facilitated by intra-amygdalar administration of β-adrenergic receptor agonist isoproterenol (Iso; 2 μg per side) 30 min before reinstatement training. The frequency and amplitude of the miniature IPSC (mIPSC) and the surface expression of the β3 and γ2 subunits of the GABA(A) receptor (GABA(A)R) were significantly lower in reinstated than in extinction rats, whereas the AMPA/NMDA ratio and the surface expression of GluR1 and GluR2 in the amygdala did not differ between groups. In amygdala slices, Iso-induced decrease in the surface β3 subunit of GABA(A) receptor was blocked by a Tat-conjugated dynamin function-blocking peptide (Tat-P4) pretreatment (10 μm for 30 min). By contrast, Tat-scramble peptide had no effect. Intravenous injection (3 μmol/kg) or intra-amygdalar infusion (30 pmol per side) of Tat-P4 interfered with reinstatement. Reinstatement increased the association between protein phosphatase 2A (PP2A) and the β3 subunit of the GABA(A)R, which was abolished by PP1/PP2A inhibitors okadaic acid and calyculin A. These results suggest the involvement of β-adrenergic receptor activation and GABA(A) receptor endocytosis in the amygdala for the reinstatement in fear memory.

  8. Post-training reversible inactivation of the rat’s basolateral amygdala interferes with hippocampus-dependent place avoidance memory in a time-dependent manner

    Czech Academy of Sciences Publication Activity Database

    Vafaei, A. A.; Ježek, Karel; Bureš, Jan; Fenton, André Antonio; Rashidy-Pour, A.

    2007-01-01

    Roč. 88, č. 1 (2007), s. 87-93 ISSN 1074-7427 R&D Projects: GA ČR(CZ) GA309/06/1231; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA ČR(CZ) GA309/97/0555; GA ČR(CZ) GA309/00/1656 Grant - others:-(XE) QLG3-CT-1999-00192; -(XE) 98-38 CNS-QUA.05 Institutional research plan: CEZ:AV0Z50110509 Keywords : avoidance * memory * amygdala Subject RIV: FH - Neurology Impact factor: 3.443, year: 2007

  9. Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats.

    Science.gov (United States)

    Ardeshiri, Motahareh Rouhi; Hosseinmardi, Narges; Akbari, Esmaeil

    2018-03-01

    Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus-dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Neuropeptide S-mediated facilitation of synaptic transmission enforces subthreshold theta oscillations within the lateral amygdala.

    Directory of Open Access Journals (Sweden)

    Susanne Meis

    Full Text Available The neuropeptide S (NPS receptor system modulates neuronal circuit activity in the amygdala in conjunction with fear, anxiety and the expression and extinction of previously acquired fear memories. Using in vitro brain slice preparations of transgenic GAD67-GFP (Δneo mice, we investigated the effects of NPS on neural activity in the lateral amygdala as a key region for the formation and extinction of fear memories. We are able to demonstrate that NPS augments excitatory glutamatergic synaptic input onto both projection neurons and interneurons of the lateral amygdala, resulting in enhanced spike activity of both types of cells. These effects were at least in part mediated by presynaptic mechanisms. In turn, inhibition of projection neurons by local interneurons was augmented by NPS, and subthreshold oscillations were strengthened, leading to their shift into the theta frequency range. These data suggest that the multifaceted effects of NPS on amygdaloid circuitry may shape behavior-related network activity patterns in the amygdala and reflect the peptide's potent activity in various forms of affective behavior and emotional memory.

  11. Eyes wide shut: amygdala mediates eyes-closed effect on emotional experience with music.

    Science.gov (United States)

    Lerner, Yulia; Papo, David; Zhdanov, Andrey; Belozersky, Libi; Hendler, Talma

    2009-07-15

    The perceived emotional value of stimuli and, as a consequence the subjective emotional experience with them, can be affected by context-dependent styles of processing. Therefore, the investigation of the neural correlates of emotional experience requires accounting for such a variable, a matter of an experimental challenge. Closing the eyes affects the style of attending to auditory stimuli by modifying the perceptual relationship with the environment without changing the stimulus itself. In the current study, we used fMRI to characterize the neural mediators of such modification on the experience of emotionality in music. We assumed that closed eyes position will reveal interplay between different levels of neural processing of emotions. More specifically, we focused on the amygdala as a central node of the limbic system and on its co-activation with the Locus Ceruleus (LC) and Ventral Prefrontal Cortex (VPFC); regions involved in processing of, respectively, 'low', visceral-, and 'high', cognitive-related, values of emotional stimuli. Fifteen healthy subjects listened to negative and neutral music excerpts with eyes closed or open. As expected, behavioral results showed that closing the eyes while listening to emotional music resulted in enhanced rating of emotionality, specifically of negative music. In correspondence, fMRI results showed greater activation in the amygdala when subjects listened to the emotional music with eyes closed relative to eyes open. More so, by using voxel-based correlation and a dynamic causal model analyses we demonstrated that increased amygdala activation to negative music with eyes closed led to increased activations in the LC and VPFC. This finding supports a system-based model of perceived emotionality in which the amygdala has a central role in mediating the effect of context-based processing style by recruiting neural operations involved in both visceral (i.e. 'low') and cognitive (i.e. 'high') related processes of emotions.

  12. Eyes wide shut: amygdala mediates eyes-closed effect on emotional experience with music.

    Directory of Open Access Journals (Sweden)

    Yulia Lerner

    Full Text Available The perceived emotional value of stimuli and, as a consequence the subjective emotional experience with them, can be affected by context-dependent styles of processing. Therefore, the investigation of the neural correlates of emotional experience requires accounting for such a variable, a matter of an experimental challenge. Closing the eyes affects the style of attending to auditory stimuli by modifying the perceptual relationship with the environment without changing the stimulus itself. In the current study, we used fMRI to characterize the neural mediators of such modification on the experience of emotionality in music. We assumed that closed eyes position will reveal interplay between different levels of neural processing of emotions. More specifically, we focused on the amygdala as a central node of the limbic system and on its co-activation with the Locus Ceruleus (LC and Ventral Prefrontal Cortex (VPFC; regions involved in processing of, respectively, 'low', visceral-, and 'high', cognitive-related, values of emotional stimuli. Fifteen healthy subjects listened to negative and neutral music excerpts with eyes closed or open. As expected, behavioral results showed that closing the eyes while listening to emotional music resulted in enhanced rating of emotionality, specifically of negative music. In correspondence, fMRI results showed greater activation in the amygdala when subjects listened to the emotional music with eyes closed relative to eyes open. More so, by using voxel-based correlation and a dynamic causal model analyses we demonstrated that increased amygdala activation to negative music with eyes closed led to increased activations in the LC and VPFC. This finding supports a system-based model of perceived emotionality in which the amygdala has a central role in mediating the effect of context-based processing style by recruiting neural operations involved in both visceral (i.e. 'low' and cognitive (i.e. 'high' related processes

  13. Posterodorsal Medial Amygdala Mediates Tail-Pinch Induced Food Intake in Female Rats.

    Science.gov (United States)

    Hu, M H; Bashir, Z; Li, X F; O'Byrne, K T

    2016-05-01

    Comfort eating during periods of stress is a common phenomenon observed in both animals and humans. However, the underlying mechanisms of stress-induced food intake remain elusive. The amygdala plays a central role in higher-order emotional processing and the posterodorsal subnucleus of the medial amygdala (MePD), in particular, is involved in food intake. Extra-hypothalamic corticotrophin-releasing factor (CRF) is well recognised for mediating behavioural responses to stress. To explore the possible role of amygdala CRF receptor activation in stress-induced food intake, we evaluated whether a stressor such as tail-pinch, which reliably induces food intake, would fail to do so in animals bearing bilateral neurotoxic lesions of the MePD. Our results showed that ibotenic acid induced lesions of the MePD markedly reduced tail-pinch induced food intake in ovariectomised, 17β-oestradiol replaced rats. In addition, intra-MePD (right side only) administration of CRF (0.002 or 0.02 ng) via chronically implanted cannulae resulted in a dose-dependent increase in food intake, although higher doses of 0.2 and 2 ng CRF had less effect, producing a bell shaped curve. Furthermore, intra-MePD (bilateral) administration of the CRF receptor antagonist, astressin (0.3 μg per side) effectively blocked tail-pinch induced food intake. These data suggest that the MePD is involved in stress-induced food intake and that the amygdala CRF system may be a mediator of comfort eating. © 2016 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.

  14. Basolateral P2X receptors mediate inhibition of NaCl transport in mouse medullary thick ascending limb (mTAL)

    DEFF Research Database (Denmark)

    Marques, Rita D; de Bruijn, Pauline I.A.; Sørensen, Mads Vaarby

    2012-01-01

    the ATP-induced inhibition of transport was reduced. A comprehensive molecular search identified P2X(4), P2X(5) and P2X(1) receptor subunit mRNA in isolated mouse mTALs. These data define that basolateral ATP exerts a significant inhibition of Na(+) absorption in mouse mTAL. Pharmacological, molecular......Extracellular nucleotides regulate epithelial transport via luminal and basolateral P2 receptors. Renal epithelia express multiple P2 receptors, which mediate significant inhibition of solute absorption. Recently, we identified several P2 receptors in the medullary thick ascending limb (m......-stimulated mTALs transported at a rate of 1197 ± 104 µA/cm(2) (n=10), which was completely blockable with luminal furosemide (100 µM). Basolateral ATP (100 µM) acutely (1 minute) and reversibly reduced the absorptive I'(sc). After 2 minutes the reduction amounted to 24.4 ± 4.0% (n=10). The non-selective P2...

  15. Identification of a novel gene regulating amygdala-mediated fear extinction.

    Science.gov (United States)

    Gunduz-Cinar, Ozge; Brockway, Emma; Lederle, Lauren; Wilcox, Troy; Halladay, Lindsay R; Ding, Ying; Oh, Hyunjung; Busch, Erica F; Kaugars, Katie; Flynn, Shaun; Limoges, Aaron; Bukalo, Olena; MacPherson, Kathryn P; Masneuf, Sophie; Pinard, Courtney; Sibille, Etienne; Chesler, Elissa J; Holmes, Andrew

    2018-01-08

    Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders.

  16. Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist produces anxiolytic-like effects and reverses abnormal firing activity of projection neurons in the basolateral nucleus of the amygdala in rats with bilateral 6-OHDA lesions.

    Science.gov (United States)

    Chen, Li; Liu, Jian; Ali, Umar; Gui, Zhen Hua; Hou, Chen; Fan, Ling Ling; Wang, Yong; Wang, Tao

    2011-02-28

    Although 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, improves the motor symptoms of Parkinson's disease (PD), the effects of MPEP on the psychiatric symptom of PD and the mechanism involved are still unclear. In the present study, we examined the effects of MPEP in anxiolytic-like behavior and firing activity of projection neurons in the basolateral nucleus of the amygdala (BLA) in rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum. Rats were divided into three groups, sham-operated group, 6-OHDA lesion with vehicle treatment group and 6-OHDA lesion with MPEP treatment group. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 31.5% loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the SNpc. The 6-OHDA-lesioned rats showed anxiety behavior and the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and no difference was found in the firing pattern of these neurons. Whereas chronic, systemic treatment of MPEP (3 mg/kg/day, i.p.; 14 days) attenuated loss of TH-ir neurons, produced anxiolytic-like effect and normalized the abnormal firing rate of projection neurons of the BLA in rats with the bilateral lesions. Systemic administration of cumulative apomorphine (10-160 μg/kg, i.v.) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA lesion with vehicle-treated and MPEP-treated rats, but the 6-OHDA lesion decreased the response of BLA projection neurons to apomorphine stimulation, while MPEP reversed the reactivity of these neurons. These data demonstrate that the partial lesion of the nigrostriatal pathway causes anxiety symptom and decreases firing rate of BLA projection neurons in the rat. Furthermore, chronic, systemic MPEP treatment has the neuroprotective and anxiolytic-like effects, and reverses the abnormal firing rate of BLA projection neurons, suggesting that MPEP has important

  17. Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning.

    Science.gov (United States)

    Tye, Kay M; Stuber, Garret D; de Ridder, Bram; Bonci, Antonello; Janak, Patricia H

    2008-06-26

    What neural changes underlie individual differences in goal-directed learning? The lateral amygdala (LA) is important for assigning emotional and motivational significance to discrete environmental cues, including those that signal rewarding events. Recognizing that a cue predicts a reward enhances an animal's ability to acquire that reward; however, the cellular and synaptic mechanisms that underlie cue-reward learning are unclear. Here we show that marked changes in both cue-induced neuronal firing and input-specific synaptic strength occur with the successful acquisition of a cue-reward association within a single training session. We performed both in vivo and ex vivo electrophysiological recordings in the LA of rats trained to self-administer sucrose. We observed that reward-learning success increased in proportion to the number of amygdala neurons that responded phasically to a reward-predictive cue. Furthermore, cue-reward learning induced an AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated increase in the strength of thalamic, but not cortical, synapses in the LA that was apparent immediately after the first training session. The level of learning attained by individual subjects was highly correlated with the degree of synaptic strength enhancement. Importantly, intra-LA NMDA (N-methyl-d-aspartate)-receptor blockade impaired reward-learning performance and attenuated the associated increase in synaptic strength. These findings provide evidence of a connection between LA synaptic plasticity and cue-reward learning, potentially representing a key mechanism underlying goal-directed behaviour.

  18. Stress hormones receptors in the amygdala mediate the effects of stress on the consolidation, but not the retrieval, of a non aversive spatial task.

    Directory of Open Access Journals (Sweden)

    Amir Segev

    Full Text Available This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level or extensive prior habituation (reduced novelty stress/arousal level. Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side, a glucocorticoid receptor (GR antagonist, or propranolol (0.75 µg/side, a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA, prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas, and (iii the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive.

  19. Stress hormones receptors in the amygdala mediate the effects of stress on the consolidation, but not the retrieval, of a non aversive spatial task.

    Science.gov (United States)

    Segev, Amir; Ramot, Assaf; Akirav, Irit

    2012-01-01

    This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 µg/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive).

  20. Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1

    Directory of Open Access Journals (Sweden)

    Neugebauer Volker

    2010-12-01

    Full Text Available Abstract Neuroplasticity in the central nucleus of the amygdala (CeA, particularly its latero-capsular division (CeLC, is an important contributor to the emotional-affective aspects of pain. Previous studies showed synaptic plasticity of excitatory transmission to the CeLC in different pain models, but pain-related changes of inhibitory transmission remain to be determined. The CeLC receives convergent excitatory inputs from the parabrachial nucleus in the brainstem and from the basolateral amygdala (BLA. In addition, feedforward inhibition of CeA neurons is driven by glutamatergic projections from the BLA area to a cluster of GABAergic neurons in the intercalated cell masses (ITC. Using patch-clamp in rat brain slices we measured monosynaptic excitatory postsynaptic currents (EPSCs and polysynaptic inhibitory currents (IPSCs that were evoked by electrical stimulation in the BLA. In brain slices from arthritic rats, input-output functions of excitatory synaptic transmission were enhanced whereas inhibitory synaptic transmission was decreased compared to control slices from normal untreated rats. A non-NMDA receptor antagonist (NBQX blocked the EPSCs and reduced the IPSCs, suggesting that non-NMDA receptors mediate excitatory transmission and also contribute to glutamate-driven feed-forward inhibition of CeLC neurons. IPSCs were blocked by a GABAA receptor antagonist (bicuculline. Bicuculline increased EPSCs under normal conditions but not in slices from arthritic rats, which indicates a loss of GABAergic control of excitatory transmission. A metabotropic glutamate receptor subtype 1 (mGluR1 antagonist (LY367385 reversed both the increase of excitatory transmission and the decrease of inhibitory transmission in the arthritis pain model but had no effect on basal synaptic transmission in control slices from normal rats. The inhibitory effect of LY367385 on excitatory transmission was blocked by bicuculline suggesting the involvement of a GABAergic

  1. Individual Differences in Animal Stress Models: Considering Resilience, Vulnerability, and the Amygdala in Mediating the Effects of Stress and Conditioned Fear on Sleep.

    Science.gov (United States)

    Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y; Sutton, Amy M; Williams, Brook L; Sanford, Larry D

    2016-06-01

    To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep. Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 μM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX). REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal. Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability. © 2016 Associated Professional Sleep Societies, LLC.

  2. Amygdala opioid receptors mediate the electroacupuncture-induced deterioration of sleep disruptions in epilepsy rats.

    Science.gov (United States)

    Yi, Pei-Lu; Lu, Chin-Yu; Cheng, Chiung-Hsiang; Tsai, Yi-Fong; Lin, Chung-Tien; Chang, Fang-Chia

    2013-11-12

    Clinical and experimental evidence demonstrates that sleep and epilepsy reciprocally affect each other. Previous studies indicated that epilepsy alters sleep homeostasis; in contrast, sleep disturbance deteriorates epilepsy. If a therapy possesses both epilepsy suppression and sleep improvement, it would be the priority choice for seizure control. Effects of acupuncture of Feng-Chi (GB20) acupoints on epilepsy suppression and insomnia treatment have been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot). Therefore, this study was designed to investigate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi acupoints on sleep disruptions in rats with focal epilepsy. Our result indicates that administration of pilocarpine into the left central nucleus of amygdala (CeA) induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep. High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints, in which a 30-min EA stimulation was performed before the dark period of the light:dark cycle in three consecutive days, further deteriorated pilocarpine-induced sleep disruptions. The EA-induced exacerbation of sleep disruption was blocked by microinjection of naloxone, μ- (naloxonazine), κ- (nor-binaltorphimine) or δ-receptor antagonists (natrindole) into the CeA, suggesting the involvement of amygdaloid opioid receptors. The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints exhibits no benefit in improving pilocarpine-induced sleep disruptions; in contrast, EA further deteriorated sleep disturbances. Opioid receptors in the CeA mediated EA-induced exacerbation of sleep disruptions in epileptic rats.

  3. Oxytocin differentially alters resting state functional connectivity between amygdala subregions and emotional control networks: Inverse correlation with depressive traits.

    Science.gov (United States)

    Eckstein, Monika; Markett, Sebastian; Kendrick, Keith M; Ditzen, Beate; Liu, Fang; Hurlemann, Rene; Becker, Benjamin

    2017-04-01

    The hypothalamic neuropeptide oxytocin (OT) has received increasing attention for its role in modulating social-emotional processes across species. Previous studies on using intranasal-OT in humans point to a crucial engagement of the amygdala in the observed neuromodulatory effects of OT under task and rest conditions. However, the amygdala is not a single homogenous structure, but rather a set of structurally and functionally heterogeneous nuclei that show distinct patterns of connectivity with limbic and frontal emotion-processing regions. To determine potential differential effects of OT on functional connectivity of the amygdala subregions, 79 male participants underwent resting-state fMRI following randomized intranasal-OT or placebo administration. In line with previous studies OT increased the connectivity of the total amygdala with dorso-medial prefrontal regions engaged in emotion regulation. In addition, OT enhanced coupling of the total amygdala with cerebellar regions. Importantly, OT differentially altered the connectivity of amygdala subregions with distinct up-stream cortical nodes, particularly prefrontal/parietal, and cerebellar down-stream regions. OT-induced increased connectivity with cerebellar regions were largely driven by effects on the centromedial and basolateral subregions, whereas increased connectivity with prefrontal regions were largely mediated by right superficial and basolateral subregions. OT decreased connectivity of the centromedial subregions with core hubs of the emotional face processing network in temporal, occipital and parietal regions. Preliminary findings suggest that effects on the superficial amygdala-prefrontal pathway were inversely associated with levels of subclinical depression, possibly indicating that OT modulation may be blunted in the context of increased pathological load. Together, the present findings suggest a subregional-specific modulatory role of OT on amygdala-centered emotion processing networks in

  4. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

    Science.gov (United States)

    Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

    2016-10-01

    Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Basomedial amygdala mediates top–down control of anxiety and fear

    Science.gov (United States)

    Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Mirzabekov, Julie J.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl

    2016-01-01

    Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway. PMID:26536109

  6. CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine.

    Science.gov (United States)

    Ecke, Laurel E; Cleck, Jessica N; White, Peter; Schug, Jonathan; Mifflin, Lauren; Blendy, Julie A

    2011-09-01

    The neuronal circuitry underlying stress- and drug-induced reinstatement of cocaine-seeking has been relatively well characterized; however, less is known regarding the long-term molecular changes following cocaine administration that may promote future reinstatement. The transcription factor cAMP response element-binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned reward, suggesting that different molecular mechanisms may underlie these two types of reinstatement. To explore the relationship between this transcription factor and reinstatement, we utilized the place-conditioning paradigm to examine alterations in gene expression in the amygdala, a neural substrate critically involved in stress-induced reinstatement, following the development of cocaine reward and subsequent extinction. Our findings demonstrate that the amygdala transcriptome was altered by CREB deficiency more than by previous cocaine experience, with an over-representation of genes involved in the immune response. However, a subset of genes involved in stress and immune response demonstrated a drug×genotype interaction, indicating that cocaine produces different long-term alterations in gene expression depending on the presence or absence of CREB. This profile of gene expression in the context of addiction enhances our understanding of the long-term molecular changes that occur throughout the addiction cycle and identifies novel genes and pathways that might lead to the creation of better therapeutic agents.

  7. Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

    NARCIS (Netherlands)

    McReynolds, Jayme R.; Donowho, Kyle; Abdi, Amin; McGaugh, James L.; Roozendaal, Benno; McIntyre, Christa K.

    Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a

  8. Mediation of the relationship between callous-unemotional traits and proactive aggression by amygdala response to fear among children with conduct problems.

    Science.gov (United States)

    Lozier, Leah M; Cardinale, Elise M; VanMeter, John W; Marsh, Abigail A

    2014-06-01

    Among youths with conduct problems, callous-unemotional (CU) traits are known to be an important determinant of symptom severity, prognosis, and treatment responsiveness. But positive correlations between conduct problems and CU traits result in suppressor effects that may mask important neurobiological distinctions among subgroups of children with conduct problems. To assess the unique neurobiological covariates of CU traits and externalizing behaviors in youths with conduct problems and determine whether neural dysfunction linked to CU traits mediates the link between callousness and proactive aggression. This cross-sectional case-control study involved behavioral testing and neuroimaging that were conducted at a university research institution. Neuroimaging was conducted using a 3-T Siemens magnetic resonance imaging scanner. It included 46 community-recruited male and female juveniles aged 10 to 17 years, including 16 healthy control participants and 30 youths with conduct problems with both low and high levels of CU traits. Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging during an implicit face-emotion processing task and analyzed using whole-brain and region of interest-based analysis of variance and multiple-regression analyses. Analysis of variance revealed no group differences in the amygdala. By contrast, consistent with the existence of suppressor effects, multiple-regression analysis found amygdala responses to fearful expressions to be negatively associated with CU traits (x = 26, y = 0, z = -12; k = 1) and positively associated with externalizing behavior (x = 24, y = 0, z = -14; k = 8) when both variables were modeled simultaneously. Reduced amygdala responses mediated the relationship between CU traits and proactive aggression. The results linked proactive aggression in youths with CU traits to hypoactive amygdala responses to emotional distress cues, consistent with theories that externalizing

  9. Amygdala electrical stimulation inducing spatial memory recovery produces an increase of hippocampal bdnf and arc gene expression.

    Science.gov (United States)

    Mercerón-Martínez, D; Almaguer-Melian, W; Alberti-Amador, E; Estupiñán, B; Fernández, I; Bergado, J A

    2016-06-01

    Amygdala seems to promote the consolidation of plastic modification in different brain areas and these long-term brain changes require a rapid de novo RNA and protein synthesis. We have previously shown that basolateral amygdala electrical stimulation produces a partial recovery of spatial memory in fimbria-fornix lesioned animals and it is also able to increase the BDNF protein content in the hippocampus. The emerging question is whether these increased BDNF protein content arises from previously synthesized RNA or from de novo RNA expression. Now we address the question if amygdala electrical stimulation 15min after daily water maze training produces a rapid de novo RNA synthesis in the hippocampus, a critical brain area for spatial memory recovery in fimbria-fornix lesioned animals. In addition, we also study RNA arc expression, a gene which is essential for memory and neural plasticity processes. To this purpose, we study amygdala stimulation effects on the expression of plasticity related-early-genes bdnf and arc in the hippocampus of fimbria-fornix lesioned animals trained in a water-maze for 4days. We also checked on the expression of both genes in non-lesioned, untrained animals (acute condition) at 0.5, 1, 2 and 24h after basolateral amygdala electrical stimulation. Our data from trained animals confirm that daily amygdala electrical stimulation 15min after water maze training produces a partial memory recovery and that is coupled to an increase of bdnf and arc genes expression in the hippocampus. Additionally, the acute study shows that a single session of amygdala stimulation induces a transient increase of both genes (peaking at 30min). These results confirm the memory improving effect of amygdala stimulation in fimbria-fornix-lesioned animals and sustain the assumption that the memory improving effect is mediated by newly synthetized BDNF acting on a memory relevant structure like the hippocampus. The increased amount of BDNF within the hippocampus

  10. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    Science.gov (United States)

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  11. Post-Training Unilateral Amygdala Lesions Selectively Impair Contextual Fear Memories

    Science.gov (United States)

    Flavell, Charlotte R.; Lee, Jonathan L. C.

    2012-01-01

    The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what…

  12. The Amygdala Is Not Necessary for Unconditioned Stimulus Inflation after Pavlovian Fear Conditioning in Rats

    Science.gov (United States)

    Rabinak, Christine A.; Orsini, Caitlin A.; Zimmerman, Joshua M.; Maren, Stephen

    2009-01-01

    The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian conditioning. However, the precise role for these structures in Pavlovian conditioning is not clear. Recent work in appetitive conditioning paradigms suggests that the amygdala, particularly the BLA, has an…

  13. Developmental exposure to an environmental PCB mixture delays the propagation of electrical kindling from the amygdala.

    Science.gov (United States)

    Bandara, Suren B; Sadowski, Renee N; Schantz, Susan L; Gilbert, Mary E

    2017-01-01

    Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6mg/kg/day of the PCB mixture dissolved in corn oil vehicle 4 weeks prior to mating and continued through gestation and up until postnatal day (PND) 21. On PND 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200μA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating attenuated focal (amygdala) excitability. A delay in kindling progression in the amygdala stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed animals in response to a an intense auditory stimulus. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that

  14. Fear potentiated startle increases phospholipase D (PLD) expression/activity and PLD-linked metabotropic glutamate receptor mediated post-tetanic potentiation in rat amygdala.

    Science.gov (United States)

    Krishnan, Balaji; Scott, Michael T; Pollandt, Sebastian; Schroeder, Bradley; Kurosky, Alexander; Shinnick-Gallagher, Patricia

    2016-02-01

    Long-term memory (LTM) of fear stores activity dependent modifications that include changes in amygdala signaling. Previously, we identified an enhanced probability of release of glutamate mediated signaling to be important in rat fear potentiated startle (FPS), a well-established translational behavioral measure of fear. Here, we investigated short- and long-term synaptic plasticity in FPS involving metabotropic glutamate receptors (mGluRs) and associated downstream proteomic changes in the thalamic-lateral amygdala pathway (Th-LA). Aldolase A, an inhibitor of phospholipase D (PLD), expression was reduced, concurrent with significantly elevated PLD protein expression. Blocking the PLD-mGluR signaling significantly reduced PLD activity. While transmitter release probability increased in FPS, PLD-mGluR agonist and antagonist actions were occluded. In the unpaired group (UNP), blocking the PLD-mGluR increased while activating the receptor decreased transmitter release probability, consistent with decreased synaptic potentials during tetanic stimulation. FPS Post-tetanic potentiation (PTP) immediately following long-term potentiation (LTP) induction was significantly increased. Blocking PLD-mGluR signaling prevented PTP and reduced cumulative PTP probability but not LTP maintenance in both groups. These effects are similar to those mediated through mGluR7, which is co-immunoprecipitated with PLD in FPS. Lastly, blocking mGluR-PLD in the rat amygdala was sufficient to prevent behavioral expression of fear memory. Thus, our study in the Th-LA pathway provides the first evidence for PLD as an important target of mGluR signaling in amygdala fear-associated memory. Importantly, the PLD-mGluR provides a novel therapeutic target for treating maladaptive fear memories in posttraumatic stress and anxiety disorders. Published by Elsevier Inc.

  15. Anxiolytic-like effects after vector-mediated overexpression of neuropeptide Y in the amygdala and hippocampus of mice

    DEFF Research Database (Denmark)

    Christiansen, Søren Hofman Oliveira; Olesen, Mikkel Vestergaard; Gøtzsche, Casper René

    2014-01-01

    , injections of rAAV-NPY caused significant anxiolytic-like effect in the open field, elevated plus maze, and light-dark transition tests. In the hippocampus, rAAV-NPY treatment was associated with anxiolytic-like effect only in the elevated plus maze. No additive effect was observed after combined r......AAV-NPY injection into both the amygdala and hippocampus where anxiolytic-like effect was found in the elevated plus maze and light-dark transition tests. Antidepressant-like effects were not detected in any of the rAAV-NPY injected groups. Immobility was even increased in the tail suspension and forced swim tests...... after intra-amygdaloid rAAV-NPY. Taken together, the present data show that rAAV-NPY treatment may confer non-additive anxiolytic-like effect after injection into the amygdala or hippocampus, being most pronounced in the amygdala...

  16. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    Science.gov (United States)

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

  17. Pattern of distribution of serotonergic fibers to the amygdala and extended amygdala in the rat.

    Science.gov (United States)

    Linley, Stephanie B; Olucha-Bordonau, Francisco; Vertes, Robert P

    2017-01-01

    As is well recognized, serotonergic (5-HT) fibers distribute widely throughout the forebrain, including the amygdala. Although a few reports have examined the 5-HT innervation of select nuclei of the amygdala in the rat, no previous report has described overall 5-HT projections to the amygdala in the rat. Using immunostaining for the serotonin transporter, SERT, we describe the complete pattern of distribution of 5-HT fibers to the amygdala (proper) and to the extended amygdala in the rat. Based on its ontogenetic origins, the amygdala was subdivided into two major parts, pallial and subpallial components, with the pallial component further divided into superficial and deep nuclei (Olucha-Bordonau et al. 2015). SERT + fibers were shown to distributed moderately to densely to the deep and cortical pallial nuclei, but, by contrast, lightly to the subpallial nuclei. Specifically, 1) of the deep pallial nuclei, the lateral, basolateral, and basomedial nuclei contained a very dense concentration of 5-HT fibers; 2) of the cortical pallial nuclei, the anterior cortical and amygdala-cortical transition zone rostrally and the posteromedial and posterolateral nuclei caudally contained a moderate concentration of 5-HT fibers; and 3) of the subpallial nuclei, the anterior nuclei and the rostral part of the medial (Me) nuclei contained a moderate concentration of 5-HT fibers, whereas caudal regions of Me as well as the central nuclei and the intercalated nuclei contained a sparse/light concentration of 5-HT fibers. With regard to the extended amygdala (primarily the bed nucleus of stria terminalis; BST), on the whole, the BST contained moderate numbers of 5-HT fibers, spread fairly uniformly throughout BST. The findings are discussed with respect to a critical serotonergic influence on the amygdala, particularly on the basal complex, and on the extended amygdala in the control of states of fear and anxiety. J. Comp. Neurol. 525:116-139, 2017. © 2016 Wiley Periodicals, Inc.

  18. Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala.

    Science.gov (United States)

    Jensen, Morten; Ratner, Cecilia; Rudenko, Olga; Christiansen, Søren H; Skov, Louise J; Hundahl, Cecilie; Woldbye, David P D; Holst, Birgitte

    2016-05-01

    Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff-induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  19. NMDA receptors in the avian amygdala and the premotor arcopallium mediate distinct aspects of appetitive extinction learning.

    Science.gov (United States)

    Gao, Meng; Lengersdorf, Daniel; Stüttgen, Maik C; Güntürkün, Onur

    2018-05-02

    Extinction learning is an essential mechanism that enables constant adaptation to ever-changing environmental conditions. The underlying neural circuit is mostly studied with rodent models using auditory cued fear conditioning. In order to uncover the variant and the invariant neural properties of extinction learning, we adopted pigeons as an animal model in an appetitive sign-tracking paradigm. The animals firstly learned to respond to two conditioned stimuli in two different contexts (CS-1 in context A and CS-2 in context B), before conditioned responses to the stimuli were extinguished in the opposite contexts (CS-1 in context B and CS-2 in context A). Subsequently, responding to both stimuli was tested in both contexts. Prior to extinction training, we locally injected the N-methyl-d-aspartate receptor (NMDAR) antagonist 2-Amino-5-phosphonovaleric acid (APV) in either the amygdala or the (pre)motor arcopallium to investigate their involvement in extinction learning. Our findings suggest that the encoding of extinction memory required the activation of amygdala, as visible by an impairment of extinction acquisition by concurrent inactivation of local NMDARs. In contrast, consolidation and subsequent retrieval of extinction memory recruited the (pre)motor arcopallium. Also, the inactivation of arcopallial NMDARs induced a general motoric slowing during extinction training. Thus, our results reveal a double dissociation between arcopallium and amygdala with respect to acquisition and consolidation of extinction, respectively. Our study therefore provides new insights on the two key components of the avian extinction network and their resemblance to the data obtained from mammals, possibly indicating a shared neural mechanism underlying extinction learning shaped by evolution. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

    Science.gov (United States)

    Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

    2016-09-01

    Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  1. Synapse-specific astrocyte gating of amygdala-related behavior.

    Science.gov (United States)

    Martin-Fernandez, Mario; Jamison, Stephanie; Robin, Laurie M; Zhao, Zhe; Martin, Eduardo D; Aguilar, Juan; Benneyworth, Michael A; Marsicano, Giovanni; Araque, Alfonso

    2017-11-01

    The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A 1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A 2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.

  2. Increased anxiety-like behavior and enhanced synaptic efficacy in the amygdala of GluR5 knockout mice.

    Directory of Open Access Journals (Sweden)

    Long-Jun Wu

    2007-01-01

    Full Text Available GABAergic transmission in the amygdala modulates the expression of anxiety. Understanding the interplay between GABAergic transmission and excitatory circuits in the amygdala is, therefore, critical for understanding the neurobiological basis of anxiety. Here, we used a multi-disciplinary approach to demonstrate that GluR5-containing kainate receptors regulate local inhibitory circuits, modulate the excitatory transmission from the basolateral amygdala to the central amygdala, and control behavioral anxiety. Genetic deletion of GluR5 or local injection of a GluR5 antagonist into the basolateral amygdala increases anxiety-like behavior. Activation of GluR5 selectively depolarized inhibitory neurons, thereby increasing GABA release and contributing to tonic GABA current in the basolateral amygdala. The enhanced GABAergic transmission leads to reduced excitatory inputs in the central amygdala. Our results suggest that GluR5 is a key regulator of inhibitory circuits in the amygdala and highlight the potential use of GluR5-specific drugs in the treatment of pathological anxiety.

  3. Testosterone reduces amygdala-orbitofrontal cortex coupling.

    NARCIS (Netherlands)

    Wingen, G.A. van; Mattern, C.; Verkes, R.J.; Buitelaar, J.K.; Fernandez, G.S.E.

    2010-01-01

    Testosterone influences various aspects of affective behavior, which is mediated by different brain regions within the emotion circuitry. Previous neuroimaging studies have demonstrated that testosterone increases neural activity in the amygdala. To investigate whether this could be due to altered

  4. Testosterone reduces amygdala-orbitofrontal cortex coupling

    NARCIS (Netherlands)

    van Wingen, Guido; Mattern, Claudia; Verkes, Robbert Jan; Buitelaar, Jan; Fernández, Guillén

    2010-01-01

    Testosterone influences various aspects of affective behavior, which is mediated by different brain regions within the emotion circuitry. Previous neuroimaging studies have demonstrated that testosterone increases neural activity in the amygdala. To investigate whether this could be due to altered

  5. Electrogenic Na+-independent Pi transport in canine renal basolateral membrane vesicles

    Energy Technology Data Exchange (ETDEWEB)

    Schwab, S.J.; Hammerman, M.R.

    1986-03-01

    To define the mechanism by which Pi exists from the renal proximal tubular cell across the basolateral membrane, we measured 32Pi uptake in basolateral membrane vesicles from dog kidney in the absence of Na+. Preloading of basolateral vesicles with 2 mM Pi transstimulated 32Pi uptake, which is consistent with counterflow. We used measurements of transstimulation to quantitate the transport component of 32Pi uptake. Transstimulation of 32Pi uptake was inhibited less than 30% by concentrations of probenecid as high as 50 mM. In contrast, transstimulation of 35SO4(2-) uptake by intravesicular SO4(2-) was inhibited 92% by 5 mM probenecid. Preloading basolateral vesicles with SO4(2-) did not result in transstimulation of 32Pi uptake. Accumulation of 32Pi in basolateral vesicles above steady state was driven by a membrane potential (intravesicular positive), consistent with Na+-independent Pi transport being accompanied by the net transfer of negative charge across the membrane. We conclude that carrier-mediated, electrogenic Na+-independent 32Pi transport can be demonstrated in basolateral vesicles from dog kidney. This process appears to be mediated, at least in part, via a mechanism different from that by which SO4(2-) is transported. Electrogenic Na+-independent Pi transport may reflect one means by which Pi reabsorbed across the luminal membrane exists from the proximal tubular cell down an electrochemical gradient.

  6. The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining.

    Science.gov (United States)

    Zimmerman, Joshua M; Rabinak, Christine A; McLachlan, Ian G; Maren, Stephen

    2007-09-01

    The basolateral complex of the amygdala (BLA) is critical for the acquisition and expression of Pavlovian fear conditioning in rats. Nonetheless, rats with neurotoxic BLA lesions can acquire conditional fear after overtraining (75 trials). The capacity of rats with BLA lesions to acquire fear memory may be mediated by the central nucleus of the amygdala (CEA). To examine this issue, we examined the influence of neurotoxic CEA lesions or reversible inactivation of the CEA on the acquisition and expression of conditional freezing after overtraining in rats. Rats with pretraining CEA lesions (whether alone or in combination with BLA lesions) did not acquire conditional freezing to either the conditioning context or an auditory conditional stimulus after extensive overtraining. Similarly, post-training lesions of the CEA or BLA prevented the expression of overtrained fear. Lastly, muscimol infusions into the CEA prevented both the acquisition and the expression of overtrained fear, demonstrating that the effects of CEA lesions are not likely due to the destruction of en passant axons. These results suggest that the CEA is essential for conditional freezing after Pavlovian fear conditioning. Moreover, overtraining may engage a compensatory fear conditioning circuit involving the CEA in animals with damage to the BLA.

  7. Tonic inhibition by orphanin FQ/nociceptin of noradrenaline neurotransmission in the amygdala

    NARCIS (Netherlands)

    Kawahara, Y; Hesselink, M.B.; van Scharrenburg, G; Westerink, B.H.C.

    2004-01-01

    The present microdialysis study investigated whether nociceptin/orphanin FQ exerts a tonic inhibition of the release of noradrenaline in the basolateral nucleus of the amygdala in awake rats. The non-peptide competitive nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist J-113397 (20 mg/kg

  8. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  9. Context Pre-Exposure Obscures Amygdala Modulation of Contextual-Fear Conditioning

    Science.gov (United States)

    Huff, Nicole C.; Wright-Hardesty, Karli J.; Higgins, Emily A.; Matus-Amat, Patricia; Rudy, Jerry W.

    2005-01-01

    We report that post-training inactivation of basolateral amygdala region (BLA) with muscimol impaired memory for contextual-fear conditioning (as measured by freezing) and intra-BLA norepinephrine enhanced this memory. However, pre-exposure to the context eliminated both of these effects. These findings provide a likely explanation of why an…

  10. Radiofrequency electromagnetic radiation exposure effects on amygdala morphology, place preference behavior and brain caspase-3 activity in rats.

    Science.gov (United States)

    Narayanan, Sareesh Naduvil; Mohapatra, Nirupam; John, Pamala; K, Nalini; Kumar, Raju Suresh; Nayak, Satheesha B; Bhat, P Gopalakrishna

    2018-03-01

    The purpose of the study was to evaluate the changes in amygdala morphology and emotional behaviors, upon exposure to chronic RF-EMR in adolescent rats. Four weeks old male albino Wistar rats were exposed to 900 MHz (power density:146.60 μW/cm2) from a mobile phone in silent-mode for 28 days. Amygdala morphology was studied using cresyl violet, TUNEL and Golgi-Cox staining. Place preference behavior was studied using light/dark chamber test and following this brain caspase-3 activity was determined. Number of healthy neurons was decreased in the basolateral amygdala and cortical amygdala but not in the central amygdala after RF-EMR exposure. It also induced apoptosis in the amygdala. RF-EMR exposure altered dendritic arborization pattern in basolateral amygdala but not in the central amygdala. Altered place preference and hyperactivity-like behavior was evident after RF-EMR exposure, but brain caspase-3 activity did not change. RF-EMR exposure perturbed normal cellular architecture of amygdala and this was associated with altered place preference. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Short-Term Adaptation of Conditioned Fear Responses Through Endocannabinoid Signaling in the Central Amygdala

    Science.gov (United States)

    Kamprath, Kornelia; Romo-Parra, Hector; Häring, Martin; Gaburro, Stefano; Doengi, Michael; Lutz, Beat; Pape, Hans-Christian

    2011-01-01

    The cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are both known to have crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. In this study we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol, no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA. Taken together, our data show the existence of CB1 proteins in the CeA, and their critical role for ensuring short-term adaptation of responses to fearful events, thereby suggesting a potential therapeutic target to accompany habituation-based therapies of post-traumatic symptoms. PMID:20980994

  12. The amygdala: securing pleasure and avoiding pain

    Directory of Open Access Journals (Sweden)

    Anushka B P Fernando

    2013-12-01

    Full Text Available The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food or aversive (e.g. electric shock. We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala’s mediation of both appetitive and fearful behavior through diverse psychological processes.

  13. Synaptic dysfunction in amygdala in intellectual disorder models.

    Science.gov (United States)

    Aincy, Marianne; Meziane, Hamid; Herault, Yann; Humeau, Yann

    2018-06-08

    The amygdala is a part of the limbic circuit that has been extensively studied in terms of synaptic connectivity, plasticity and cellular organization since decades (Ehrlich et al., 2009; Ledoux, 2000; Maren, 2001). Amygdala sub-nuclei, including lateral, basolateral and central amygdala appear now as "hubs" providing in parallel and in series neuronal processing enabling the animal to elicit freezing or escaping behavior in response to external threats. In rodents, these behaviors are easily observed and quantified following associative fear conditioning. Thus, studies on amygdala circuit in association with threat/fear behavior became very popular in laboratories and are often used among other behavioral tests to evaluate learning abilities of mouse models for various neuropsychiatric conditions including genetically encoded intellectual disabilities (ID). Yet, more than 100 human X-linked genes - and several hundreds of autosomal genes - have been associated with ID in humans. These mutations introduced in mice can generate social deficits, anxiety dysregulations and fear learning impairments (McNaughton et al., 2008; Houbaert et al., 2013; Jayachandran et al., 2014; Zhang et al., 2015). Noteworthy, a significant proportion of the coded ID gene products are synaptic proteins. It is postulated that the loss of function of these proteins could destabilize neuronal circuits by global changes of the balance between inhibitory and excitatory drives onto neurons. However, whereas amygdala related behavioral deficits are commonly observed in ID models, the role of most of these ID-genes in synaptic function and plasticity in the amygdala are only sparsely studied. We will here discuss some of the concepts that emerged from amygdala-targeted studies examining the role of syndromic and non-syndromic ID genes in fear-related behaviors and/or synaptic function. Along describing these cases, we will discuss how synaptic deficits observed in amygdala circuits could impact

  14. Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner.

    Science.gov (United States)

    Cannady, Reginald; Fisher, Kristen R; Graham, Caitlin; Crayle, Jesse; Besheer, Joyce; Hodge, Clyde W

    2017-05-01

    Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Accordingly, we have shown that glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in the amygdala is required for the positive reinforcing effects of alcohol, which underlie the initial stages of addiction. It is unknown, however, if enhanced AMPAR activity in the amygdala facilitates alcohol self-administration, which is a kernel premise of glutamate hypotheses of addiction. Here, we show that low-dose alcohol (0.6 g/kg/30 minutes) self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 (pGluA1 S831) in the central amygdala (CeA), basolateral amygdala and nucleus accumbens core (AcbC) of selectively bred alcohol-preferring P-rats as compared with behavior-matched (non-drug) sucrose controls. The functional role of enhanced AMPAR activity was assessed via site-specific infusion of the AMPAR positive modulator, aniracetam, in the CeA and AcbC prior to alcohol self-administration. Intra-CeA aniracetam increased alcohol-reinforced but not sucrose-reinforced responding and was ineffective following intra-AcbC infusion. Because GluA1 S831 is a Ca2+/calmodulin-dependent protein kinase II (CaMKII) substrate, we sought to determine if AMPAR regulation of enhanced alcohol self-administration is dependent on CaMKII activity. Intra-CeA infusion of the cell-permeable CaMKII peptide inhibitor myristolated autocamtide-2-related inhibitory peptide (m-AIP) dose-dependently reduced alcohol self-administration. A subthreshold dose of m-AIP also blocked the aniracetam-induced escalation of alcohol self-administration, demonstrating that AMPAR-mediated potentiation of alcohol reinforcement requires CaMKII activity in the amygdala. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling in the amygdala may promote escalated alcohol use

  15. Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics.

    Science.gov (United States)

    Lukas, Michael; Toth, Iulia; Veenema, Alexa H; Neumann, Inga D

    2013-06-01

    Brain oxytocin (OXT) plays an important role in short-term social memory in laboratory rodents. Here we monitored local release of OXT and its functional involvement in the maintenance and retrieval of social memory during the social discrimination test. We further assessed, if the local effects of OXT within the medial amygdala (MeA) and lateral septum (LS) on social discrimination abilities were dependent on the biological relevance of the social stimulus, thus comparing male juvenile versus adult female conspecifics. OXT release was increased in the LS of male rats during the retrieval, but not during the acquisition or maintenance, of social memory for male juvenile stimuli. Blockade of OXT activity by intracerebroventricular (ICV) administration of a specific OXT receptor antagonist (OXTR-A, rats: 0.75 μg/5 μl, mice: 2 μg/2 μl) immediately after acquisition of social memory impaired the maintenance of social memory, and consequently discrimination abilities during retrieval of social memory. In contrast, ICV OXTR-A was without effect when administered 20 min prior to retrieval of social memory in both species. Non-social memory measured in the object discrimination test was not affected by ICV OXTR-A in male mice, indicating that brain OXT is mainly required for memory formation in a social context. The biological relevance of the social stimulus seems to importantly determine social memory abilities, as male rats recognized a previously encountered female adult stimulus for at least 2h (versus 60 min for male juveniles), with a region-dependent contribution of endogenous OXT; while bilateral administration of OXTR-A into the MeA (0.1 μg/1 μl) impaired social memory for adult females only, administration of OXTR-A into the LS via retrodialysis (10 μg/ml, 1.0 μl/min) impaired social memory for both male juveniles and female adults. Overall, these results indicate that brain OXT is a critical mediator of social memory in male rodents and that, depending

  16. Unique insula subregion resting-state functional connectivity with amygdala complexes in posttraumatic stress disorder and its dissociative subtype.

    Science.gov (United States)

    Nicholson, Andrew A; Sapru, Iman; Densmore, Maria; Frewen, Paul A; Neufeld, Richard W J; Théberge, Jean; McKinnon, Margaret C; Lanius, Ruth A

    2016-04-30

    The insula and amygdala are implicated in the pathophysiology of posttraumatic stress disorder (PTSD), where both have been shown to be hyper/hypoactive in non-dissociative (PTSD-DS) and dissociative subtype (PTSD+DS) PTSD patients, respectively, during symptom provocation. However, the functional connectivity between individual insula subregions and the amygdala has not been investigated in persons with PTSD, with or without the dissociative subtype. We examined insula subregion (anterior, mid, and posterior) functional connectivity with the bilateral amygdala using a region-of-interest seed-based approach via PickAtlas and SPM8. Resting-state fMRI was conducted with (n=61) PTSD patients (n=44 PTSD-DS; n=17 PTSD+DS), and (n=40) age-matched healthy controls. When compared to controls, the PTSD-DS group displayed increased insula connectivity (bilateral anterior, bilateral mid, and left posterior) to basolateral amygdala clusters in both hemispheres, and the PTSD+DS group displayed increased insula connectivity (bilateral anterior, left mid, and left posterior) to the left basolateral amygdala complex. Moreover, as compared to PTSD-DS, increased insula subregion connectivity (bilateral anterior, left mid, and right posterior) to the left basolateral amygdala was found in PTSD+DS. Depersonalization/derealization symptoms and PTSD symptom severity correlated with insula subregion connectivity to the basolateral amygdala within PTSD patients. This study is an important first step in elucidating patterns of neural connectivity associated with unique symptoms of arousal/interoception, emotional processing, and awareness of bodily states, in PTSD and its dissociative subtype. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal

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    Marian L Logrip

    2014-04-01

    Full Text Available Alcohol use disorders are persistent problems with high recidivism rates despite repeated efforts to quit drinking. Neuroadaptations that result from alcohol exposure and that persist during periods of abstinence represent putative molecular determinants of the propensity to relapse. Previously we demonstrated a positive association between phosphodiesterase 10A (PDE10A gene expression and elevations in relapse-like alcohol self-administration in rats with a history of stress exposure. Because alcohol withdrawal is characterized by heightened anxiety-like behavior, activation of stress-responsive brain regions and an elevated propensity to self-administer alcohol, we hypothesized that Pde10a expression also would be upregulated in reward- and stress-responsive brain regions during periods of acute (8-10 h and protracted (6 wk alcohol withdrawal. During acute withdrawal, elevated Pde10a mRNA expression was found in the medial and basolateral amygdala, as well as the infralimbic and anterior cingulate subdivisions of the medial prefrontal cortex, relative to alcohol-naïve controls. The basolateral amygdala was the only region with elevated Pde10a mRNA expression during both acute and protracted withdrawal. In contrast to the elevations, Pde10a mRNA levels tended to be reduced during protracted withdrawal in the dorsal striatum, prelimbic prefrontal cortex, and medial amygdala. Together these results implicate heightened PDE10A expression in the basolateral amygdala as a lasting neuroadaptation associated with alcohol dependence.

  18. Amygdala and Hippocampus Enlargement during Adolescence in Autism

    Science.gov (United States)

    Groen, Wouter; Teluij, Michelle; Buitelaar, Jan; Tendolkar, Indira

    2010-01-01

    Objective: The amygdala and hippocampus are key components of the neural system mediating emotion perception and regulation and are thought to be involved in the pathophysiology of autism. Although some studies in children with autism suggest that there is an enlargement of amygdala and hippocampal volume, findings in adolescence are sparse.…

  19. Amygdala and hippocampus enlargement during adolescence in autism.

    NARCIS (Netherlands)

    Groen, W.B.; Teluij, M.; Buitelaar, J.K.; Tendolkar, I.

    2010-01-01

    OBJECTIVE: The amygdala and hippocampus are key components of the neural system mediating emotion perception and regulation and are thought to be involved in the pathophysiology of autism. Although some studies in children with autism suggest that there is an enlargement of amygdala and hippocampal

  20. Influence of CO2 on electrophysiology and ionic permeability of the basolateral membrane of frog skin

    International Nuclear Information System (INIS)

    Stoddard, J.S.

    1984-01-01

    When short-circuited epithelia of frog skin bathed in an alkaline Ringer solution equilibrated with room air, are exposed to a Ringer solution equilibrated with 5% CO 2 , inhibition of transepithelial Na + transport is observed accompanied by a marked depolarization of the basolateral membrane voltage as measured with intracellular microelectrodes. To study further the mechanisms involved, basolateral membrane influxes and effluxes of 24 Na, 42 K, and 36 Cl were measured in control and CO 2 -treated isolated epithelia. In control epithelia, studies of the bidirectional 24 Na fluxes confirmed the existence of an important basolateral membrane permeability to Na + . In control epithelia, the apical membranes of the cells were found to be virtually impermeable to Cl - , while basolateral membranes were highly permeable to Cl - . Although CO 2 caused a partial inhibition of pump activity as assessed from decreases of pump-mediated Na + efflux and K + influx, CO 2 caused little or no change of the leak influx of Na + or K + . K + efflux was increased markedly with CO 2 resulting in a net loss of K + from the cells. Cl - influx was increased and Cl - efflux was decreased by CO 2 leading to a net influx of Cl - . Analysis of the data according to criteria involving changes of flux, ionic equilibrium potentials, mass and charge balance restrictions indicated that the principle changes involve a transient decrease in electrical conductance to K + with a concurrent increase in electrical conductance to HCO 3 - (OH - or H + ) of the basolateral membranes of the cells

  1. Contributions of the Nucleus Accumbens Shell in Mediating the Enhancement in Memory Following Noradrenergic Activation of Either the Amygdala or Hippocampus.

    Science.gov (United States)

    Kerfoot, Erin C; Williams, Cedric L

    2018-01-01

    The nucleus accumbens shell is a site of converging inputs during memory processing for emotional events. The accumbens receives input from the nucleus of the solitary tract (NTS) regarding changes in peripheral autonomic functioning following emotional arousal. The shell also receives input from the amygdala and hippocampus regarding affective and contextual attributes of new learning experiences. The successful encoding of affect or context is facilitated by activating noradrenergic systems in either the amygdala or hippocampus. Recent findings indicate that memory enhancement produced by activating NTS neurons, is attenuated by suppressing accumbens functioning after learning. This finding illustrates the significance of the shell in integrating information from the periphery to modulate memory for arousing events. However, it is not known if the accumbens shell plays an equally important role in consolidating information that is initially processed in the amygdala and hippocampus. The present study determined if the convergence of inputs from these limbic regions within the nucleus accumbens contributes to successful encoding of emotional events into memory. Male Sprague-Dawley rats received bilateral cannula implants 2 mm above the accumbens shell and a second bilateral implant 2 mm above either the amygdala or hippocampus. The subjects were trained for 6 days to drink from a water spout. On day 7, a 0.35 mA footshock was initiated as the rat approached the spout and was terminated once the rat escaped into a white compartment. Subjects were then given intra-amygdala or hippocampal infusions of PBS or a dose of norepinephrine (0.2 μg) previously shown to enhance memory. Later, all subjects were given intra-accumbens infusion of muscimol to functionally inactivate the shell. Muscimol inactivation of the accumbens shell was delayed to allow sufficient time for norepinephrine to activate intracellular cascades that lead to long-term synaptic modifications

  2. Contributions of the Nucleus Accumbens Shell in Mediating the Enhancement in Memory Following Noradrenergic Activation of Either the Amygdala or Hippocampus

    Directory of Open Access Journals (Sweden)

    Erin C. Kerfoot

    2018-02-01

    Full Text Available The nucleus accumbens shell is a site of converging inputs during memory processing for emotional events. The accumbens receives input from the nucleus of the solitary tract (NTS regarding changes in peripheral autonomic functioning following emotional arousal. The shell also receives input from the amygdala and hippocampus regarding affective and contextual attributes of new learning experiences. The successful encoding of affect or context is facilitated by activating noradrenergic systems in either the amygdala or hippocampus. Recent findings indicate that memory enhancement produced by activating NTS neurons, is attenuated by suppressing accumbens functioning after learning. This finding illustrates the significance of the shell in integrating information from the periphery to modulate memory for arousing events. However, it is not known if the accumbens shell plays an equally important role in consolidating information that is initially processed in the amygdala and hippocampus. The present study determined if the convergence of inputs from these limbic regions within the nucleus accumbens contributes to successful encoding of emotional events into memory. Male Sprague-Dawley rats received bilateral cannula implants 2 mm above the accumbens shell and a second bilateral implant 2 mm above either the amygdala or hippocampus. The subjects were trained for 6 days to drink from a water spout. On day 7, a 0.35 mA footshock was initiated as the rat approached the spout and was terminated once the rat escaped into a white compartment. Subjects were then given intra-amygdala or hippocampal infusions of PBS or a dose of norepinephrine (0.2 μg previously shown to enhance memory. Later, all subjects were given intra-accumbens infusion of muscimol to functionally inactivate the shell. Muscimol inactivation of the accumbens shell was delayed to allow sufficient time for norepinephrine to activate intracellular cascades that lead to long-term synaptic

  3. Intra-Amygdala Injections of CREB Antisense Impair Inhibitory Avoidance Memory: Role of Norepinephrine and Acetylcholine

    Science.gov (United States)

    Canal, Clinton E.; Chang, Qing; Gold, Paul E.

    2008-01-01

    Infusions of CREB antisense into the amygdala prior to training impair memory for aversive tasks, suggesting that the antisense may interfere with CRE-mediated gene transcription and protein synthesis important for the formation of new memories within the amygdala. However, the amygdala also appears to modulate memory formation in distributed…

  4. Childhood Cumulative Risk Exposure and Adult Amygdala Volume and Function.

    Science.gov (United States)

    Evans, Gary W; Swain, James E; King, Anthony P; Wang, Xin; Javanbakht, Arash; Ho, S Shaun; Angstadt, Michael; Phan, K Luan; Xie, Hong; Liberzon, Israel

    2016-06-01

    Considerable work indicates that early cumulative risk exposure is aversive to human development, but very little research has examined the neurological underpinnings of these robust findings. This study investigates amygdala volume and reactivity to facial stimuli among adults (mean 23.7 years of age, n = 54) as a function of cumulative risk exposure during childhood (9 and 13 years of age). In addition, we test to determine whether expected cumulative risk elevations in amygdala volume would mediate functional reactivity of the amygdala during socioemotional processing. Risks included substandard housing quality, noise, crowding, family turmoil, child separation from family, and violence. Total and left hemisphere adult amygdala volumes were positively related to cumulative risk exposure during childhood. The links between childhood cumulative risk exposure and elevated amygdala responses to emotionally neutral facial stimuli in adulthood were mediated by the corresponding amygdala volumes. Cumulative risk exposure in later adolescence (17 years of age), however, was unrelated to subsequent adult amygdala volume or function. Physical and socioemotional risk exposures early in life appear to alter amygdala development, rendering adults more reactive to ambiguous stimuli such as neutral faces. These stress-related differences in childhood amygdala development might contribute to the well-documented psychological distress as a function of early risk exposure. © 2015 Wiley Periodicals, Inc.

  5. Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity.

    Science.gov (United States)

    Shoshan, Noa; Segev, Amir; Abush, Hila; Mizrachi Zer-Aviv, Tomer; Akirav, Irit

    2017-10-01

    Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long-term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short-term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1

  6. Serotonin, Amygdala and Fear: Assembling the Puzzle.

    Science.gov (United States)

    Bocchio, Marco; McHugh, Stephen B; Bannerman, David M; Sharp, Trevor; Capogna, Marco

    2016-01-01

    The fear circuitry orchestrates defense mechanisms in response to environmental threats. This circuitry is evolutionarily crucial for survival, but its dysregulation is thought to play a major role in the pathophysiology of psychiatric conditions in humans. The amygdala is a key player in the processing of fear. This brain area is prominently modulated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT input to the amygdala has drawn particular interest because genetic and pharmacological alterations of the 5-HT transporter (5-HTT) affect amygdala activation in response to emotional stimuli. Nonetheless, the impact of 5-HT on fear processing remains poorly understood.The aim of this review is to elucidate the physiological role of 5-HT in fear learning via its action on the neuronal circuits of the amygdala. Since 5-HT release increases in the basolateral amygdala (BLA) during both fear memory acquisition and expression, we examine whether and how 5-HT neurons encode aversive stimuli and aversive cues. Next, we describe pharmacological and genetic alterations of 5-HT neurotransmission that, in both rodents and humans, lead to altered fear learning. To explore the mechanisms through which 5-HT could modulate conditioned fear, we focus on the rodent BLA. We propose that a circuit-based approach taking into account the localization of specific 5-HT receptors on neurochemically-defined neurons in the BLA may be essential to decipher the role of 5-HT in emotional behavior. In keeping with a 5-HT control of fear learning, we review electrophysiological data suggesting that 5-HT regulates synaptic plasticity, spike synchrony and theta oscillations in the BLA via actions on different subcellular compartments of principal neurons and distinct GABAergic interneuron populations. Finally, we discuss how recently developed optogenetic tools combined with electrophysiological recordings and behavior could progress the knowledge of the mechanisms underlying 5

  7. Antisense-mediated isoform switching of steroid receptor coactivator-1 in the central nucleus of the amygdala of the mouse brain

    Directory of Open Access Journals (Sweden)

    Zalachoras Ioannis

    2013-01-01

    Full Text Available Abstract Background Antisense oligonucleotide (AON-mediated exon skipping is a powerful tool to manipulate gene expression. In the present study we investigated the potential of exon skipping by local injection in the central nucleus of the amygdala (CeA of the mouse brain. As proof of principle we targeted the splicing of steroid receptor coactivator-1 (SRC-1, a protein involved in nuclear receptor function. This nuclear receptor coregulator exists in two splice variants (SRC-1a and SRC-1e which display differential distribution and opposing activities in the brain, and whose mRNAs differ in a single SRC-1e specific exon. Methods For proof of principle of feasibility, we used immunofluorescent stainings to study uptake by different cell types, translocation to the nucleus and potential immunostimulatory effects at different time points after a local injection in the CeA of the mouse brain of a control AON targeting human dystrophin with no targets in the murine brain. To evaluate efficacy we designed an AON targeting the SRC-1e-specific exon and with qPCR analysis we measured the expression ratio of the two splice variants. Results We found that AONs were taken up by corticotropin releasing hormone expressing neurons and other cells in the CeA, and translocated into the cell nucleus. Immune responses after AON injection were comparable to those after sterile saline injection. A successful shift of the naturally occurring SRC-1a:SRC-1e expression ratio in favor of SRC-1a was observed, without changes in total SRC-1 expression. Conclusions We provide a proof of concept for local neuropharmacological use of exon skipping by manipulating the expression ratio of the two splice variants of SRC-1, which may be used to study nuclear receptor function in specific brain circuits. We established that exon skipping after local injection in the brain is a versatile and useful tool for the manipulation of splice variants for numerous genes that are relevant

  8. Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.

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    Johannes Björkstrand

    Full Text Available Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

  9. Effects of p75NTR deficiency on cholinergic innervation of the amygdala and anxiety-like behavior.

    Science.gov (United States)

    Busch, Ruben; Baldus, Marian; Vogt, Miriam A; Berger, Stefan M; Bartsch, Dusan; Gass, Peter; von Bohlen Und Halbach, Oliver

    2017-05-01

    The p75 neurotrophin receptor (p75NTR) is a low-affinity receptor that is capable of binding neurotrophins. Two different p75NTR knockout mouse lines are available either with a deletion in Exon III (p75NTR E x III -/- ) or in Exon IV (p75NTR E x IV -/- ). In p75NTR E x III knockout mice, only the full-length p75NTR is deleted, whereas in p75NTR E x IV knockout mice, the full-length as well as the truncated isoform of the receptor is deleted. Deletion of p75NTR has been shown to affect, among others, the septohippocampal cholinergic innervation pattern and neuronal plasticity within the hippocampus. We hypothesize that deletion of p75NTR also alters the morphology and physiology of a further key structure of the limbic system, the amygdala. Our results indicate that deletion of p75NTR also increases cholinergic innervation in the basolateral amygdala in adult as well as aged p75NTR E x III -/- and p75NTR E x IV -/- mice. The p75NTR E x IV -/- mice did not display altered long-term potentiation (LTP) in the basolateral amygdala as compared to age-matched control littermates. However, p75NTR E x III -/- mice display stronger LTP in the basolateral amygdala compared to age-matched controls. Bath-application of K252a (a trk antagonist) did not inhibit the induction of LTP in the basolateral amygdala, but reduced the level of LTP in p75NTR E x III -/- mice to levels seen in respective controls. Moreover, p75NTR E x III -/- mice display altered behavior in the dark/light box. Thus, deletion of p75NTR in mice leads to physiological and morphological changes in the amygdala and altered behavior that is linked to the limbic system. © 2017 International Society for Neurochemistry.

  10. 5-HT2CReceptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors.

    Science.gov (United States)

    Ji, Guangchen; Zhang, Wei; Mahimainathan, Lenin; Narasimhan, Madhusudhanan; Kiritoshi, Takaki; Fan, Xiuzhen; Wang, Jigong; Green, Thomas A; Neugebauer, Volker

    2017-02-08

    Neuroplasticity in the amygdala drives pain-related behaviors. The central nucleus (CeA) serves major amygdala output functions and can generate emotional-affective behaviors and modulate nocifensive responses. The CeA receives excitatory and inhibitory inputs from the basolateral nucleus (BLA) and serotonin receptor subtype 5-HT 2C R in the BLA, but not CeA, has been implicated anxiogenic behaviors and anxiety disorders. Here, we tested the hypothesis that 5-HT 2C R in the BLA plays a critical role in CeA plasticity and neuropathic pain behaviors in the rat spinal nerve ligation (SNL) model. Local 5-HT 2C R knockdown in the BLA with stereotaxic injection of 5-HT 2C R shRNA AAV vector decreased vocalizations and anxiety- and depression-like behaviors and increased sensory thresholds of SNL rats, but had no effect in sham controls. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that 5-HT 2C R knockdown blocked the increase in neuronal activity (increased responsiveness, irregular spike firing, and increased burst activity) in SNL rats. At the synaptic level, 5-HT 2C R knockdown blocked the increase in excitatory transmission from BLA to CeA recorded in brain slices from SNL rats using whole-cell patch-clamp conditions. Inhibitory transmission was decreased by 5-HT 2C R knockdown in control and SNL conditions to a similar degree. The findings can be explained by immunohistochemical data showing increased expression of 5-HT 2C R in non-GABAergic BLA cells in SNL rats. The results suggest that increased 5-HT 2C R in the BLA contributes to neuropathic-pain-related amygdala plasticity by driving synaptic excitation of CeA neurons. As a rescue strategy, 5-HT 2C R knockdown in the BLA inhibits neuropathic-pain-related behaviors. SIGNIFICANCE STATEMENT Neuroplasticity in the amygdala has emerged as an important pain mechanism. This study identifies a novel target and rescue strategy to control abnormally enhanced amygdala activity in an

  11. Factors that Determine the Non-Linear Amygdala Influence on Hippocampus-Dependent Memory

    OpenAIRE

    Akirav, Irit; Richter-Levin, Gal

    2006-01-01

    Stressful experiences are known to either improve or impair hippocampal-dependent memory tasks and synaptic plasticity. These positive and negative effects of stress on the hippocampus have been largely documented, however little is known about the mechanism involved in the twofold influence of stress on hippocampal functioning and about what factors define an enhancing or inhibitory outcome. We have recently demonstrated that activation of the basolateral amygdala can produce a biphasic effe...

  12. H1-histamine receptors in the amygdala are involved in emotional memory but do not mediate anxiety-related behaviors in mice submitted to EPM testing.

    Science.gov (United States)

    Serafim, K R; Gianlorenço, A C L; Daher, F P; Mattioli, R

    2012-10-01

    This study investigated the role of amygdala H(1) receptors in state-dependent memory deficits induced by l-histidine (LH). Tests using an elevated plus-maze (EPM) were performed on two consecutive days: Trial 1 (T1) and Trial 2 (T2). Before each trial, mice were intraperitoneally (IP) injected with LH (500mg/kg). Two hours later, they were microinjected with the H(1) receptor antagonist, chlorpheniramine (CPA 0.016, 0.052, or 0.16 nmol/0.1μl), or saline (SAL) into the amygdala and submitted to the EPM. LH-CPA did not affect trial 1 performances in the EPM, which indicated that these drugs did not affect anxiety. Emotional memory, as revealed by a reduction in open arm exploration between both trials, was present in the SAL-SAL groups as well as in the SAL-CPA groups for the lower doses of CPA (0.016 and 0.052nmol). On the contrary, neither the LH-SAL group nor the LH-CPA groups exhibited this decrease in open arm activity between both trials, which reveals that LH impaired emotional memory. While intra-amygdalar CPA did not interact with LH effect, it impaired per se the emotional memory performances at the highest dose (0.16nmol). No significant changes were observed in the number of enclosed arm entries (EAE), an EPM index of general exploratory activity. These results may be attributed to a combined effect in the different nucleus of the amygdala. Taken together, these results suggest that the H(1) receptors in the amygdala are not implicated in anxiety-like behaviors but are involved in emotional states induced by the T1/T2 EPM protocol in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Effect of Protein Malnutrition on Efferent Projections of Amygdala to the Hippocampus

    Directory of Open Access Journals (Sweden)

    Gholamreza Hassanzadeh

    2010-11-01

    Full Text Available ABSTRACTIntroduction: Previous investigations have shown that protein malnutrition can alters the structure and function of some areas of hippocampal formation. We investigated the effect of protein malnutrition on amygdaloid projections to the CA1 hippocampal area. In this study we investigated level and pattern of distribution of efferent projections from amygdala to hippocampus in the rat by Horseradish Peroxidas (HRP neural tract tracing in 2 groups Control group fed with regular diet (% 18 proteinsand case group fed with low protein diet (%8. We used SPSS 11.0 (T test & mann-withney Software for data analysis.Methods: Following injection of HRP to CA1 region of hippocampus in the control group Rats, Labelled neurons showed more density in the Basolateral, Cortical and Medial nuclear Groups. Having done the analysis and examining the relations between the case data and those of the control groups, we found that number of labelled neurons in the Basolateral, Cortical & medial nuclei were decreased in the case group(p<0.05. Our findings showed that different nuclei of amygdala (Basolateral, Cortical and Medial send projections to CA1 region of hippocampus Among, them basolateral nuclei group send the most projections . Discussion: This results may be caused by decrease of activity of neural cells after protein malnutrition, that can results in impairment in growth and development of nervous system. Also it is possible that axoplasmic transfer rate maybe decreased in this condition.

  14. Effect of Protein Malnutrition on Efferent Projections of Amygdala to the Hippocampus

    Directory of Open Access Journals (Sweden)

    Gholamreza Hassanzadeh

    2010-11-01

    Full Text Available ABSTRACTIntroduction: Previous investigations have shown that protein malnutrition can alters the structure and function of some areas of hippocampal formation. We investigated the effect of protein malnutrition on amygdaloid projections to the CA1 hippocampal area. In this study we investigated level and pattern of distribution of efferent projections from amygdala to hippocampus in the rat by Horseradish Peroxidas (HRP neural tract tracing in 2 groups; Control group fed with regular diet (% 18 proteinsand case group fed with low protein diet (%8. We used SPSS 11.0 (T test & mann-withney Software for data analysis.Methods: Following injection of HRP to CA1 region of hippocampus in the control group Rats, Labelled neurons showed more density in the Basolateral, Cortical and Medial nuclear Groups. Having done the analysis and examining the relations between the case data and those of the control groups, we found that number of labelled neurons in the Basolateral, Cortical & medial nuclei were decreased in the case group(p<0.05. Our findings showed that different nuclei of amygdala (Basolateral, Cortical and Medial send projections to CA1 region of hippocampus; Among, them basolateral nuclei group send the most projections . Discussion: This results may be caused by decrease of activity of neural cells after protein malnutrition, that can results in impairment in growth and development of nervous system. Also it is possible that axoplasmic transfer rate maybe decreased in this condition.

  15. Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids.

    Science.gov (United States)

    Boitard, Chloé; Maroun, Mouna; Tantot, Frédéric; Cavaroc, Amandine; Sauvant, Julie; Marchand, Alain; Layé, Sophie; Capuron, Lucile; Darnaudery, Muriel; Castanon, Nathalie; Coutureau, Etienne; Vouimba, Rose-Marie; Ferreira, Guillaume

    2015-03-04

    In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor-malaise and tone-shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function. Copyright © 2015 the authors 0270-6474/15/354092-12$15.00/0.

  16. Administration of the Phosphodiesterase Type 4 Inhibitor Rolipram into the Amygdala at a Specific Time Interval after Learning Increases Recognition Memory Persistence

    Science.gov (United States)

    Werenicz, Aline; Christoff, Raissa R.; Blank, Martina; Jobim, Paulo F. C.; Pedroso, Thiago R.; Reolon, Gustavo K.; Schroder, Nadja; Roesler, Rafael

    2012-01-01

    Here we show that administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram into the basolateral complex of the amygdala (BLA) at a specific time interval after training enhances memory consolidation and induces memory persistence for novel object recognition (NOR) in rats. Intra-BLA infusion of rolipram immediately, 1.5 h, or 6 h…

  17. Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.

    Science.gov (United States)

    Schoch, Hannah; Kreibich, Arati S; Ferri, Sarah L; White, Rachel S; Bohorquez, Dominique; Banerjee, Anamika; Port, Russell G; Dow, Holly C; Cordero, Lucero; Pallathra, Ashley A; Kim, Hyong; Li, Hongzhe; Bilker, Warren B; Hirano, Shinji; Schultz, Robert T; Borgmann-Winter, Karin; Hahn, Chang-Gyu; Feldmeyer, Dirk; Carlson, Gregory C; Abel, Ted; Brodkin, Edward S

    2017-02-01

    Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits. Mice lacking one copy of Pcdh10 (Pcdh10 +/- ) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala. Male Pcdh10 +/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10 +/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine. Our studies reveal that male Pcdh10 +/- mice have synaptic and behavioral deficits, and establish Pcdh10 +/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Basolateral cholesterol depletion alters Aquaporin-2 post-translational modifications and disrupts apical plasma membrane targeting.

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    Moeller, Hanne B; Fuglsang, Cecilia Hvitfeldt; Pedersen, Cecilie Nøhr; Fenton, Robert A

    2018-01-01

    Apical plasma membrane accumulation of the water channel Aquaporin-2 (AQP2) in kidney collecting duct principal cells is critical for body water homeostasis. Posttranslational modification (PTM) of AQP2 is important for regulating AQP2 trafficking. The aim of this study was to determine the role of cholesterol in regulation of AQP2 PTM and in apical plasma membrane targeting of AQP2. Cholesterol depletion from the basolateral plasma membrane of a collecting duct cell line (mpkCCD14) using methyl-beta-cyclodextrin (MBCD) increased AQP2 ubiquitylation. Forskolin, cAMP or dDAVP-mediated AQP2 phosphorylation at Ser269 (pS269-AQP2) was prevented by cholesterol depletion from the basolateral membrane. None of these effects on pS269-AQP2 were observed when cholesterol was depleted from the apical side of cells, or when MBCD was applied subsequent to dDAVP stimulation. Basolateral, but not apical, MBCD application prevented cAMP-induced apical plasma membrane accumulation of AQP2. These studies indicate that manipulation of the cholesterol content of the basolateral plasma membrane interferes with AQP2 PTM and subsequently regulated apical plasma membrane targeting of AQP2. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex.

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    Felix-Ortiz, A C; Burgos-Robles, A; Bhagat, N D; Leppla, C A; Tye, K M

    2016-05-03

    The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and social behaviors. It remains to be elucidated, however, whether direct projections from the BLA to the mPFC play a functional role in these behaviors. We used optogenetic approaches in behaving mice to either activate or inhibit BLA inputs to the mPFC during behavioral assays that assess anxiety-like behavior and social interaction. Channelrhodopsin-2 (ChR2)-mediated activation of BLA inputs to the mPFC produced anxiogenic effects in the elevated plus maze and open field test, whereas halorhodopsin (NpHR)-mediated inhibition produced anxiolytic effects. Furthermore, activation of the BLA-mPFC pathway reduced social interaction in the resident-intruder test, whereas inhibition facilitated social interaction. These results establish a causal relationship between activity in the BLA-mPFC pathway and the bidirectional modulation of anxiety-related and social behaviors. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Increased N-Ethylmaleimide-Sensitive Factor Expression in Amygdala and Perirhinal Cortex during Habituation of Taste Neophobia

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    Beatriz Gómez-Chacón

    2016-01-01

    Full Text Available Interactions between GluR2 and N-ethylmaleimide-sensitive factor (NSF mediate AMPA receptors trafficking. This might be linked with molecular mechanisms related with memory formation. Previous research has shown basolateral amygdala (BLA dependent activity changes in the perirhinal cortex (PRh during the formation of taste memory. In the present experiments we investigate both the behavioral performance and the expression profile of NSF and GluR2 genes in several brain areas, including PRh, BLA, and hippocampus. Twenty-one naïve male Wistar rats were exposed to a saccharin solution (0.4% during the first (novel, the second (Familiar I, and the sixth presentation (Familiar II. Total RNA was extracted and gene expression was measured by quantitative PCR (qPCR using TaqMan gene expression assays. In addition the expression of the synaptic plasticity related immediate early genes, Homer 1 and Narp, was also assessed. We have found increased expression of NSF gene in BLA and PRh in Group Familiar I in comparison with Familiar II. No changes in the expression of GluR2, Homer 1, and Narp genes were found. The results suggest the relevance of a potential network in the temporal lobe for taste recognition memory and open new possibilities for understanding the molecular mechanisms mediating the impact of sensory experience on brain circuit function.

  1. Decreased expression of extracellular matrix proteins and trophic factors in the amygdala complex of depressed mice after chronic immobilization stress

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    Jung Soonwoong

    2012-06-01

    Full Text Available Abstract Background The amygdala plays an essential role in controlling emotional behaviors and has numerous connections to other brain regions. The functional role of the amygdala has been highlighted by various studies of stress-induced behavioral changes. Here we investigated gene expression changes in the amygdala in the chronic immobilization stress (CIS-induced depression model. Results Eight genes were decreased in the amygdala of CIS mice, including genes for neurotrophic factors and extracellular matrix proteins. Among these, osteoglycin, fibromodulin, insulin-like growth factor 2 (Igf2, and insulin-like growth factor binding protein 2 (Igfbp2 were further analyzed for histological expression changes. The expression of osteoglycin and fibromodulin simultaneously decreased in the medial, basolateral, and central amygdala regions. However, Igf2 and Igfbp2 decreased specifically in the central nucleus of the amygdala. Interestingly, this decrease was found only in the amygdala of mice showing higher immobility, but not in mice displaying lower immobility, although the CIS regimen was the same for both groups. Conclusions These results suggest that the responsiveness of the amygdala may play a role in the sensitivity of CIS-induced behavioral changes in mice.

  2. Regulation of the fear network by mediators of stress: Norepinephrine alters the balance between Cortical and Subcortical afferent excitation of the Lateral Amygdala

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    Luke R Johnson

    2011-05-01

    Full Text Available Pavlovian auditory fear conditioning crucially involves the integration of information about and acoustic conditioned stimulus (CS and an aversive unconditioned stimulus (US in the lateral nucleus of the amygdala (LA. The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE, regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased towards the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance towards the faster but more primitive subcortical input.

  3. Disorganized attachment in infancy predicts greater amygdala volume in adulthood.

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    Lyons-Ruth, K; Pechtel, P; Yoon, S A; Anderson, C M; Teicher, M H

    2016-07-15

    Early life stress in rodents is associated with increased amygdala volume in adulthood. In humans, the amygdala develops rapidly during the first two years of life. Thus, disturbed care during this period may be particularly important to amygdala development. In the context of a 30-year longitudinal study of impoverished, highly stressed families, we assessed whether disorganization of the attachment relationship in infancy was related to amygdala volume in adulthood. Amygdala volumes were assessed among 18 low-income young adults (8M/10F, 29.33±0.49years) first observed in infancy (8.5±5.6months) and followed longitudinally to age 29. In infancy (18.58±1.02mos), both disorganized infant attachment behavior and disrupted maternal communication were assessed in the standard Strange Situation Procedure (SSP). Increased left amygdala volume in adulthood was associated with both maternal and infant components of disorganized attachment interactions at 18 months of age (overall r=0.679, pamygdala volume. Left amygdala volume was further associated with dissociation and limbic irritability in adulthood. Finally, left amygdala volume mediated the prediction from attachment disturbance in infancy to limbic irritability in adulthood. Results point to the likely importance of quality of early care for amygdala development in human children as well as in rodents. The long-term prediction found here suggests that the first two years of life may be an early sensitive period for amygdala development during which clinical intervention could have particularly important consequences for later child outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory.

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    Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

    2015-05-19

    Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons.

  5. Modulation of Long-term Potentiation of Cortico-amygdala Synaptic Responses and Auditory Fear Memory by Dietary Polyunsaturated Fatty Acid

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    Daisuke Yamada

    2016-08-01

    Full Text Available Converging evidence suggests that an imbalance of ω3 to ω6 polyunsaturated fatty acid (PUFA in the brain is involved in mental illnesses such as anxiety disorders. However, the underlying mechanism is unknown. We previously reported that the dietary ratio of ω3 to ω6 PUFA alters this ratio in the brain, and influences contextual fear memory. In addition to behavioral change, enhancement of cannabinoid CB1 receptor-mediated short-term synaptic plasticity and facilitation of the agonist sensitivity of CB1 receptors have been observed in excitatory synaptic responses in the basolateral nucleus of the amygdala. However, it is not known whether long-term synaptic plasticity in the amygdala is influenced by the dietary ratio of ω3 to ω6 PUFA. In the present study, we examined long-term potentiation (LTP of optogenetically–evoked excitatory synaptic responses in synapses between the terminal of the projection from the auditory cortex and the pyramidal cells in the lateral nucleus of the amygdala. We found that LTP in this pathway was attenuated in mice fed a diet with a high ω3 to ω6 PUFA ratio (0.97, compared with mice fed a diet with a low ω3 to ω6 PUFA ratio (0.14. Furthermore, mice in the former condition showed reduced fear responses in an auditory fear conditioning test, compared with mice in the latter condition. In both electrophysiological and behavioral experiments, the effect of a diet with a high ω3 to ω6 PUFA ratio was completely blocked by treatment with a CB1 receptor antagonist. Furthermore, a significant reduction was observed in cholesterol content, but not in the level of an endogenous CB1 receptor agonist, 2-arachidonoylglycerol, in brain samples containing the amygdala. These results suggest that the balance of ω3 to ω6 PUFA has an impact on fear memory and cortico-amygdala synaptic plasticity, both in a CB1 receptor–dependent manner.

  6. Acute Ethanol Administration Upregulates Synaptic α4-Subunit of Neuronal Nicotinic Acetylcholine Receptors within the Nucleus Accumbens and Amygdala

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    Josephine R. Tarren

    2017-10-01

    Full Text Available Alcohol and nicotine are two of the most frequently abused drugs, with their comorbidity well described. Previous data show that chronic exposure to nicotine upregulates high-affinity nicotinic acetylcholine receptors (nAChRs in several brain areas. Effects of ethanol on specific brain nAChR subtypes within the mesolimbic dopaminergic (DA pathway may be a key element in the comorbidity of ethanol and nicotine. However, it is unknown how alcohol affects the abundance of these receptor proteins. In the present study, we measured the effect of acute binge ethanol on nAChR α4 subunit levels in the prefrontal cortex (PFC, nucleus accumbens (NAc, ventral tegmental area (VTA, and amygdala (Amg by western blot analysis using a knock-in mouse line, generated with a normally functioning α4 nAChR subunit tagged with yellow fluorescent protein (YFP. We observed a robust increase in α4-YFP subunit levels in the NAc and the Amg following acute ethanol, with no changes in the PFC and VTA. To further investigate whether this upregulation was mediated by increased local mRNA transcription, we quantified mRNA levels of the Chrna4 gene using qRT-PCR. We found no effect of ethanol on α4 mRNA expression, suggesting that the upregulation of α4 protein rather occurs post-translationally. The quantitative counting of YFP immunoreactive puncta further revealed that α4-YFP protein is upregulated in presynaptic boutons of the dopaminergic axons projecting to the shell and the core regions of the NAc as well as to the basolateral amygdala (BLA, but not to the central or lateral Amg. Together, our results demonstrate that a single exposure to binge ethanol upregulates level of synaptic α4∗ nAChRs in dopaminergic inputs to the NAc and BLA. This upregulation could be linked to the functional dysregulation of dopaminergic signalling observed during the development of alcohol dependence.

  7. Involvement of the amygdala in memory storage: Interaction with other brain systems

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    McGaugh, James L.; Cahill, Larry; Roozendaal, Benno

    1996-01-01

    There is extensive evidence that the amygdala is involved in affectively influenced memory. The central hypothesis guiding the research reviewed in this paper is that emotional arousal activates the amygdala and that such activation results in the modulation of memory storage occurring in other brain regions. Several lines of evidence support this view. First, the effects of stress-related hormones (epinephrine and glucocorticoids) are mediated by influences involving the amygdala. In rats, lesions of the amygdala and the stria terminalis block the effects of posttraining administration of epinephrine and glucocorticoids on memory. Furthermore, memory is enhanced by posttraining intra-amygdala infusions of drugs that activate β-adrenergic and glucocorticoid receptors. Additionally, infusion of β-adrenergic blockers into the amygdala blocks the memory-modulating effects of epinephrine and glucocorticoids, as well as those of drugs affecting opiate and GABAergic systems. Second, an intact amygdala is not required for expression of retention. Inactivation of the amygdala prior to retention testing (by posttraining lesions or drug infusions) does not block retention performance. Third, findings of studies using human subjects are consistent with those of animal experiments. β-Blockers and amygdala lesions attenuate the effects of emotional arousal on memory. Additionally, 3-week recall of emotional material is highly correlated with positron-emission tomography activation (cerebral glucose metabolism) of the right amygdala during encoding. These findings provide strong evidence supporting the hypothesis that the amygdala is involved in modulating long-term memory storage. PMID:8942964

  8. Oxytocin increases amygdala reactivity to threatening scenes in females.

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    Lischke, Alexander; Gamer, Matthias; Berger, Christoph; Grossmann, Annette; Hauenstein, Karlheinz; Heinrichs, Markus; Herpertz, Sabine C; Domes, Gregor

    2012-09-01

    The neuropeptide oxytocin (OT) is well known for its profound effects on social behavior, which appear to be mediated by an OT-dependent modulation of amygdala activity in the context of social stimuli. In humans, OT decreases amygdala reactivity to threatening faces in males, but enhances amygdala reactivity to similar faces in females, suggesting sex-specific differences in OT-dependent threat-processing. To further explore whether OT generally enhances amygdala-dependent threat-processing in females, we used functional magnetic resonance imaging (fMRI) in a randomized within-subject crossover design to measure amygdala activity in response to threatening and non-threatening scenes in 14 females following intranasal administration of OT or placebo. Participants' eye movements were recorded to investigate whether an OT-dependent modulation of amygdala activity is accompanied by enhanced exploration of salient scene features. Although OT had no effect on participants' gazing behavior, it increased amygdala reactivity to scenes depicting social and non-social threat. In females, OT may, thus, enhance the detection of threatening stimuli in the environment, potentially by interacting with gonadal steroids, such as progesterone and estrogen. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Depressive-like history alters persistent pain behavior in rats: Opposite contribution of frontal cortex and amygdala implied.

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    Qi, Wei-Jing; Wang, Wei; Wang, Ning; Wang, Jin-Yan; Luo, Fei

    2013-08-01

    Numerous studies have shown that pain perception is strongly influenced by depression. However, very few studies have examined whether pain perception is altered in the remission period of depression, and what role the fronto-limbic circuits may play in the behavioral changes associated with remission. Using an unpredictable chronic mild stress (UCMS) animal model of depression, the present study investigated pain-related behaviors in rats with prior exposure to a UCMS stimulus. The γ-aminobutyric acid (GABA) A receptor agonist muscimol was microinjected bilaterally into the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) to examine the modulation of pain by these brain regions in the recovery state. Rats with a depression-like history displayed increased ongoing pain behavior in the formalin test, although their thermal pain thresholds were unchanged. Intra-BLA muscimol during the recovery phase dramatically decreased formalin-induced pain behavior and also significantly increased rats' sucrose preference. By contrast, in the mPFC, muscimol produced the opposite effect, suggesting different, perhaps opposing, roles of the BLA and mPFC in mediating the influence of prior UCMS exposure on pain perception. Taken together, these results demonstrated that a depressive experience may cause long-term alterations in limbic circuit excitability and thus lead to long-lasting changes in pain perception.

  10. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  11. Lateral Orbitofrontal Cortical Modulation on the Medial Prefrontal Cortex-Amygdala Pathway: Differential Regulation of Intra-Amygdala GABAA and GABAB Receptors.

    Science.gov (United States)

    Chang, Chun-Hui

    2017-07-01

    The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex and lateral orbitofrontal cortex. Earlier studies have shown that lateral orbitofrontal cortex activation exerts an inhibitory gating on medial prefrontal cortex-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to medial prefrontal cortex activation, tested lateral orbitofrontal cortex gating at different delays (lateral orbitofrontal cortex-medial prefrontal cortex delays: 25, 50, 100, 250, 500, and 1000 milliseconds), and examined differential contribution of GABAA and GABAB receptors with iontophoresis. Relative to baseline, lateral orbitofrontal cortex stimulation exerted an inhibitory modulatory gating on the medial prefrontal cortex-amygdala pathway and was effective up to a long delay of 500 ms (long-delay latencies at 100, 250, and 500 milliseconds). Moreover, blockade of intra-amygdala GABAA receptors with bicuculline abolished the lateral orbitofrontal cortex inhibitory gating at both short- (25 milliseconds) and long-delay (100 milliseconds) intervals, while blockade of GABAB receptors with saclofen reversed the inhibitory gating at long delay (100 milliseconds) only. Among the majority of the neurons examined (8 of 9), inactivation of either GABAA or GABAB receptors during baseline did not change evoked probability per se, suggesting that local feed-forward inhibitory mechanism is pathway specific. Our results suggest that the effect of lateral orbitofrontal cortex inhibitory modulatory gating was effective up to 500 milliseconds and that intra-amygdala GABAA and GABAB receptors differentially modulate the short- and long-delay lateral orbitofrontal cortex inhibitory gating on the medial prefrontal cortex-amygdala pathway.

  12. Distinct contributions of reactive oxygen species in amygdala to bee venom-induced spontaneous pain-related behaviors.

    Science.gov (United States)

    Lu, Yun-Fei; Neugebauer, Volker; Chen, Jun; Li, Zhen

    2016-04-21

    Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, play essential roles in physiological plasticity and are also involved in the pathogenesis of persistent pain. Roles of peripheral and spinal ROS in pain have been well established, but much less is known about ROS in the amygdala, a brain region that plays an important role in pain modulation. The present study explored the contribution of ROS in the amygdala to bee venom (BV)-induced pain behaviors. Our data show that the amygdala is activated following subcutaneous BV injection into the left hindpaw, which is reflected in the increased number of c-Fos positive cells in the central and basolateral amygdala nuclei in the right hemisphere. Stereotaxic administration of a ROS scavenger (tempol, 10mM), NADPH oxidase inhibitor (baicalein, 5mM) or lipoxygenase inhibitor (apocynin, 10mM) into the right amygdala attenuated the BV-induced spontaneous licking and lifting behaviors, but had no effect on BV-induced paw flinch reflexes. Our study provides further evidence for the involvement of the amygdala in nociceptive processing and pain behaviors, and that ROS in amygdala may be a potential target for treatment strategies to inhibit pain. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

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    Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

    2017-03-15

    A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

  14. MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice.

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    Murphy, Conor P; Li, Xiang; Maurer, Verena; Oberhauser, Michael; Gstir, Ronald; Wearick-Silva, Luis Eduardo; Viola, Thiago Wendt; Schafferer, Simon; Grassi-Oliveira, Rodrigo; Whittle, Nigel; Hüttenhofer, Alexander; Bredy, Timothy W; Singewald, Nicolas

    2017-06-15

    MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety- and trauma-related disorders, where often memory-associated gene expression is adversely affected. The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction. Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional downregulation following successful fear extinction in S1 mice. These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders. Copyright © 2017 Society of Biological

  15. Recurrent hypoglycemia increases anxiety and amygdala norepinephrine release during subsequent hypoglycemia

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    Ewan eMcNay

    2015-11-01

    Full Text Available Recurrent hypoglycemia (RH is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp, a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and pre-frontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e. less time spent in the open arms of the plus-maze. The results show that RH has widespread effects on subsequent brain function, which vary by neural system.

  16. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice.

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    Lin, Tzu-Wei; Shih, Yao-Hsiang; Chen, Shean-Jen; Lien, Chi-Hsiang; Chang, Chia-Yuan; Huang, Tung-Yi; Chen, Shun-Hua; Jen, Chauying J; Kuo, Yu-Min

    2015-02-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF/TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Aβ40 and Aβ42 in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-AKT and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aβ in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aβ clearance. Physical

  17. Glutamate Receptor GluA1 Subunit Is Implicated in Capsaicin Induced Modulation of Amygdala LTP but Not LTD

    Science.gov (United States)

    Gebhardt, Christine; Albrecht, Doris

    2018-01-01

    Capsaicin has been shown to modulate synaptic plasticity in various brain regions including the amygdala. Whereas in the lateral amygdala the modulatory effect of capsaicin on long-term potentiation (LA-LTP) is mediated by TRPV1 channels, we have recently shown that capsaicin-induced enhancement of long term depression (LA-LTD) is mediated by…

  18. Modulation of cannabinoid signaling by amygdala α2-adrenergic system in fear conditioning.

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    Nasehi, Mohammad; Zamanparvar, Majid; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-03-01

    The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Growing evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. In addition, there is an interaction between the cannabinoid and noradrenergic system that has significant functional and behavioral implications. Considering the importance of these systems in forming memories for fearful events, we have investigated the involvement of basolateral amygdala (BLA) α2-adrenoceptors on ACPA (as selective cannabinoid CB1 agonist)-induced inhibition of the acquisition of contextual and auditory conditioned fear. A contextual and auditory fear conditioning apparatus for assess fear memory in adult male NMRI mice was used. Pre-training, intraperitoneal administration of ACPA decreased the percentage freezing time in contextual (at doses of 0.05 and 0.1mg/kg) and auditory (at dose of 0.1 mg/kg) in the fear conditioning task, indicating memory acquisition deficit. The same result was observed with intra-BLA microinjection of clonidine (0.001-0.5 μg/mouse, for both memories), as α2-adrenoceptor agonist and yohimbine (at doses of 0.005 and 0.05 for contextual and at dose of 0.05 μg/mouse for auditory fear memory), as α2-adrenoceptor antagonist. In addition, intra-BLA microinjection of clonidine (0.0005 μg/mouse) did not alter ACPA response in both conditions, while the same dose of yohimbine potentiated ACPA response at the lower dose on contextual fear memory. It is concluded that BLA α2-adrenergic receptors may be involved in context- but not tone-dependent fear memory impairment induced by activation of CB1 receptors. Copyright © 2015. Published by Elsevier B.V.

  19. Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4alpha and PGC1alpha.

    Science.gov (United States)

    Dietrich, Christoph G; Martin, Ina V; Porn, Anne C; Voigt, Sebastian; Gartung, Carsten; Trautwein, Christian; Geier, Andreas

    2007-09-01

    Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.

  20. Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats.

    Science.gov (United States)

    Reppucci, Christina J; Petrovich, Gorica D

    2016-07-01

    The amygdala and medial prefrontal cortex (mPFC) are highly interconnected telencephalic areas critical for cognitive processes, including associative learning and decision making. Both structures strongly innervate the lateral hypothalamus (LHA), an important component of the networks underlying the control of feeding and other motivated behaviors. The amygdala-prefrontal-lateral hypothalamic system is therefore well positioned to exert cognitive control over behavior. However, the organization of this system is not well defined, particularly the topography of specific circuitries between distinct cell groups within these complex, heterogeneous regions. This study used two retrograde tracers to map the connections from the amygdala (central and basolateral area nuclei) and mPFC to the LHA in detail, and to determine whether amygdalar pathways to the mPFC and to LHA originate from the same or different neurons. One tracer was placed into a distinct mPFC area (dorsal anterior cingulate, prelimbic, infralimbic, or rostromedial orbital), and the other into dorsal or ventral LHA. We report that the central nucleus and basolateral area of the amygdala send projections to distinct LHA regions, dorsal and ventral, respectively. The basolateral area, but not central nucleus, also sends substantial projections to the mPFC, topographically organized rostrocaudal to dorsoventral. The entire mPFC, in turn, projects to the LHA, providing a separate route for potential amygdalar influence following mPFC processing. Nearly all amygdalar projections to the mPFC and to the LHA originated from different neurons suggesting amygdala and amygdala-mPFC processing influence the LHA independently, and the balance of these parallel pathways ultimately controls motivated behaviors.

  1. Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder.

    Science.gov (United States)

    Koch, Saskia B J; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L; Veltman, Dick J; Olff, Miranda

    2016-07-01

    The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD.

  2. Strychnine and taurine modulation of amygdala-associated anxiety-like behavior is 'state' dependent.

    Science.gov (United States)

    McCool, Brian A; Chappell, Ann

    2007-03-12

    Strychnine-sensitive glycine receptors are expressed in many adult forebrain regions, yet the biological function of these receptors outside the spinal cord/brainstem is poorly understood. We have recently shown that rat lateral/basolateral amygdala neurons express strychnine-sensitive glycine-gated currents whose pharmacological and molecular characteristics are consistent with those established for classic ligand-gated chloride channels. The current studies were undertaken to establish the behavioral role, if any, of these strychnine-sensitive glycine receptors. Adult Long-Evans male rats were implanted with guide cannulae targeted at the lateral amygdala and were microinjected with standard artificial cerebrospinal fluid with or without various doses of strychnine or taurine. Anxiety-like behaviors were assessed with the elevated plus maze or the light/dark box. In the elevated plus maze, strychnine decreased closed-arm time and increased open-arm time, suggestive of an anxiolytic effect. Similarly, strychnine produced a modest anxiolytic effect in the light/dark box. Post hoc analysis of 'open-arm' time and 'light-side' time indicated that aCSF-treated animals were distributed into two apparent groups that displayed either high or low amounts of anxiety-like behavior in a given apparatus. Surprisingly, the pharmacological effects of both strychnine and taurine in these assays were dependent upon a given animal's behavioral phenotype. Together, these findings are significant because they suggest that the basal 'emotional state' of the animal could influence the behavioral outcome associated with drug application directly into the lateral/basolateral amygdala. Furthermore, our findings also suggest that compounds acting at amygdala strychnine-sensitive glycine receptors may actively modulate this basal anxiety-like state.

  3. Statistical modeling implicates neuroanatomical circuit mediating stress relief by 'comfort' food.

    Science.gov (United States)

    Ulrich-Lai, Yvonne M; Christiansen, Anne M; Wang, Xia; Song, Seongho; Herman, James P

    2016-07-01

    A history of eating highly palatable foods reduces physiological and emotional responses to stress. For instance, we have previously shown that limited sucrose intake (4 ml of 30 % sucrose twice daily for 14 days) reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress. However, the neural mechanisms underlying stress relief by such 'comfort' foods are unclear, and could reveal an endogenous brain pathway for stress mitigation. As such, the present work assessed the expression of several proteins related to neuronal activation and/or plasticity in multiple stress- and reward-regulatory brain regions of rats after limited sucrose (vs. water control) intake. These data were then subjected to a series of statistical analyses, including Bayesian modeling, to identify the most likely neurocircuit mediating stress relief by sucrose. The analyses suggest that sucrose reduces HPA activation by dampening an excitatory basolateral amygdala-medial amygdala circuit, while also potentiating an inhibitory bed nucleus of the stria terminalis principle subdivision-mediated circuit, resulting in reduced HPA activation after stress. Collectively, the results support the hypothesis that sucrose limits stress responses via plastic changes to the structure and function of stress-regulatory neural circuits. The work also illustrates that advanced statistical methods are useful approaches to identify potentially novel and important underlying relationships in biological datasets.

  4. Amygdala Modulation of Cerebellar Learning.

    Science.gov (United States)

    Farley, Sean J; Radley, Jason J; Freeman, John H

    2016-02-17

    Previous studies showed that amygdala lesions or inactivation slow the acquisition rate of cerebellum-dependent eyeblink conditioning, a type of associative motor learning. The current study was designed to determine the behavioral nature of amygdala-cerebellum interactions, to identify the neural pathways underlying amygdala-cerebellum interactions, and to examine how the amygdala influences cerebellar learning mechanisms in rats. Pharmacological inactivation of the central amygdala (CeA) severely impaired acquisition and retention of eyeblink conditioning, indicating that the amygdala continues to interact with the cerebellum after conditioning is consolidated (Experiment 1). CeA inactivation also substantially reduced stimulus-evoked and learning-related neuronal activity in the cerebellar anterior interpositus nucleus during acquisition and retention of eyeblink conditioning (Experiment 2). A very small proportion of cerebellar neurons responded to the conditioned stimulus (CS) during CeA inactivation. Finally, retrograde and anterograde tracing experiments identified the basilar pontine nucleus at the confluence of outputs from CeA that may support amygdala modulation of CS input to the cerebellum (Experiment 3). Together, these results highlight a role for the CeA in the gating of CS-related input to the cerebellum during motor learning that is maintained even after the conditioned response is well learned. The current study is the first to demonstrate that the amygdala modulates sensory-evoked and learning-related neuronal activity within the cerebellum during acquisition and retention of associative learning. The findings suggest a model of amygdala-cerebellum interactions in which the amygdala gates conditioned stimulus inputs to the cerebellum through a direct projection from the medial central nucleus to the basilar pontine nucleus. Amygdala gating of sensory input to the cerebellum may be an attention-like mechanism that facilitates cerebellar learning

  5. Stress, memory and the amygdala.

    Science.gov (United States)

    Roozendaal, Benno; McEwen, Bruce S; Chattarji, Sumantra

    2009-06-01

    Emotionally significant experiences tend to be well remembered, and the amygdala has a pivotal role in this process. But the efficient encoding of emotional memories can become maladaptive - severe stress often turns them into a source of chronic anxiety. Here, we review studies that have identified neural correlates of stress-induced modulation of amygdala structure and function - from cellular mechanisms to their behavioural consequences. The unique features of stress-induced plasticity in the amygdala, in association with changes in other brain regions, could have long-term consequences for cognitive performance and pathological anxiety exhibited in people with affective disorders.

  6. Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder.

    Science.gov (United States)

    Aghajani, Moji; Veer, Ilya M; van Hoof, Marie-José; Rombouts, Serge A R B; van der Wee, Nic J; Vermeiren, Robert R J M

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. © 2016 Wiley Periodicals, Inc.

  7. Basolateral sorting of the coxsackie and adenovirus receptor through interaction of a canonical YXXPhi motif with the clathrin adaptors AP-1A and AP-1B.

    Science.gov (United States)

    Carvajal-Gonzalez, Jose Maria; Gravotta, Diego; Mattera, Rafael; Diaz, Fernando; Perez Bay, Andres; Roman, Angel C; Schreiner, Ryan P; Thuenauer, Roland; Bonifacino, Juan S; Rodriguez-Boulan, Enrique

    2012-03-06

    The coxsackie and adenovirus receptor (CAR) plays key roles in epithelial barrier function at the tight junction, a localization guided in part by a tyrosine-based basolateral sorting signal, (318)YNQV(321). Sorting motifs of this type are known to route surface receptors into clathrin-mediated endocytosis through interaction with the medium subunit (μ2) of the clathrin adaptor AP-2, but how they guide new and recycling membrane proteins basolaterally is unknown. Here, we show that YNQV functions as a canonical YxxΦ motif, with both Y318 and V321 required for the correct basolateral localization and biosynthetic sorting of CAR, and for interaction with a highly conserved pocket in the medium subunits (μ1A and μ1B) of the clathrin adaptors AP-1A and AP-1B. Knock-down experiments demonstrate that AP-1A plays a role in the biosynthetic sorting of CAR, complementary to the role of AP-1B in basolateral recycling of this receptor. Our study illustrates how two clathrin adaptors direct basolateral trafficking of a plasma membrane protein through interaction with a canonical YxxΦ motif.

  8. Altered resting-state amygdala functional connectivity after 36 hours of total sleep deprivation.

    Directory of Open Access Journals (Sweden)

    Yongcong Shao

    Full Text Available Recent neuroimaging studies have identified a potentially critical role of the amygdala in disrupted emotion neurocircuitry in individuals after total sleep deprivation (TSD. However, connectivity between the amygdala and cerebral cortex due to TSD remains to be elucidated. In this study, we used resting-state functional MRI (fMRI to investigate the functional connectivity changes of the basolateral amygdala (BLA and centromedial amygdala (CMA in the brain after 36 h of TSD.Fourteen healthy adult men aged 25.9 ± 2.3 years (range, 18-28 years were enrolled in a within-subject crossover study. Using the BLA and CMA as separate seed regions, we examined resting-state functional connectivity with fMRI during rested wakefulness (RW and after 36 h of TSD.TSD resulted in a significant decrease in the functional connectivity between the BLA and several executive control regions (left dorsolateral prefrontal cortex [DLPFC], right dorsal anterior cingulate cortex [ACC], right inferior frontal gyrus [IFG]. Increased functional connectivity was found between the BLA and areas including the left posterior cingulate cortex/precuneus (PCC/PrCu and right parahippocampal gyrus. With regard to CMA, increased functional connectivity was observed with the rostral anterior cingulate cortex (rACC and right precentral gyrus.These findings demonstrate that disturbance in amygdala related circuits may contribute to TSD psychophysiology and suggest that functional connectivity studies of the amygdala during the resting state may be used to discern aberrant patterns of coupling within these circuits after TSD.

  9. Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney

    International Nuclear Information System (INIS)

    Rogers, S.A.; Hammerman, M.R.

    1989-01-01

    To delineate pathways for signal transduction by growth hormone (GH) in proximal tubule, the authors incubated basolateral membranes isolated from canine kidney with human growth hormone (hGH) or human prolactin (hPrl) and measured levels of inositol trisphosphate (InsP 3 ) in suspensions and of diacylglycerol extractable from the membranes. Incubation with hGH, but not hPrl, increased levels of InsP 3 and diacylglycerol in a concentration-dependent manner. Half-maximal effects occurred between 0.1 and 1 nM hGH. Increased levels of InsP 3 were measured after as little as 5 sec of incubation with 1 nM hGH, and increase was maximal after 15 sec. Increases were no longer detectable after 60 sec because of dephosphorylation of InsP 3 in membrane suspensions. hGH did not affect rates of dephosphorylation. hGH-stimulated increases in InsP 3 were detectable in membranes suspended in 0, 0.1, and 0.2 μM calcium but not in 0.3 or 1.0 μM calcium. 125 I-labeled hGH-receptor complexes with M r values of 66,000 and 140,000 were identified in isolated basolateral membranes. The findings establish that GH activates phospholipase C in isolated canine renal proximal tubular basolateral membranes, potentially after binding to a specific receptor. This process could mediate signal transmission by GH across the plasma membrane of the proximal tubular cell and elsewhere

  10. Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing.

    Science.gov (United States)

    Wellman, Cara L; Camp, Marguerite; Jones, V Morgan; MacPherson, Kathryn P; Ihne, Jessica; Fitzgerald, Paul; Maroun, Mouna; Drabant, Emily; Bogdan, Ryan; Hariri, Ahmad R; Holmes, Andrew

    2013-12-01

    Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry. © 2013.

  11. Optogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine.

    Science.gov (United States)

    Warlow, Shelley M; Robinson, Mike J F; Berridge, Kent C

    2017-08-30

    Addiction is often characterized by intense motivation for a drug, which may be narrowly focused at the expense of other rewards. Here, we examined the role of amygdala-related circuitry in the amplification and narrowing of motivation focus for intravenous cocaine. We paired optogenetic channelrhodopsin (ChR2) stimulation in either central nucleus of amygdala (CeA) or basolateral amygdala (BLA) of female rats with one particular nose-poke porthole option for earning cocaine infusions (0.3 mg/kg, i.v.). A second alternative porthole earned identical cocaine but without ChR2 stimulation. Consequently, CeA rats quickly came to pursue their CeA ChR2-paired cocaine option intensely and exclusively, elevating cocaine intake while ignoring their alternative cocaine alone option. By comparison, BLA ChR2 pairing failed to enhance cocaine motivation. CeA rats also emitted consummatory bites toward their laser-paired porthole, suggesting that higher incentive salience made that cue more attractive. A separate progressive ratio test of incentive motivation confirmed that CeA ChR2 amplified rats' motivation, raising their breakpoint effort price for cocaine by 10-fold. However, CeA ChR2 laser on its own lacked any reinforcement value: laser by itself was never self-stimulated, not even by the same rats in which it amplified motivation for cocaine. Conversely, CeA inhibition by muscimol/baclofen microinjections prevented acquisition of cocaine self-administration and laser preference, whereas CeA inhibition by optogenetic halorhodopsin suppressed cocaine intake, indicating that CeA circuitry is needed for ordinary cocaine motivation. We conclude that CeA ChR2 excitation paired with a cocaine option specifically focuses and amplifies motivation to produce intense pursuit and consumption focused on that single target. SIGNIFICANCE STATEMENT In addiction, intense incentive motivation often becomes narrowly focused on a particular drug of abuse. Here we show that pairing central

  12. Anticonvulsant effect of aqueous extract of Valeriana officinalis in amygdala-kindled rats: possible involvement of adenosine.

    Science.gov (United States)

    Rezvani, Mohammad Ebrahim; Roohbakhsh, Ali; Allahtavakoli, Mohammad; Shamsizadeh, Ali

    2010-02-03

    Valeriana officinalis L. (valerian) root extract has been used as an antiepileptic herbal medicine in Iran. In the present study the effect of valerian extracts on an experimental model of temporal lobe epilepsy (TLE) was evaluated. Moreover, the involvement of adenosine system in the actions of aqueous extract of valerian was evaluated. Bipolar stimulating and monopolar recording electrodes were implanted stereotaxically in the right basolateral amygdala of male Sprague-Dawley rats. After kindling, the effect of aqueous (200, 500 and 800 mg/kg; intraperitoneal) and petroleum ether (PE; 50 and 100mg/kg; intraperitoneal) extracts of valerian and CPT (selective A(1) receptor antagonist; 10 and 20 microM; intracerebroventricular) on afterdischarge duration (ADD), duration of stage 5 seizure (S5D) and latency to the onset of bilateral forelimb clonuses (S4L) were measured. The effect of CPT (10 microM) on the response of aqueous extract of valerian (500 mg/kg) was also determined. The results showed that aqueous extract of valerian had anticonvulsant effect. However, PE extract and CPT (20 microM) had proconvulsant effect. Administration of CPT (10 microM) before the administration of aqueous extract decreased the anticonvulsant effect of valerian. The results showed significant anticonvulsant effect for aqueous but not PE extract of valerian. Moreover, CPT as a selective adenosine A(1) receptor antagonist decreased the anticonvulsant effect of valerian aqueous extract. Therefore, we concluded that part of anticonvulsant effect of valerian probably is mediated through activation of adenosine system. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  13. Molecular and Neuronal Plasticity Mechanisms in the Amygdala-Prefrontal Cortical Circuit: Implications for Opiate Addiction Memory Formation

    Directory of Open Access Journals (Sweden)

    Laura G Rosen

    2015-11-01

    Full Text Available The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related ‘trigger’ memories that may persist for lengthy periods of time, even during abstinence, in both humans and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC and basolateral nucleus of the amygdala (BLA share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway’s ventral tegmental area (VTA and nucleus accumbens (NAc and can modulate dopamine (DA transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modelling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK and the Ca2+/calmodulin

  14. Serotonin transporter genotype modulates functional connectivity between amygdala and PCC/PCu during mood recovery

    OpenAIRE

    Fang, Zhuo; Zhu, Senhua; Gillihan, Seth J.; Korczykowski, Marc; Detre, John A.; Rao, Hengyi

    2013-01-01

    The short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with increased susceptibility to depression. Previous neuroimaging studies have consistently showed increased amygdala activity during the presentation of negative stimuli or regulation of negative emotion in the homozygous short allele carriers, suggesting the key role of amygdala response in mediating increased risk for depression. The brain default mode network (DMN) has also been sho...

  15. Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice

    OpenAIRE

    Romo-Parra, H.; Blaesse, P.; Sosulina, L.; Pape, H.-C.

    2015-01-01

    Neurosteroids are formed de novo in the brain and can modulate both inhibitory and excitatory neurotransmission. Recent evidence suggests that the anxiolytic effects of neurosteroids are mediated by the amygdala, a key structure for emotional and cognitive behaviors. Tonic inhibitory signaling via extrasynaptic type A γ-aminobutyric acid receptors (GABAARs) is known to be crucially involved in regulating network activity in various brain regions including subdivisions of the amygdala. Here we...

  16. Involvement of the amygdala in memory storage: Interaction with other brain systems

    OpenAIRE

    McGaugh, James L.; Cahill, Larry; Roozendaal, Benno

    1996-01-01

    There is extensive evidence that the amygdala is involved in affectively influenced memory. The central hypothesis guiding the research reviewed in this paper is that emotional arousal activates the amygdala and that such activation results in the modulation of memory storage occurring in other brain regions. Several lines of evidence support this view. First, the effects of stress-related hormones (epinephrine and glucocorticoids) are mediated by influences involving ...

  17. Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease.

    Science.gov (United States)

    Takeda, Takahiro; Seilhean, Danielle; Le Ber, Isabelle; Millecamps, Stéphanie; Sazdovitch, Véronique; Kitagawa, Kazuo; Uchihara, Toshiki; Duyckaerts, Charles

    2017-09-01

    TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds. Conventional and immunological stainings were performed and we quantified the numerical density of inclusions on a regional basis. TDP-43 inclusions in amygdala could be seen in 10 out of 26 sFTLD/MND cases, 5 out of 9 FTLD/MND-C9 cases, and all 4 FTLD-GRN cases. Their numerical density was lower in FTLD/MND-C9 than in sFTLD/MND and FTLD-GRN. TDP-43 inclusions were more numerous in the ventral region of the basolateral nucleus group in all subtypes. This contrast was apparent in sporadic and C9-mutated FTLD/MND, while it was less evident in FTLD-GRN. Such differences in subregional involvement of amygdala may be related to the region-specific neuronal connections that are differentially affected in FTLD/MND and FTLD-GRN. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  18. Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: Implications for psychopathology.

    Science.gov (United States)

    Cacciaglia, Raffaele; Nees, Frauke; Grimm, Oliver; Ridder, Stephanie; Pohlack, Sebastian T; Diener, Slawomira J; Liebscher, Claudia; Flor, Herta

    2017-02-01

    Stress exposure causes a structural reorganization in neurons of the amygdala. In particular, animal models have repeatedly shown that both acute and chronic stress induce neuronal hypertrophy and volumetric increase in the lateral and basolateral nuclei of amygdala. These effects are visible on the behavioral level, where stress enhances anxiety behaviors and provokes greater fear learning. We assessed stress and anxiety levels in a group of 18 healthy human trauma-exposed individuals (TR group) compared to 18 non-exposed matched controls (HC group), and related these measurements to amygdala volume. Traumas included unexpected adverse experiences such as vehicle accidents or sudden loss of a loved one. As a measure of aversive learning, we implemented a cued fear conditioning paradigm. Additionally, to provide a biological marker of chronic stress, we measured the sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis using a dexamethasone suppression test. Compared to the HC, the TR group showed significantly higher levels of chronic stress, current stress and trait anxiety, as well as increased volume of the left amygdala. Specifically, we observed a focal enlargement in its lateral portion, in line with previous animal data. Compared to HC, the TR group also showed enhanced late acquisition of conditioned fear and deficient extinction learning, as well as salivary cortisol hypo-suppression to dexamethasone. Left amygdala volumes positively correlated with suppressed morning salivary cortisol. Our results indicate differences in trauma-exposed individuals which resemble those previously reported in animals exposed to stress and in patients with post-traumatic stress disorder and depression. These data provide new insights into the mechanisms through which traumatic stress might prompt vulnerability for psychopathology. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. From circuits to behaviour in the amygdala

    Science.gov (United States)

    Janak, Patricia H.; Tye, Kay M.

    2015-01-01

    The amygdala has long been associated with emotion and motivation, playing an essential part in processing both fearful and rewarding environmental stimuli. How can a single structure be crucial for such different functions? With recent technological advances that allow for causal investigations of specific neural circuit elements, we can now begin to map the complex anatomical connections of the amygdala onto behavioural function. Understanding how the amygdala contributes to a wide array of behaviours requires the study of distinct amygdala circuits. PMID:25592533

  20. Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit.

    Science.gov (United States)

    Verma, Dilip; Wood, James; Lach, Gilliard; Herzog, Herbert; Sperk, Guenther; Tasan, Ramon

    2016-01-01

    Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders.

  1. Distinctive amygdala subregions involved in emotion-modulated Stroop interference.

    Science.gov (United States)

    Han, Hyun Jung; Lee, Kanghee; Kim, Hyun Taek; Kim, Hackjin

    2014-05-01

    Despite the well-known role of the amygdala in mediating emotional interference during tasks requiring cognitive resources, no definite conclusion has yet been reached regarding the differential roles of functionally and anatomically distinctive subcomponents of the amygdala in such processes. In this study, we examined female participants and attempted to separate the neural processes for the detection of emotional information from those for the regulation of cognitive interference from emotional distractors by adding a temporal gap between emotional stimuli and a subsequent cognitive Stroop task. Reaction time data showed a significantly increased Stroop interference effect following emotionally negative stimuli compared with neutral stimuli, and functional magnetic resonance imaging data revealed that the anterior ventral amygdala (avAMYG) showed greater responses to negative stimuli compared with neutral stimuli. In addition, individuals who scored high in neuroticism showed greater posterior dorsal amygdala (pdAMYG) responses to incongruent compared with congruent Stroop trials following negative stimuli, but not following neutral stimuli. Taken together, the findings of this study demonstrated functionally distinctive contributions of the avAMYG and pdAMYG to the emotion-modulated Stroop interference effect and suggested that the avAMYG encodes associative values of emotional stimuli whereas the pdAMYG resolves cognitive interference from emotional distractors.

  2. Amygdala Reactivity and Negative Emotionality: Divergent Correlates of Antisocial Personality and Psychopathy Traits in a Community Sample

    Science.gov (United States)

    Hyde, Luke W.; Byrd, Amy L.; Votruba-Drzal, Elizabeth; Hariri, Ahmad R.; Manuck, Stephen B.

    2014-01-01

    Previous studies have emphasized that antisocial personality disorder (APD) and psychopathy overlap highly but differ critically in several features, notably negative emotionality (NEM) and possibly amygdala reactivity to social signals of threat and distress. Here we examined whether dimensions of psychopathy and APD correlate differentially with NEM and amygdala reactivity to emotional faces. Testing these relationships among healthy individuals, dimensions of psychopathy and APD were generated by the profile matching technique of Lynam and Widiger (2001), using facet scales of the NEO Personality Inventory-Revised, and amygdala reactivity was measured using a well-established emotional faces task, in a community sample of 103 men and women. Higher psychopathy scores were associated with lower NEM and lower amygdala reactivity, whereas higher APD scores were related to greater NEM and greater amygdala reactivity, but only after overlapping variance in APD and psychopathy was adjusted for in the statistical model. Amygdala reactivity did not mediate the relationship of APD and psychopathy scores to NEM. Supplemental analyses also compared other measures of factors within psychopathy in predicting NEM and amygdala reactivity and found that Factor 2 psychopathy was positively related to NEM and amygdala reactivity across measures of psychopathy. The overall findings replicate seminal observations on NEM in psychopathy by Hicks and Patrick (2006) and extend this work to neuroimaging in a normative population. They also suggest that one critical way in which APD and psychopathy dimensions may differ in their etiology is through their opposing levels of NEM and amygdala reactivity to threat. PMID:24661171

  3. Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation

    Science.gov (United States)

    Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andrew C.; Botteron, Kelly N.; Harms, Michael P.; Barch, Deanna M.

    2015-01-01

    Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID:26595470

  4. Impairment of fear memory consolidation in maternally stressed male mouse offspring: evidence for nongenomic glucocorticoid action on the amygdala.

    Science.gov (United States)

    Lee, Eun Jeong; Son, Gi Hoon; Chung, Sooyoung; Lee, Sukwon; Kim, Jeongyeon; Choi, Sukwoo; Kim, Kyungjin

    2011-05-11

    The environment in early life elicits profound effects on fetal brain development that can extend into adulthood. However, the long-lasting impact of maternal stress on emotional learning remains largely unknown. Here, we focus on amygdala-related learning processes in maternally stressed mice. In these mice, fear memory consolidation and certain related signaling cascades were significantly impaired, though innate fear, fear memory acquisition, and synaptic NMDA receptor expression in the amygdala were unaltered. In accordance with these findings, maintenance of long-term potentiation (LTP) at amygdala synapses, but not its induction, was significantly impaired in the maternally stressed animals. Interestingly, amygdala glucocorticoid receptor expression was reduced in the maternally stressed mice, and administration of glucocorticoids (GCs) immediately after fear conditioning and LTP induction restored memory consolidation and LTP maintenance, respectively, suggesting that a weakening of GC signaling was responsible for the observed impairment. Furthermore, microinfusion of a membrane-impermeable form of GC (BSA-conjugated GC) into the amygdala mimicked the restorative effects of GC, indicating that a nongenomic activity of GC mediates the restorative effect. Together, these findings suggest that prenatal stress induces long-term dysregulation of nongenomic GC action in the amygdala of adult offspring, resulting in the impairment of fear memory consolidation. Since modulation of amygdala activity is known to alter the consolidation of emotionally influenced memories allocated in other brain regions, the nongenomic action of GC on the amygdala shown herein may also participate in the amygdala-dependent modulation of memory consolidation.

  5. Strychnine and Taurine Modulation of Amygdala-associated Anxiety-like Behavior is ‘State’ Dependent

    Science.gov (United States)

    McCool, Brian A.; Chappell, Ann

    2007-01-01

    Strychnine-sensitive glycine receptors are expressed in many adult forebrain regions, yet the biological function of these receptors outside the spinal cord/brainstem is poorly understood. We have recently shown that rat lateral/basolateral amygdala neurons express strychnine-sensitive glycine-gated currents whose pharmacological and molecular characteristics are consistent with those established for classic ligand-gated chloride channels. The current studies were undertaken to establish the behavioral role, if any, of these strychnine-sensitive glycine receptors. Adult Long-Evans male rats were implanted with guide cannulae targeted at the lateral amygdala and were micro-injected with standard artificial cerebrospinal fluid with or without various doses of strychnine or taurine. Anxiety-like behaviors were assessed with the elevated plus-maze or the light/dark box. In the elevated plus maze, strychnine decreased closed-arm time and increased open-arm time, suggestive of an anxiolytic effect. Similarly, strychnine produced a modest anxiolytic effect in the light/dark box. Post-hoc analysis of ‘open-arm’ time and ‘light-side’ time indicated that aCSF-treated animals were distributed into two apparent groups that displayed either high or low amounts of anxiety-like behavior in a given apparatus. Surprisingly, the pharmacological effects of both strychnine and taurine in these assays were dependent upon a given animal’s behavioral phenotype. Together, these findings are significant because they suggest that the basal ‘emotional state’ of the animal could influence the behavioral outcome associated with drug application directly into the lateral/basolateral amygdala. Furthermore, our findings also suggest that compounds acting at amygdala strychnine-sensitive glycine receptors may actively modulate this basal anxiety-like state. PMID:17207866

  6. Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats.

    Science.gov (United States)

    Giorgi, Osvaldo; Corda, Maria G; Sabariego, Marta; Giugliano, Valentina; Piludu, Maria A; Rosas, Michela; Acquas, Elio

    2015-05-01

    Roman high (RHA)- and low (RLA)-avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short- and long-term neuronal plasticity via activation of the extracellular signal-regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction. © 2014 Wiley Periodicals, Inc.

  7. Stress, memory and the amygdala

    NARCIS (Netherlands)

    Roozendaal, Benno; McEwen, Bruce S.; Chattarji, Sumantra

    Emotionally significant experiences tend to be well remembered, and the amygdala has a pivotal role in this process. But the efficient encoding of emotional memories can become maladaptive - severe stress often turns them into a source of chronic anxiety. Here, we review studies that have identified

  8. The interplay between the hippocampus and the amygdala in regulating aberrant hippocampal neurogenesis during protracted abstinence from alcohol dependence

    Directory of Open Access Journals (Sweden)

    Chitra D Mandyam

    2013-06-01

    Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.

  9. Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala.

    Science.gov (United States)

    Koenigs, Michael; Grafman, Jordan

    2009-10-01

    Posttraumatic stress disorder (PTSD) is characterized by recurrent distressing memories of an emotionally traumatic event. In this review, the authors present neuroscientific data highlighting the function of two brain areas--the amygdala and ventromedial prefrontal cortex (vmPFC)--in PTSD and related emotional processes. A convergent body of human and nonhuman studies suggests that the amygdala mediates the acquisition and expression of conditioned fear and the enhancement of emotional memory, whereas the vmPFC mediates the extinction of conditioned fear and the volitional regulation of negative emotion. It has been theorized that the vmPFC exerts inhibition on the amygdala, and that a defect in this inhibition could account for the symptoms of PTSD. This theory is supported by functional imaging studies of PTSD patients, who exhibit hypoactivity in the vmPFC but hyperactivity in the amygdala. A recent study of brain-injured and trauma-exposed combat veterans confirms that amygdala damage reduces the likelihood of developing PTSD. But contrary to the prediction of the top-down inhibition model, vmPFC damage also reduces the likelihood of developing PTSD. The putative roles of the amygdala and the vmPFC in the pathophysiology of PTSD, as well as implications for potential treatments, are discussed in light of these results.

  10. Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation Within the Amygdala

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    Antonio Aubry

    2016-10-01

    Full Text Available Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by which stress affects the amygdala and amygdala-dependent fear memories remain unclear. Here we review the literature on the enhancing effects of acute and chronic stress on the acquisition and/or consolidation of a fear memory, as measured by auditory Pavlovian fear conditioning, and discuss potential mechanisms by which these changes occur in the amygdala. We hypothesize that stress-mediated activation of glucocorticoid receptors (GR and norepinephrine release within the amygdala leads to the mobilization of AMPA receptors to the synapse, which underlies stress-induced increases in fear memory. We discuss the implications of this hypothesis for evaluating the effects of stress on extinction and for developing treatments for anxiety disorders. Understanding how stress-induced changes in glucocorticoid and norepinephrine signaling might converge to affect emotional learning by increasing the trafficking of AMPA receptors and enhancing amygdala excitability is a promising area for future research.

  11. Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation within the Amygdala.

    Science.gov (United States)

    Aubry, Antonio V; Serrano, Peter A; Burghardt, Nesha S

    2016-01-01

    Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by which stress affects the amygdala and amygdala-dependent fear memories remain unclear. Here we review the literature on the enhancing effects of acute and chronic stress on the acquisition and/or consolidation of a fear memory, as measured by auditory Pavlovian fear conditioning, and discuss potential mechanisms by which these changes occur in the amygdala. We hypothesize that stress-mediated activation of glucocorticoid receptors (GR) and norepinephrine release within the amygdala leads to the mobilization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the synapse, which underlies stress-induced increases in fear memory. We discuss the implications of this hypothesis for evaluating the effects of stress on extinction and for developing treatments for anxiety disorders. Understanding how stress-induced changes in glucocorticoid and norepinephrine signaling might converge to affect emotional learning by increasing the trafficking of AMPA receptors and enhancing amygdala excitability is a promising area for future research.

  12. Different patterns of amygdala priming differentially affect dentate gyrus plasticity and corticosterone, but not CA1 plasticity.

    Directory of Open Access Journals (Sweden)

    Rose-Marie eVouimba

    2013-05-01

    Full Text Available Stress-induced activation of the amygdala is involved in the modulation of memory processes in the hippocampus. However, stress effects on amygdala and memory remain complex. The activation of the basolateral amygdala (BLA was found to modulate plasticity in other brain areas, including the hippocampus. We previously demonstrated a differential effect of BLA priming on LTP in the CA1 and the dentate gyrus (DG. While BLA priming suppressed long term potentiation (LTP in CA1, it was found to enhance it in the DG. However, since the amygdala itself is amenable to experience-induced plasticity it is thus conceivable that when activity within the amygdala is modified this will have impact on the way the amygdala modulates activity and plasticity in other brain areas. In the current study we examined the effects of different patterns of BLA activation on the modulation of LTP in the DG and CA1, as well as on serum corticosterone (CORT. In CA1, BLA priming impaired LTP induction as was reported before. In contrast, in the DG, varying BLA stimulation intensity and frequency resulted in differential effects on LTP, ranging from no effect to strong impairment or enhancement. Varying BLA stimulation patterns resulted in also differential alterations in Serum CORT, leading to higher CORT levels being positively correlated with LTP magnitude in DG but not in CA1.The results support the notion of a differential role for the DG in aspects of memory, and add to this view the possibility that DG-associated aspects of memory will be enhanced under more emotional or stressful conditions. It is interesting to think of BLA patterns of activation and the differential levels of circulating CORT as two arms of the emotional and stress response that attempt to synchronize brain activity to best meet the challenge. It is foreseeable to think of abnormal such synchronization under extreme conditions, which would lead to the development of maladaptive behavior.

  13. Distinct Roles for the Amygdala and Orbitofrontal Cortex in Representing the Relative Amount of Expected Reward.

    Science.gov (United States)

    Saez, Rebecca A; Saez, Alexandre; Paton, Joseph J; Lau, Brian; Salzman, C Daniel

    2017-07-05

    The same reward can possess different motivational meaning depending upon its magnitude relative to other rewards. To study the neurophysiological mechanisms mediating assignment of motivational meaning, we recorded the activity of neurons in the amygdala and orbitofrontal cortex (OFC) of monkeys during a Pavlovian task in which the relative amount of liquid reward associated with one conditioned stimulus (CS) was manipulated by changing the reward amount associated with a second CS. Anticipatory licking tracked relative reward magnitude, implying that monkeys integrated information about recent rewards to adjust the motivational meaning of a CS. Upon changes in relative reward magnitude, neural responses to reward-predictive cues updated more rapidly in OFC than amygdala, and activity in OFC but not the amygdala was modulated by recent reward history. These results highlight a distinction between the amygdala and OFC in assessing reward history to support the flexible assignment of motivational meaning to sensory cues. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Auditory responses in the amygdala to social vocalizations

    Science.gov (United States)

    Gadziola, Marie A.

    The underlying goal of this dissertation is to understand how the amygdala, a brain region involved in establishing the emotional significance of sensory input, contributes to the processing of complex sounds. The general hypothesis is that communication calls of big brown bats (Eptesicus fuscus) transmit relevant information about social context that is reflected in the activity of amygdalar neurons. The first specific aim analyzed social vocalizations emitted under a variety of behavioral contexts, and related vocalizations to an objective measure of internal physiological state by monitoring the heart rate of vocalizing bats. These experiments revealed a complex acoustic communication system among big brown bats in which acoustic cues and call structure signal the emotional state of a sender. The second specific aim characterized the responsiveness of single neurons in the basolateral amygdala to a range of social syllables. Neurons typically respond to the majority of tested syllables, but effectively discriminate among vocalizations by varying the response duration. This novel coding strategy underscores the importance of persistent firing in the general functioning of the amygdala. The third specific aim examined the influence of acoustic context by characterizing both the behavioral and neurophysiological responses to natural vocal sequences. Vocal sequences differentially modify the internal affective state of a listening bat, with lower aggression vocalizations evoking the greatest change in heart rate. Amygdalar neurons employ two different coding strategies: low background neurons respond selectively to very few stimuli, whereas high background neurons respond broadly to stimuli but demonstrate variation in response magnitude and timing. Neurons appear to discriminate the valence of stimuli, with aggression sequences evoking robust population-level responses across all sound levels. Further, vocal sequences show improved discrimination among stimuli

  15. Serotonin Transporter Genotype Modulates Functional Connectivity between Amygdala and PCC/PCu during Mood Recovery

    Directory of Open Access Journals (Sweden)

    Zhuo eFang

    2013-10-01

    Full Text Available The short (S allele of the serotonin transporter-linked polymorphic region (5-HTTLPR has been associated with increased susceptibility to depression. Previous neuroimaging studies have consistently showed increased amygdala activity during the presentation of negative stimuli or regulation of negative emotion in the homozygous short allele carriers, suggesting the key role of amygdala response in mediating increased risk for depression. The default brain network (DMN has also been shown to modulate amygdala activity. However, it remains unclear whether 5-HTTLPR genetic variation modulates functional connectivity between the amygdala and regions of DMN. In this study, we re-analyzed our previous imaging dataset and examined the effects of 5-HTTLPR genetic variation on amygdala connectivity. A total of 15 homozygous short (S/S and 15 homozygous long individuals (L/L were scanned in functional MRI during four blocks: baseline, sad mood, mood recovery, and return to baseline. The S/S and L/L groups showed a similar pattern of functional connectivity and no differences were found between the two groups during baseline and sad mood scans. However, during mood recovery, the S/S group showed significantly reduced anti-correlations between amygdala and posterior cingulate cortex/precuneus (PCC/PCu compared to the L/L group. Moreover, PCC/PCu-amygdala connectivity correlated with amygdala activity in the S/S group but not the L/L group. These results suggest that 5-HTTLPR genetic variation modulates amygdala connectivity which subsequently affects its activity during mood regulation, providing an additional mechanism by which the S allele confers depression risk.

  16. Serotonin transporter genotype modulates functional connectivity between amygdala and PCC/PCu during mood recovery.

    Science.gov (United States)

    Fang, Zhuo; Zhu, Senhua; Gillihan, Seth J; Korczykowski, Marc; Detre, John A; Rao, Hengyi

    2013-01-01

    The short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with increased susceptibility to depression. Previous neuroimaging studies have consistently showed increased amygdala activity during the presentation of negative stimuli or regulation of negative emotion in the homozygous short allele carriers, suggesting the key role of amygdala response in mediating increased risk for depression. The brain default mode network (DMN) has also been shown to modulate amygdala activity. However, it remains unclear whether 5-HTTLPR genetic variation modulates functional connectivity (FC) between the amygdala and regions of DMN. In this study, we re-analyzed our previous imaging dataset and examined the effects of 5-HTTLPR genetic variation on amygdala connectivity. A total of 15 homozygous short (S/S) and 15 homozygous long individuals (L/L) were scanned in functional magnetic resonance imaging (fMRI) during four blocks: baseline, sad mood, mood recovery, and return to baseline. The S/S and L/L groups showed a similar pattern of FC and no differences were found between the two groups during baseline and sad mood scans. However, during mood recovery, the S/S group showed significantly reduced anti-correlation between amygdala and posterior cingulate cortex/precuneus (PCC/PCu) compared to the L/L group. Moreover, PCC/PCu-amygdala connectivity correlated with amygdala activity in the S/S group but not the L/L group. These results suggest that 5-HTTLPR genetic variation modulates amygdala connectivity which subsequently affects its activity during mood regulation, providing an additional mechanism by which the S allele confers depression risk.

  17. Amygdala responses to Valence and its interaction by arousal revealed by MEG.

    Science.gov (United States)

    Styliadis, Charalampos; Ioannides, Andreas A; Bamidis, Panagiotis D; Papadelis, Christos

    2014-07-01

    It is widely accepted that the amygdala plays a crucial role in the processing of emotions. The precise nature of its involvement is however unclear. We hypothesized that ambivalent findings from neuroimaging studies that report amygdala's activity in emotions, are due to distinct functional specificity of amygdala's sub-divisions and specifically to differential reactivity to arousal and valence. The goal of the present study is to characterize the amygdala response to affective stimuli by disentangling the contributions of arousal and valence. Our hypothesis was prompted by recent reports claiming anatomical sub-divisions of amygdala based on cytoarchitecture and the functional maps obtained from diverse behavioral, emotional, and physiological stimulation. We measured magnetoencephalography (MEG) recordings from 12 healthy individuals passively exposed to affective stimuli from the International Affective Picture System (IAPS) collection using a 2 (Valence levels)× 2 (Arousal levels) design. Source power was estimated using a beamformer technique with the activations referring to the amygdala sub-divisions defined through probabilistic cytoarchitectonic maps. Right laterobasal amygdala activity was found to mediate negative valence (elicited by unpleasant stimuli) while left centromedial activity was characterized by an interaction of valence by arousal (arousing pleasant stimuli). We did not find a main effect for amygdala activations in any of its sub-divisions for arousal modulation. To the best of our knowledge, our findings from non-invasive MEG data indicate for the first time, a distinct functional specificity of amygdala anatomical sub-divisions in the emotional processing. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Inhibitory modulation of medial prefrontal cortical activation on lateral orbitofrontal cortex-amygdala information flow.

    Science.gov (United States)

    Chang, Chun-Hui; Ho, Ta-Wen

    2017-09-01

    The basolateral complex of the amygdala (BLA) receives input from the lateral orbitofrontal cortex (lOFC) for cue-outcome contingencies and the medial prefrontal cortex (mPFC) for emotion control. Here we examined how the mPFC modulates lOFC-BLA information flow. We found that the majority of BLA neurons responsive to lOFC stimulation were also responsive to mPFC stimulation. Activation of the mPFC exerted an inhibitory modulation of the lOFC-BLA pathway, which was reversed with intra-amygdala blockade of GABAergic receptors. mPFC tetanus potentiated the lOFC-BLA pathway, but did not alter its inhibitory modulatory gating. These results show that the mPFC potently inhibits lOFC drive of the BLA in a GABA-dependent manner, which is informative in understanding the normal and potential pathophysiological state of emotion and contingency associations in regulating behaviour. Several neocortical projections converge onto the basolateral complex of the amygdala (BLA), including the lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC). Lateral orbitofrontal input to the BLA is important for cue-outcome contingencies, while medial prefrontal input is essential for emotion control. In this study, we examined how the mPFC, specifically the infralimbic division of the mPFC, modulates lOFC-BLA information flow, using combined in vivo extracellular single-unit recordings and pharmacological manipulations in anaesthetized rats. We found that the majority (over 95%) of BLA neurons that responded to lOFC stimulation also responded to mPFC stimulation. Compared to basal condition, pharmacological (N-methyl-d-aspartate) or electrical activation of the mPFC exerted an inhibitory modulation of the lOFC-BLA pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABA A and GABA B antagonists (bicuculline and saclofen). Moreover, mPFC tetanus potentiated the lOFC-BLA pathway, but mPFC tetanus or low-frequency stimulation did

  19. Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules.

    Science.gov (United States)

    Schulze, Ulf; Brast, Sabine; Grabner, Alexander; Albiker, Christian; Snieder, Beatrice; Holle, Svenja; Schlatter, Eberhard; Schröter, Rita; Pavenstädt, Hermann; Herrmann, Edwin; Lambert, Carsten; Spoden, Gilles A; Florin, Luise; Saftig, Paul; Ciarimboli, Giuliano

    2017-04-01

    CD63 is a ubiquitously expressed member of the tetraspanin superfamily. Using a mating-based split-ubiquitin-yeast 2-hybrid system, pull-down experiments, total internal reflection fluorescence microscopy, Förster resonance energy transfer, and biotinylation assays, we found that CD63 interacts with human organic cation transporter 2 (hOCT2), which transports endogenous and exogenous substrates, such as neurotransmitters and drugs in several epithelial cells. CD63 overexpression affects cellular localization of hOCT2 expressed in human embryonic kidney (HEK)293 cells. Studies with CD63-knockout mice indicate that in renal proximal tubules, CD63 determines the insertion of the mouse ortholog of the transporter into the proper membrane domain and mediates transporter regulation by trafficking processes. In polarized Madin-Darby kidney canine kidney (MDCK) epithelial cells, CD63 and hOCT2 colocalize with the small GTPase Rab4, which controls the rapid recycling from sorting endosomes back to the cell surface. Suitable negative and positive control experiments were performed for each experimental approach. Empty vector transfected cells and wild-type mice were used as control. CD63 seems to play a role in the recycling of hOCT2 from endosomes to the basolateral membrane in polarized epithelia. These data indicate that CD63 has a previously uncharacterized function in regulating trafficking of specific membrane proteins in polarized cells.-Schulze, U., Brast, S., Grabner, A., Albiker, C., Snieder, B., Holle, S., Schlatter, E., Schröter, R., Pavenstädt, H., Herrmann, E., Lambert, C., Spoden, G. A., Florin, L., Saftig, P., Ciarimboli, G. Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. © FASEB.

  20. Hepatic taurine transport: a Na+-dependent carrier on the basolateral plasma membrane

    International Nuclear Information System (INIS)

    Bucuvalas, J.C.; Goodrich, A.L.; Suchy, F.J.

    1987-01-01

    Highly purified rat basolateral liver plasma membrane vesicles were used examine the mechanism and the driving forces for hepatic uptake of the β-amino acid, taurine. An inwardly directed 100 mM NaCl gradient stimulated the initial rate of taurine uptake and energized a transient twofold accumulation of taurine above equilibrium (overshoot). In contrast, uptake was slower and no overshoot was detected in the presence of a KCl gradient. A negative intravesicular electrical potential generated by the presence of permeant anions or an outwardly directed K + gradient with valinomycin increased Na + -stimulated taurine uptake. External Cl - stimulated Na + -dependent taurine uptake independent of effects on the transmembrane electrical potential difference. Na + -dependent taurine uptake showed a sigmoidal dependence on extravesicular Na + concentration, suggesting multiple Na + ions are involved in the translocation of each taurine molecule. Na + -dependent taurine uptake demonstrated Michaelis-Menten kinetics with a maximum velocity of 0.537 nmol x mg protein -1 x min -1 and an apparent K/sub m/ of 174 μM. [ 3 H]taurine uptake was inhibited by the presence of excess unlabeled taurine, β-alanine, or hypotaurine but not by L-glutamine or L-alanine. In summary, using basolateral liver plasma membrane vesicles, the authors have shown that hepatic uptake of taurine occurs by a carrier-mediated, secondary active transport process specific for β-amino acids. Uptake is electrogenic, stimulated by external Cl - , and requires multiple Na + ions for the translocation of each taurine molecule

  1. Amygdala activity associated with social choice in mice.

    Science.gov (United States)

    Mihara, Takuma; Mensah-Brown, Kobina; Sobota, Rosanna; Lin, Robert; Featherstone, Robert; Siegel, Steven J

    2017-08-14

    Studies suggest that the amygdala is a key region for regulation of anxiety, fear and social function. Therefore, dysfunction of the amygdala has been proposed as a potential mechanism for negative symptoms in schizophrenia. This may be due to NMDA receptor-mediated hypofunction, which is thought to be related to the pathogenesis of schizophrenia. In this study, electroencephalographic amygdala activity was assessed in mice during the three-chamber social test. This activity was also evaluated following exposure to the NMDA receptor antagonist ketamine. Vehicle-treated mice spent significantly more time in the social than the non-social chamber. This social preference was eliminated by ketamine. However, ketamine-treated mice spent significantly less time in the social chamber and significantly more time in the nonsocial chamber than vehicle-treated mice. There were no significant differences in induced powers between social and non-social chamber entries in vehicle-treated mice, except for theta frequencies, which featured greater induced theta power during non-social chamber entry. Ketamine eliminated differences in induced theta power between social and non-social chamber entries. Moreover, ketamine increased the induced gamma power during social chamber entry compared to that of vehicle-treated mice. All other frequency ranges were not significantly influenced by zone or drug condition. All significant findings were upon entry to chambers not during interaction. Results suggest that impaired function of NMDA receptor-mediated glutamate transmission can induce social impairments and amygdala dysfunction, similar to the pattern in schizophrenia. Future studies will utilize this method to evaluate mechanisms of social dysfunction and development of treatments of social impairments in schizophrenia. Copyright © 2017. Published by Elsevier B.V.

  2. Pathophysiological Alterations In The Basolateral Amygdala And Neurodegeneration Of Limbic Structures During Epileptogenesis Induced By Status Epilepticus

    Science.gov (United States)

    2009-02-05

    pedestal (MS363; Plastics ONE Inc., Roanoke, VA) and attached to the skull with dental acrylic cement . Anesthesia was reversed by i.p. injection of 1 mg/kg...Armentia M, Power J (2003) The amgydaloid complex: anatomy and physiology. Physiol Rev 83:803-34. Salazar AM, Jabbari B, Vance SC, Grafman J, Amin D

  3. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.

    Science.gov (United States)

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-05-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.

  4. Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety.

    Science.gov (United States)

    Makovac, Elena; Watson, David R; Meeten, Frances; Garfinkel, Sarah N; Cercignani, Mara; Critchley, Hugo D; Ottaviani, Cristina

    2016-11-01

    Generalized anxiety disorder (GAD) is characterized by excessive worry, autonomic dysregulation and functional amygdala dysconnectivity, yet these illness markers have rarely been considered together, nor their interrelationship tested longitudinally. We hypothesized that an individual's capacity for emotion regulation predicts longer-term changes in amygdala functional connectivity, supporting the modification of GAD core symptoms. Sixteen patients with GAD (14 women) and individually matched controls were studied at two time points separated by 1 year. Resting-state fMRI data and concurrent measurement of vagally mediated heart rate variability were obtained before and after the induction of perseverative cognition. A greater rise in levels of worry following the induction predicted a stronger reduction in connectivity between right amygdala and ventromedial prefrontal cortex, and enhanced coupling between left amygdala and ventral tegmental area at follow-up. Similarly, amplified physiological responses to the induction predicted increased connectivity between right amygdala and thalamus. Longitudinal shifts in a distinct set of functional connectivity scores were associated with concomitant changes in GAD symptomatology over the course of the year. Results highlight the prognostic value of indices of emotional dysregulation and emphasize the integral role of the amygdala as a critical hub in functional neural circuitry underlying the progression of GAD symptomatology. © The Author (2016). Published by Oxford University Press.

  5. Impact of sleep quality on amygdala reactivity, negative affect, and perceived stress.

    Science.gov (United States)

    Prather, Aric A; Bogdan, Ryan; Hariri, Ahmad R

    2013-05-01

    Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress. Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level-dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index. Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (β values = 0.18-1.86, p values .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (β values = 0.29-0.44, p values sleep quality or in women, irrespective of sleep quality. This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men.

  6. Role of anxiety in the pathophysiology of irritable bowel syndrome: importance of the amygdala

    Directory of Open Access Journals (Sweden)

    Brent Myers

    2009-06-01

    Full Text Available A common characteristic of irritable bowel syndrome (IBS is that symptoms, including abdominal pain and abnormal bowel habits, are often triggered or exacerbated during periods of stress and anxiety. However, the impact of anxiety and affective disorders on the gastrointestinal (GI tract is poorly understood and may in part explain the lack of effective therapeutic approaches to treat IBS. The amygdala is an important structure for regulating anxiety with the central nucleus of the amygdala (CeA facilitating the activation of the hypothalamic-pituitary-adrenal (HPA axis and the autonomic nervous system in response to stress. Moreover, chronic stress enhances function of the amygdala and promotes neural plasticity throughout the amygdaloid complex. This review outlines the latest findings obtained from human studies and animal models related to the role of the emotional brain in the regulation of enteric function, specifically how increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone (CORT or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. A focus of the review is the relative importance of mineralocorticoid receptor (MR and glucocorticoid receptor (GR-mediated mechanisms within the amygdala in the regulation of anxiety and nociceptive behaviors that are characteristic features of IBS. This review also discusses several outstanding questions important for future research on the role of the amygdala in the generation of abnormal GI function that may lead to potential targets for new therapies to treat functional bowel disorders such as IBS.

  7. Role of anxiety in the pathophysiology of irritable bowel syndrome: importance of the amygdala.

    Science.gov (United States)

    Myers, Brent; Greenwood-Van Meerveld, Beverley

    2009-01-01

    A common characteristic of irritable bowel syndrome (IBS) is that symptoms, including abdominal pain and abnormal bowel habits, are often triggered or exacerbated during periods of stress and anxiety. However, the impact of anxiety and affective disorders on the gastrointestinal (GI) tract is poorly understood and may in part explain the lack of effective therapeutic approaches to treat IBS. The amygdala is an important structure for regulating anxiety with the central nucleus of the amygdala facilitating the activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system in response to stress. Moreover, chronic stress enhances function of the amygdala and promotes neural plasticity throughout the amygdaloid complex. This review outlines the latest findings obtained from human studies and animal models related to the role of the emotional brain in the regulation of enteric function, specifically how increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. A focus of the review is the relative importance of mineralocorticoid receptor and glucocorticoid receptor-mediated mechanisms within the amygdala in the regulation of anxiety and nociceptive behaviors that are characteristic features of IBS. This review also discusses several outstanding questions important for future research on the role of the amygdala in the generation of abnormal GI function that may lead to potential targets for new therapies to treat functional bowel disorders such as IBS.

  8. EBIO, an agent causing maintained epithelial chloride secretion by co-ordinate actions at both apical and basolateral membranes.

    Science.gov (United States)

    MacVinish, L J; Keogh, J; Cuthbert, A W

    2001-01-01

    The effect of 1-ethyl-2-benzimidazolone (EBIO) on electrogenic chloride secretion in murine colonic and nasal epithelium was investigated by the short-circuit technique. In the colon, EBIO produces a sustained current increase in the presence of amiloride, which is sensitive to furosemide. In nasal epithelium EBIO causes only a small, transient current increase. Sustained increases in current were obtained in response to forskolin in both epithelia. To examine the mechanisms by which EBIO increases chloride secretion, the effects on intracellular mediators were measured in colonic crypts. There was no effect on [Ca(2+)]i but cAMP content was increased, more so in the presence of IBMX, indicating a direct effect on adenylate cyclase. In colonic epithelia in which the apical surface was permeabilized by nystatin, and the tissue subjected to an apical to basolateral K(+) gradient, EBIO caused a current increase that was entirely sensitive to charybdotoxin (ChTX). In similarly permeabilized colons Br-cAMP caused a current increase that was entirely sensitive to 293B. Thus EBIO increases chloride secretion in the colon by coordinated actions at both the apical and basolateral faces of the cells. These include direct and indirect actions on Ca(2+)-sensitive and cAMP-sensitive K(+) channels respectively, and indirect actions on the basolateral cotransporter and apical CFTR chloride channels via cAMP. In CF colonic epithelia EBIO did not evoke chloride secretion. It is not clear why the nasal epithelium responds poorly to EBIO whereas it gives a sustained response to the related compound chlorzoxazone.

  9. MRI Amygdala Volume in Williams Syndrome

    Science.gov (United States)

    Capitao, Liliana; Sampaio, Adriana; Sampaio, Cassandra; Vasconcelos, Cristiana; Fernandez, Montse; Garayzabal, Elena; Shenton, Martha E.; Goncalves, Oscar F.

    2011-01-01

    One of the most intriguing characteristics of Williams Syndrome individuals is their hypersociability. The amygdala has been consistently implicated in the etiology of this social profile, particularly given its role in emotional and social behavior. This study examined amygdala volume and symmetry in WS individuals and in age and sex matched…

  10. The Amygdala: An Agent of Change in Adolescent Neural Networks

    Science.gov (United States)

    Scherf, K. Suzanne; Smyth, Joshua M.; Delgado, Mauricio R.

    2013-01-01

    A unique component of adolescent development is the need to master new developmental tasks in which peer interactions become primary (for the purposes of becoming autonomous from parents, forming intimate friendships, and romantic/sexual partnerships). Previously, it has been suggested that the ability to master these tasks requires an important re-organization in the relation between perceptual, motivational, affective, and cognitive systems in a very general and broad way that is fundamentally influenced by the infusion of sex hormones during pubertal development (Scherf et al., 2012). Herein, we extend this argument to suggest that the amygdala, which is vastly connected with cortical and subcortical regions and contains sex hormone receptors, may lie at the heart of this re-organization. We propose that during adolescent development there is a shift in the attribution of relevance to existing stimuli and contexts that is mediated by the amygdala (e.g., heightened relevance of peer faces, reduced relevance of physical distance from parents). As a result, amygdala inputs to existing stable neural networks are re-weighted (increased or decreased), which destabilizes the functional interactions among regions within these networks and allows for a critical restructuring of the network functional organization. This process of network re-organization enables processing of qualitatively new kinds of social information and the emergence of novel behaviors that support mastery of adolescent-specific developmental tasks. PMID:23756154

  11. Effects of early life stress on amygdala and striatal development

    Directory of Open Access Journals (Sweden)

    Dominic S. Fareri

    2016-06-01

    Full Text Available Species-expected caregiving early in life is critical for the normative development and regulation of emotional behavior, the ability to effectively evaluate affective stimuli in the environment, and the ability to sustain social relationships. Severe psychosocial stressors early in life (early life stress; ELS in the form of the absence of species expected caregiving (i.e., caregiver deprivation, can drastically impact one’s social and emotional success, leading to the onset of internalizing illness later in life. Development of the amygdala and striatum, two key regions supporting affective valuation and learning, is significantly affected by ELS, and their altered developmental trajectories have important implications for cognitive, behavioral and socioemotional development. However, an understanding of the impact of ELS on the development of functional interactions between these regions and subsequent behavioral effects is lacking. In this review, we highlight the roles of the amygdala and striatum in affective valuation and learning in maturity and across development. We discuss their function separately as well as their interaction. We highlight evidence across species characterizing how ELS induced changes in the development of the amygdala and striatum mediate subsequent behavioral changes associated with internalizing illness, positing a particular import of the effect of ELS on their interaction.

  12. Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

    Science.gov (United States)

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

  13. Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

    Science.gov (United States)

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.

  14. Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

    Directory of Open Access Journals (Sweden)

    Ana Montero-Pedrazuela

    Full Text Available Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.

  15. Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level

    NARCIS (Netherlands)

    Wingen, G.A. van; Zylicz, S.A.; Pieters, S.; Mattern, C.; Verkes, R.J.; Buitelaar, J.K.; Fernandez, G.S.E.

    2009-01-01

    Testosterone modulates mood and sexual function in women. However, androgen levels decline with age, which may relate to the age-associated change in sexual functioning and the prevalence of mood and anxiety disorders. These effects of testosterone are potentially mediated by the amygdala. In the

  16. Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level.

    NARCIS (Netherlands)

    Wingen, G.A. van; Zylicz, S.A.; Pieters, S.; Mattern, C.; Verkes, R.J.; Buitelaar, J.K.; Fernandez, G.S.E.

    2009-01-01

    Testosterone modulates mood and sexual function in women. However, androgen levels decline with age, which may relate to the age-associated change in sexual functioning and the prevalence of mood and anxiety disorders. These effects of testosterone are potentially mediated by the amygdala. In the

  17. Arginine-vasopressin content of hippocampus and amygdala during passive avoidance behavior in rats

    NARCIS (Netherlands)

    Kloet, E.R. de; Laczi, F.; Gaffori, O.; Wied, D. de

    1983-01-01

    Arginine-vasopressin (AVP) is involved in memory processes. The memory effects of AVP are mediated by neuronal mechanisms taking place in limbic-midbrain structures. Therefore, immunoreactive AVP (IR-AVP) was measured in hippocampus and amygdala of male Wistar rats during acquisition and retention

  18. Basolateral Cl- channels in the larval bullfrog skin epithelium

    DEFF Research Database (Denmark)

    Hillyard, Stanley D.; Rios, K.; Larsen, Erik Hviid

    2002-01-01

    The addition of 150 U/ml nystatin to the mucosal surface of isolated skin from larval bullfrogs increases apical membrane permeability and allows a voltage clamp to be applied to the basolateral membrane. With identical Ringer's solutions bathing either side of the tissue the short-circuit current......, respectively. The Lorentzian plateau was minimal at the lowest ISC and increased as the ISC became greater in the positive or negative direction. Current-voltage plots with identical Ringer's on either side of the tissue showed a pattern of outward rectification. Cell attached patches of cells isolated from...... the skin with collagenase-trypsin treatment showed spontaneous channel activity with a conductance of 20.9 pS at a pipette potential, -Vp=20 mV. Current-voltage plots of single channels showed a similar pattern of rectification to that of the intact skin, and partial replacement of Cl- by gluconate...

  19. Amygdala contribution to selective dimensions of emotion

    Science.gov (United States)

    Bechara, Antoine; Damasio, Hanna; Tranel, Daniel; Cacioppo, John T.

    2007-01-01

    The amygdala has been implicated in emotional processes, although the precise nature of the emotional deficits following amygdala lesions remains to be fully elucidated. Cognitive disturbances in the perception, recognition or memory of emotional stimuli have been suggested by some, whereas others have proposed changes in emotional arousal. To address this issue, measures of emotional arousal and valence (positivity and negativity) to a graded series of emotional pictures were obtained from patients with lesions of the amygdala and from a clinical contrast group with lesions that spared this structure. Relative to the contrast group, patients with damage to the amygdala evidenced a complete lack of an arousal gradient across negative stimuli, although they displayed a typical arousal gradient to positive stimuli. These results were not attributable to the inability of amygdala patients to process the hostile or hospitable nature of the stimuli, as the amygdala group accurately recognized and categorized both positive and negative features of the stimuli. The relative lack of emotional arousal to negative stimuli may account for many of the clinical features of amygdala lesions. PMID:18414599

  20. Comparative distribution of relaxin-3 inputs and calcium-binding protein-positive neurons in rat amygdala

    Directory of Open Access Journals (Sweden)

    Fabio N Santos

    2016-04-01

    Full Text Available The neural circuits involved in mediating complex behaviors are being rapidly elucidated using various newly developed and powerful anatomical and molecular techniques, providing insights into the neural basis for anxiety disorders, depression, addiction, and dysfunctional social behaviors. Many of these behaviors and associated physiological processes involve the activation of the amygdala in conjunction with cortical and hippocampal circuits. Ascending subcortical projections provide modulatory inputs to the extended amygdala and its related nodes (or ‘hubs’ within these key circuits. One such input arises from the nucleus incertus (NI in the tegmentum, which sends amino acid- and peptide-containing projections throughout the forebrain. Notably, a distinct population of GABAergic NI neurons expresses the highly-conserved neuropeptide, relaxin-3, and relaxin-3 signaling has been implicated in the modulation of reward/motivation and anxiety- and depressive-like behaviors in rodents via actions within the extended amygdala. Thus, a detailed description of the relaxin-3 innervation of the extended amygdala would provide an anatomical framework for an improved understanding of NI and relaxin-3 modulation of these and other specific amygdala-related functions. Therefore, in this study, we examined the distribution of NI projections and relaxin-3-positive elements (axons/fibers/terminals within the amygdala, relative to the distribution of neurons expressing the calcium-binding proteins, parvalbumin, calretinin and/or calbindin. Anterograde tracer injections into the NI revealed a topographic distribution of NI efferents within the amygdala that was near identical to the distribution of relaxin-3-immunoreactive fibers. Highest densities of anterogradely-labeled elements and relaxin-3-immunoreactive fibers were observed in the medial nucleus of the amygdala, medial divisions of the bed nucleus of the stria terminalis (BST and in the endopiriform

  1. AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

    Science.gov (United States)

    Duvarci, Sevil; Pare, Denis

    2014-01-01

    We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. PMID:24908482

  2. Maladaptive social information processing in childhood predicts young men's atypical amygdala reactivity to threat.

    Science.gov (United States)

    Choe, Daniel Ewon; Shaw, Daniel S; Forbes, Erika E

    2015-05-01

    Maladaptive social information processing, such as hostile attributional bias and aggressive response generation, is associated with childhood maladjustment. Although social information processing problems are correlated with heightened physiological responses to social threat, few studies have examined their associations with neural threat circuitry, specifically amygdala activation to social threat. A cohort of 310 boys participated in an ongoing longitudinal study and completed questionnaires and laboratory tasks assessing their social and cognitive characteristics the boys were between 10 and 12 years of age. At age 20, 178 of these young men underwent functional magnetic resonance imaging and a social threat task. At age 22, adult criminal arrest records and self-reports of impulsiveness were obtained. Path models indicated that maladaptive social information-processing at ages 10 and 11 predicted increased left amygdala reactivity to fear faces, an ambiguous threat, at age 20 while accounting for childhood antisocial behavior, empathy, IQ, and socioeconomic status. Exploratory analyses indicated that aggressive response generation - the tendency to respond to threat with reactive aggression - predicted left amygdala reactivity to fear faces and was concurrently associated with empathy, antisocial behavior, and hostile attributional bias, whereas hostile attributional bias correlated with IQ. Although unrelated to social information-processing problems, bilateral amygdala reactivity to anger faces at age 20 was unexpectedly predicted by low IQ at age 11. Amygdala activation did not mediate associations between social information processing and number of criminal arrests, but both impulsiveness at age 22 and arrests were correlated with right amygdala reactivity to anger facial expressions at age 20. Childhood social information processing and IQ predicted young men's amygdala response to threat a decade later, which suggests that childhood social

  3. Relation between Amygdala Structure and Function in Adolescents with Bipolar Disorder

    Science.gov (United States)

    Kalmar, Jessica H.; Wang, Fei; Chepenik, Lara G.; Womer, Fay Y.; Jones, Monique M.; Pittman, Brian; Shah, Maulik P.; Martin, Andres; Constable, R. Todd; Blumberg, Hilary P.

    2009-01-01

    Adolescents with bipolar disorder showed decreased amygdala volume and increased amygdala response to emotional faces. Amygdala volume is inversely related to activation during emotional face processing.

  4. Attack priming in female Syrian golden hamsters is associated with a c-fos-coupled process within the corticomedial amygdala.

    Science.gov (United States)

    Potegal, M; Ferris, C F; Hebert, M; Meyerhoff, J; Skaredoff, L

    1996-12-01

    Allowing a resident hamster a single "priming" attack on a conspecific induces a transient aggressive arousal as indicated by a reduction in the latency and increase in the probability of attack on a second intruder presented within the next 30 min. We present two lines of evidence identifying the corticomedial amygdala as an important locus mediating this effect. (1) Attack priming significantly increases the number of neurons expressing immunocytochemically identified Fos protein in the corticomedial amygdala, but not elsewhere. Pursuit and biting of an inanimate object does not induce corticomedial amygdala c-fos expression of the same pattern or magnitude. The corticomedial amygdala contribution to the priming effect involves more than a non-specific arousal, since corticomedial amygdala c-fos expression does not correlate with locomotor activity, a standard indicator of such arousal. (2) Radiofrequency lesions of the corticomedial amygdala reduce aggression, the greatest reduction occurring with the more anterior lesions. Other behaviors, including a priming-like locomotor practice effect in a running wheel, are unaffected by corticomedial amygdala lesions. These findings suggest that attack priming is an aggression-specific effect resulting from a Fos-coupled change within neural circuitry of which the corticomedial amygdala is a part. From a theoretical point of view, these experiments suggest a new approach to the analysis of the mechanisms underlying aggressive behavior and the persistence of aggressive arousal. We present a sketch of a quantitative neurobehavioral model which relates attack probability to neural activation within the corticomedial amygdala. From a methodological viewpoint, these experiments extend the utility of mapping c-fos expression as a technique for localizing endogenous, behavior-specific processes within the central nervous system.

  5. Amygdala reactivity and negative emotionality: divergent correlates of antisocial personality and psychopathy traits in a community sample.

    Science.gov (United States)

    Hyde, Luke W; Byrd, Amy L; Votruba-Drzal, Elizabeth; Hariri, Ahmad R; Manuck, Stephen B

    2014-02-01

    Previous studies have emphasized that antisocial personality disorder (APD) and psychopathy overlap highly but differ critically in several features, notably negative emotionality (NEM) and possibly amygdala reactivity to social signals of threat and distress. Here we examined whether dimensions of psychopathy and APD correlate differentially with NEM and amygdala reactivity to emotional faces. Testing these relationships among healthy individuals, dimensions of psychopathy and APD were generated by the profile matching technique of Lynam and Widiger (2001), using facet scales of the NEO Personality Inventory-Revised, and amygdala reactivity was measured using a well-established emotional faces task, in a community sample of 103 men and women. Higher psychopathy scores were associated with lower NEM and lower amygdala reactivity, whereas higher APD scores were related to greater NEM and greater amygdala reactivity, but only after overlapping variance in APD and psychopathy was adjusted for in the statistical model. Amygdala reactivity did not mediate the relationship of APD and psychopathy scores to NEM. Supplemental analyses also compared other measures of factors within psychopathy in predicting NEM and amygdala reactivity and found that Factor 2 psychopathy was positively related to NEM and amygdala reactivity across measures of psychopathy. The overall findings replicate seminal observations on NEM in psychopathy by Hicks and Patrick (2006) and extend this work to neuroimaging in a normative population. They also suggest that one critical way in which APD and psychopathy dimensions may differ in their etiology is through their opposing levels of NEM and amygdala reactivity to threat. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  6. An oxytocin receptor polymorphism predicts amygdala reactivity and antisocial behavior in men.

    Science.gov (United States)

    Waller, Rebecca; Corral-Frías, Nadia S; Vannucci, Bianca; Bogdan, Ryan; Knodt, Annchen R; Hariri, Ahmad R; Hyde, Luke W

    2016-08-01

    Variability in oxytocin (OXT) signaling is associated with individual differences in sex-specific social behavior across species. The effects of OXT signaling on social behavior are, in part, mediated through its modulation of amygdala function. Here, we use imaging genetics to examine sex-specific effects of three single-nucleotide polymorphisms in the human oxytocin receptor gene (OXTR; rs1042778, rs53576 and rs2254298) on threat-related amygdala reactivity and social behavior in 406 Caucasians. Analyses revealed that among men but not women, OXTR rs1042778 TT genotype was associated with increased right amygdala reactivity to angry facial expressions, which was uniquely related to higher levels of antisocial behavior among men. Moderated meditation analysis suggested a trending indirect effect of OXTR rs1042778 TT genotype on higher antisocial behavior via increased right amygdala reactivity to angry facial expressions in men. Our results provide evidence linking genetic variation in OXT signaling to individual differences in amygdala function. The results further suggest that these pathways may be uniquely important in shaping antisocial behavior in men. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  7. Subregional Shape Alterations in the Amygdala in Patients with Panic Disorder

    Science.gov (United States)

    Kim, Geon Ha; Kang, Hee Jin; Kim, Bori R.; Jeon, Saerom; Im, Jooyeon Jamie; Hyun, Heejung; Moon, Sohyeon; Lim, Soo Mee; Lyoo, In Kyoon

    2016-01-01

    Background The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder. Methods Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals. Results There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45). Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation. PMID:27336300

  8. Subregional Shape Alterations in the Amygdala in Patients with Panic Disorder.

    Science.gov (United States)

    Yoon, Sujung; Kim, Jieun E; Kim, Geon Ha; Kang, Hee Jin; Kim, Bori R; Jeon, Saerom; Im, Jooyeon Jamie; Hyun, Heejung; Moon, Sohyeon; Lim, Soo Mee; Lyoo, In Kyoon

    2016-01-01

    The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder. Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals. There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45). Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation.

  9. Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission.

    Science.gov (United States)

    Sengupta, Ayesha; Bocchio, Marco; Bannerman, David M; Sharp, Trevor; Capogna, Marco

    2017-02-15

    The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT 2A and 5-HT 1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT 1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output. SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders

  10. Structural Connectivity of the Developing Human Amygdala

    Science.gov (United States)

    Saygin, Zeynep M.; Osher, David E.; Koldewyn, Kami; Martin, Rebecca E.; Finn, Amy; Saxe, Rebecca; Gabrieli, John D.E.; Sheridan, Margaret

    2015-01-01

    A large corpus of research suggests that there are changes in the manner and degree to which the amygdala supports cognitive and emotional function across development. One possible basis for these developmental differences could be the maturation of amygdalar connections with the rest of the brain. Recent functional connectivity studies support this conclusion, but the structural connectivity of the developing amygdala and its different nuclei remains largely unstudied. We examined age related changes in the DWI connectivity fingerprints of the amygdala to the rest of the brain in 166 individuals of ages 5-30. We also developed a model to predict age based on individual-subject amygdala connectivity, and identified the connections that were most predictive of age. Finally, we segmented the amygdala into its four main nucleus groups, and examined the developmental changes in connectivity for each nucleus. We observed that with age, amygdalar connectivity becomes increasingly sparse and localized. Age related changes were largely localized to the subregions of the amygdala that are implicated in social inference and contextual memory (the basal and lateral nuclei). The central nucleus’ connectivity also showed differences with age but these differences affected fewer target regions than the basal and lateral nuclei. The medial nucleus did not exhibit any age related changes. These findings demonstrate increasing specificity in the connectivity patterns of amygdalar nuclei across age. PMID:25875758

  11. Mediatization

    DEFF Research Database (Denmark)

    Hjarvard, Stig

    2017-01-01

    Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction....... From the perspective of mediatization research, the most important effect of the media stems from their embeddedness in culture and society....

  12. The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats.

    Science.gov (United States)

    Lonsdale, Deborah; Burnham, W McIntyre

    2003-12-01

    Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model. Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5alpha-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined. Progesterone had a median effective dose (ED50) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5alpha-dihydroprogesterone had an ED50 of 2.9 mg/kg against generalized kindled convulsions and an ED50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5alpha-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval. Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion.

  13. Anhedonic behavior in cryptochrome 2-deficient mice is paralleled by altered diurnal patterns of amygdala gene expression.

    Science.gov (United States)

    Savalli, Giorgia; Diao, Weifei; Berger, Stefanie; Ronovsky, Marianne; Partonen, Timo; Pollak, Daniela D

    2015-07-01

    Mood disorders are frequently paralleled by disturbances in circadian rhythm-related physiological and behavioral states and genetic variants of clock genes have been associated with depression. Cryptochrome 2 (Cry2) is one of the core components of the molecular circadian machinery which has been linked to depression, both, in patients suffering from the disease and animal models of the disorder. Despite this circumstantial evidence, a direct causal relationship between Cry2 expression and depression has not been established. Here, a genetic mouse model of Cry2 deficiency (Cry2 (-/-) mice) was employed to test the direct relevance of Cry2 for depression-like behavior. Augmented anhedonic behavior in the sucrose preference test, without alterations in behavioral despair, was observed in Cry2 (-/-) mice. The novelty suppressed feeding paradigm revealed reduced hyponeophagia in Cry2 (-/-) mice compared to wild-type littermates. Given the importance of the amygdala in the regulation of emotion and their relevance for the pathophysiology of depression, potential alterations in diurnal patterns of basolateral amygdala gene expression in Cry2 (-/-) mice were investigated focusing on core clock genes and neurotrophic factor systems implicated in the pathophysiology of depression. Differential expression of the clock gene Bhlhe40 and the neurotrophic factor Vegfb were found in the beginning of the active (dark) phase in Cry2 (-/-) compared to wild-type animals. Furthermore, amygdala tissue of Cry2 (-/-) mice contained lower levels of Bdnf-III. Collectively, these results indicate that Cry2 exerts a critical role in the control of depression-related emotional states and modulates the chronobiological gene expression profile in the mouse amygdala.

  14. Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala.

    Directory of Open Access Journals (Sweden)

    Harini Lakshminarasimhan

    Full Text Available Recent findings on stress induced structural plasticity in rodents have identified important differences between the hippocampus and amygdala. The same chronic immobilization stress (CIS, 2 h/day causes growth of dendrites and spines in the basolateral amygdala (BLA, but dendritic atrophy in hippocampal area CA3. CIS induced morphological changes also differ in their temporal longevity--BLA hypertrophy, unlike CA3 atrophy, persists even after 21 days of stress-free recovery. Furthermore, a single session of acute immobilization stress (AIS, 2 h leads to a significant increase in spine density 10 days, but not 1 day, later in the BLA. However, little is known about the molecular correlates of the differential effects of chronic and acute stress. Because BDNF is known to be a key regulator of dendritic architecture and spines, we investigated if the levels of BDNF expression reflect the divergent effects of stress on the hippocampus and amygdala. CIS reduces BDNF in area CA3, while it increases it in the BLA of male Wistar rats. CIS-induced increase in BDNF expression lasts for at least 21 days after the end of CIS in the BLA. But CIS-induced decrease in area CA3 BDNF levels, reverses to normal levels within the same period. Finally, BDNF is up regulated in the BLA 1 day after AIS and this increase persists even 10 days later. In contrast, AIS fails to elicit any significant change in area CA3 at either time points. Together, these findings demonstrate that both acute and chronic stress trigger opposite effects on BDNF levels in the BLA versus area CA3, and these divergent changes also follow distinct temporal profiles. These results point to a role for BDNF in stress-induced structural plasticity across both hippocampus and amygdala, two brain areas that have also been implicated in the cognitive and affective symptoms of stress-related psychiatric disorders.

  15. Distinct recruitment of the hippocampal, thalamic, and amygdalar neurons projecting to the prelimbic cortex in male and female rats during context-mediated renewal of responding to food cues.

    Science.gov (United States)

    Anderson, Lauren C; Petrovich, Gorica D

    2018-02-26

    Persistent responding to food cues may underlie the difficulty to resist palatable foods and to maintain healthy eating habits. Renewal of responding after extinction is a model of persistent food seeking that can be used to study the underlying neural mechanisms. In context-mediated renewal, a return to the context in which the initial cue-food learning occurred induces robust responding to the cues that were extinguished elsewhere. Previous work found sex differences in context-mediated renewal and in the recruitment of the ventromedial prefrontal cortex (vmPFC) during that behavior. Males exhibited renewal of responding to food cues and had higher Fos induction in the prelimbic area (PL) of the vmPFC, while females failed to exhibit renewal of responding and had lower Fos induction in the PL. The main aim of the current study was to determine key components of the PL circuitry mediating renewal. The focus was on inputs from three areas important in appetitive associative learning and contextual processing: the amygdala, ventral hippocampal formation, and the paraventricular nucleus of the thalamus. The goal was to determine whether neurons from these areas that send direct projections to the PL (identified with a retrograde tracer) are selectively activated (Fos induction) during renewal and whether they are differently recruited in males and females. The Fos induction patterns demonstrated that the PL-projecting neurons in each of these areas were recruited in a sex-specific way that corresponded to the behavioral differences between males and females. These pathways were selectively activated in the male experimental group-the only group that showed renewal behavior. The findings suggest the pathways from the ventral hippocampal formation, paraventricular nucleus of the thalamus, and basolateral amygdala to the PL mediate renewal in males. The lack of recruitment in females suggests that under activation of these pathways may underlie their lack of renewal

  16. Alcohol attenuates amygdala-frontal connectivity during processing social signals in heavy social drinkers: a preliminary pharmaco-fMRI study.

    Science.gov (United States)

    Gorka, Stephanie M; Fitzgerald, Daniel A; King, Andrea C; Phan, K Luan

    2013-09-01

    Convergent evidence shows that alcohol exerts its effects on social behavior via modulation of amygdala reactivity to affective stimuli. Given that affective processing involves dynamic interactions between the amygdala and the prefrontal cortex (PFC), alcohol's effects are likely to extend beyond regional changes in brain activity to changes that manifest on a broader functional circuit level. The current study examines alcohol's effects on functional connectivity (i.e., "coupling") between the amygdala and the PFC during the processing of socio-emotional stimuli using functional magnetic resonance imaging (fMRI). In a randomized, double blind, placebo-controlled, within-subjects cross-over design, 12 heavy, social drinkers performed an fMRI task designed to probe amygdala response to socio-emotional stimuli (angry, fearful, and happy faces) following acute ingestion of alcohol or placebo. Functional connectivity between the amygdala and PFC was examined and compared between alcohol and placebo sessions using a conventional generalized psychophysiological interaction (gPPI) analysis. Relative to placebo, alcohol reduced functional coupling between the amygdala and the right orbitofrontal cortex (OFC) during processing of both angry and fearful faces. Alcohol also reduced functional coupling between the amygdala and left OFC during processing of happy faces. These preliminary findings suggest that alcohol's effects on social behavior may be mediated by alternations in functional connectivity between the amygdala and OFC during processing of emotional faces.

  17. Mesencephalic basolateral domain specification is dependent on Sonic Hedgehog

    Science.gov (United States)

    Martinez-Lopez, Jesus E.; Moreno-Bravo, Juan A.; Madrigal, M. Pilar; Martinez, Salvador; Puelles, Eduardo

    2015-01-01

    In the study of central nervous system morphogenesis, the identification of new molecular markers allows us to identify domains along the antero-posterior and dorso-ventral (DV) axes. In the past years, the alar and basal plates of the midbrain have been divided into different domains. The precise location of the alar-basal boundary is still under discussion. We have identified Barhl1, Nhlh1 and Six3 as appropriate molecular markers to the adjacent domains of this transition. The description of their expression patterns and the contribution to the different mesencephalic populations corroborated their role in the specification of these domains. We studied the influence of Sonic Hedgehog on these markers and therefore on the specification of these territories. The lack of this morphogen produced severe alterations in the expression pattern of Barhl1 and Nhlh1 with consequent misspecification of the basolateral (BL) domain. Six3 expression was apparently unaffected, however its distribution changed leading to altered basal domains. In this study we confirmed the localization of the alar-basal boundary dorsal to the BL domain and demonstrated that the development of the BL domain highly depends on Shh. PMID:25741244

  18. Amygdala EphB2 Signaling Regulates Glutamatergic Neuron Maturation and Innate Fear.

    Science.gov (United States)

    Zhu, Xiao-Na; Liu, Xian-Dong; Zhuang, Hanyi; Henkemeyer, Mark; Yang, Jing-Yu; Xu, Nan-Jie

    2016-09-28

    The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved. Generation of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB-ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions in the postnatal

  19. The Role of Orbitofrontal-Amygdala Interactions in Updating Action-Outcome Valuations in Macaques.

    Science.gov (United States)

    Fiuzat, Emily C; Rhodes, Sarah E V; Murray, Elisabeth A

    2017-03-01

    A previous study revealed that, although monkeys with bilateral lesions of either the orbitofrontal cortex (OFC) or the amygdala could learn an action-outcome task, they could not adapt their choices in response to devalued outcomes. Specifically, they could not adjust their choice between two actions after the value of the outcome associated with one of the actions had decreased. Here, we investigated whether OFC needs to interact functionally with the amygdala in mediating such choices. Rhesus monkeys were trained to make two mutually exclusive actions on a touch-sensitive screen: "tap" and "hold." Taps led to the availability of one kind of food outcome; holds produced a different food. On each trial, monkeys could choose either a tap or a hold to earn the corresponding food reward. After consuming one of the two foods to satiety, monkeys were then tested on their ability to adapt their choices in response to the updated relative valuation of the two predicted outcomes. Whereas intact (control) monkeys shifted their choices toward the action associated with the higher value (nonsated) food, monkeys with crossed surgical disconnection of the amygdala and OFC did not. These findings demonstrate that amygdala-OFC interactions are necessary for choices among actions based on the updated value of predicted outcomes and they also have a bearing on the idea that OFC specializes in stimulus- or object-based choices in contrast to action- or response-based choices. SIGNIFICANCE STATEMENT Dysfunctional interactions between orbitofrontal cortex (OFC) and the amygdala underlie several mental health disorders, often related to value-based decision making. Understanding the underlying neural circuitry may help to develop therapies for those suffering from mood and anxiety disorders and provide insight into addiction. Here, we investigated whether the amygdala must interact with OFC to make adaptive choices. Monkeys learned to perform two different actions, "tap" for one kind

  20. Basolateral chloride loading by the anion exchanger type 2: role in fluid secretion by the human airway epithelial cell line Calu-3.

    Science.gov (United States)

    Huang, Junwei; Shan, Jiajie; Kim, Dusik; Liao, Jie; Evagelidis, Alexandra; Alper, Seth L; Hanrahan, John W

    2012-11-01

    Anion exchanger type 2 (AE2 or SLC4A2) is an electroneutral Cl(-)/HCO(3)(-) exchanger expressed at the basolateral membrane of many epithelia. It is thought to participate in fluid secretion by airway epithelia. However, the role of AE2 in fluid secretion remains uncertain, due to the lack of specific pharmacological inhibitors, and because it is electrically silent and therefore does not contribute directly to short-circuit current (I(sc)). We have studied the role of AE2 in Cl(-) and fluid secretion by the airway epithelial cell line Calu-3. After confirming expression of its mRNA and protein, a knock-down cell line called AE2-KD was generated by lentivirus-mediated RNA interference in which AE2 mRNA and protein levels were reduced 90%. Suppressing AE2 increased the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) by ∼70% without affecting the levels of NKCC1 (Na(+)-K(+)-2Cl(-) cotransporter) or NBCe1 (Na(+)-nHCO(3)(-) cotransporter). cAMP agonists stimulated fluid secretion by parental Calu-3 and scrambled shRNA cells >6.5-fold. In AE2-KD cells this response was reduced by ∼70%, and the secreted fluid exhibited elevated pH and [HCO(3)(-)] as compared with the control lines. Unstimulated equivalent short-circuit current (I(eq)) was elevated in AE2-KD cells, but the incremental response to forskolin was unaffected. The modest bumetanide-induced reductions in both I(eq) and fluid secretion were more pronounced in AE2-KD cells. Basolateral Cl(-)/HCO(3)(-) exchange measured by basolateral pH-stat in cells with permeabilized apical membranes was abolished in AE2-KD monolayers, and the intracellular alkalinization resulting from basolateral Cl(-) removal was reduced by ∼80% in AE2-KD cells. These results identify AE2 as a major pathway for basolateral Cl(-) loading during cAMP-stimulated secretion of Cl(-) and fluid by Calu-3 cells, and help explain the large bumetanide-insensitive component of fluid secretion reported previously in

  1. Posterior Orbitofrontal and Anterior Cingulate Pathways to the Amygdala Target Inhibitory and Excitatory Systems with Opposite Functions.

    Science.gov (United States)

    Zikopoulos, Basilis; Höistad, Malin; John, Yohan; Barbas, Helen

    2017-05-17

    The bidirectional dialogue of the primate posterior orbitofrontal cortex (pOFC) with the amygdala is essential in cognitive-emotional functions. The pOFC also sends a uniquely one-way excitatory pathway to the amygdalar inhibitory intercalated masses (IM), which inhibit the medial part of the central amygdalar nucleus (CeM). Inhibition of IM has the opposite effect, allowing amygdalar activation of autonomic structures and emotional arousal. Using multiple labeling approaches to identify pathways and their postsynaptic sites in the amygdala in rhesus monkeys, we found that the anterior cingulate cortex innervated mostly the basolateral and CeM amygdalar nuclei, poised to activate CeM for autonomic arousal. By contrast, a pathway from pOFC to IM exceeded all other pathways to the amygdala by density and size and proportion of large and efficient terminals. Moreover, whereas pOFC terminals in IM innervated each of the three distinct classes of inhibitory neurons, most targeted neurons expressing dopamine- and cAMP-regulated phosphoprotein (DARPP-32+), known to be modulated by dopamine. The predominant pOFC innervation of DARPP-32+ neurons suggests activation of IM and inhibition of CeM, resulting in modulated autonomic function. By contrast, inhibition of DARPP-32 neurons in IM by high dopamine levels disinhibits CeM and triggers autonomic arousal. The findings provide a mechanism to help explain how a strong pOFC pathway, which is poised to moderate activity of CeM, through IM, can be undermined by the high level of dopamine during stress, resulting in collapse of potent inhibitory mechanisms in the amygdala and heightened autonomic drive, as seen in chronic anxiety disorders. SIGNIFICANCE STATEMENT The dialogue between prefrontal cortex and amygdala allows thoughts and emotions to influence actions. The posterior orbitofrontal cortex sends a powerful pathway that targets a special class of amygdalar intercalated mass (IM) inhibitory neurons, whose wiring may help

  2. Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

    DEFF Research Database (Denmark)

    Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.

    2008-01-01

    Serotonergic systems in the dorsal raphe nucleus are thought to play an important role in the regulation of anxiety states. To investigate responses of neurons in the dorsal raphe nucleus to a mild anxiety-related stimulus, we exposed rats to an open-field, under low-light or high-light conditions...... of neurons in the midbrain raphe complex that projects to forebrain circuits regulating anxiety states, we used cholera toxin B subunit (CTb) as a retrograde tracer to identify neurons projecting to the basolateral amygdaloid complex (BL) in combination with c-Fos immunostaining to identify cells...... that activated neurons were serotonergic, non-serotonergic, or both. These data are consistent with the hypothesis that exposure to anxiogenic stimuli activates a subset of neurons in the midbrain raphe complex projecting to amygdala anxiety circuits Udgivelsesdato: 2008/12/10...

  3. Impact of Sleep Quality on Amygdala Reactivity, Negative Affect, and Perceived Stress

    Science.gov (United States)

    Prather, Aric A.; Bogdan, Ryan; Ahmad R. Hariri, PhD

    2013-01-01

    Objective Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress. Methods Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level–dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index. Results Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (β values = 0.18–1.86, p values .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (β values = 0.29–0.44, p values < .05). In contrast, no significant associations were observed in men reporting good global sleep quality or in women, irrespective of sleep quality. Conclusions This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men. PMID:23592753

  4. Subregional Shape Alterations in the Amygdala in Patients with Panic Disorder.

    Directory of Open Access Journals (Sweden)

    Sujung Yoon

    Full Text Available The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder.Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals.There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45. Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p < 0.05.The current findings suggest that subregion-specific shape alterations in the right amygdala may be involved in the development and maintenance of panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation.

  5. Amygdala interconnections with the cingulate motor cortex in the rhesus monkey.

    Science.gov (United States)

    Morecraft, Robert J; McNeal, David W; Stilwell-Morecraft, Kimberly S; Gedney, Matthew; Ge, Jizhi; Schroeder, Clinton M; van Hoesen, Gary W

    2007-01-01

    Amygdala interconnections with the cingulate motor cortices were investigated in the rhesus monkey. Using multiple tracing approaches, we found a robust projection from the lateral basal nucleus of the amygdala to Layers II, IIIa, and V of the rostral cingulate motor cortex (M3). A smaller source of amygdala input arose from the accessory basal, cortical, and lateral nuclei, which targeted only the rostral region of M3. We also found a light projection from the lateral basal nucleus to the same layers of the caudal cingulate motor cortex (M4). Experiments examining this projection to cingulate somatotopy using combined neural tracing strategies and stereology to estimate the total number of terminal-like immunoreactive particles demonstrated that the amygdala projection terminates heavily in the face representation of M3 and moderately in its arm representation. Fewer terminal profiles were found in the leg representation of M3 and the face, arm, and leg representations of M4. Anterograde tracers placed directly into M3 and M4 revealed the amygdala connection to be reciprocal and documented corticofugal projections to the facial nucleus, surrounding pontine reticular formation, and spinal cord. Clinically, such pathways would be in a position to contribute to mediating movements in the face, neck, and upper extremity accompanying medial temporal lobe seizures that have historically characterized this syndrome. Alterations within or disruption of the amygdalo-cingulate projection to the rostral part of M3 may also have an adverse effect on facial expression in patients presenting with neurological or neuropsychiatric abnormalities of medial temporal lobe involvement. Finally, the prominent amygdala projection to the face region of M3 may significantly influence the outcome of higher-order facial expressions associated with social communication and emotional constructs such as fear, anger, happiness, and sadness.

  6. Lesions of lateral or central amygdala abolish aversive Pavlovian-to-instrumental transfer in rats.

    Directory of Open Access Journals (Sweden)

    Vincent D Campese

    2014-05-01

    Full Text Available Aversive Pavlovian conditioned stimuli (CSs elicit defensive reactions (e.g., freezing and motivate instrumental actions like active avoidance (AA. Pavlovian reactions require connections between the lateral (LA and central (CeA nuclei of the amygdala, whereas AA depends on LA and basal amygdala (BA. Thus, the neural circuits mediating conditioned reactions and motivation appear to diverge in the amygdala. However, AA is not ideal for studying conditioned motivation, because Pavlovian and instrumental learning are intermixed. Pavlovian-to-instrumental transfer (PIT allows for the study of conditioned motivation in isolation. PIT refers to the ability of a Pavlovian CS to modulate a separately-trained instrumental action. The role of the amygdala in aversive PIT is unknown. We designed an aversive PIT procedure in rats and tested the effects of LA, BA and CeA lesions. Rats received Pavlovian tone-shock pairings followed by Sidman shock-avoidance training. PIT was assessed by comparing shuttling rates in the presence and absence of the tone. Tone presentations facilitated instrumental responding. Aversive PIT was abolished by lesions of LA or CeA, but was unaffected by lesions of BA. These results suggest that LA and CeA are essential for aversive conditioned motivation. More specifically, the results are consistent with a model of amygdala processing in which the CS is encoded in the LA and then, via connections to CeA, the motivation to perform the aversive task is enhanced. These findings have implications for understanding the contribution of amygdala circuits to aversive instrumental motivation, but also for the relation of aversive and appetitive behavioral control.

  7. Na+-independent D-glucose transport in rabbit renal basolateral membranes

    International Nuclear Information System (INIS)

    Cheung, P.T.; Hammerman, M.R.

    1988-01-01

    To define the mechanism by which glucose is transported across the basolateral membrane of the renal proximal tubular cell, we measured D-[14C]glucose uptake in basolateral membrane vesicles from rabbit kidney. Na+-dependent D-glucose transport, demonstrable in brush-border vesicles, could not be demonstrated in basolateral membrane vesicles. In the absence of Na+, the uptake of D-[14C]glucose in basolateral vesicles was more rapid than that of L-[3H]glucose over a concentration range of 1-50 mM. Subtraction of the latter from the former uptakes revealed a saturable process with apparent Km of 9.9 mM and Vmax of 0.80 nmol.mg protein-1.s-1. To characterize the transport component of D-glucose uptake in basolateral vesicles, we measured trans stimulation of 2 mM D-[14C]glucose entry in the absence of Na+. Trans stimulation could be effected by preloading basolateral vesicles with D-glucose, 2-deoxy-D-glucose, or 3-O-methyl-D-glucose, but not with L-glucose or alpha-methyl-D-glucoside. Trans-stimulated D-[14C]glucose uptake was inhibited by 0.1 mM phloretin or cytochalasin B but not phlorizin. In contrast, Na+-dependent D-[14C]glucose transport in brush-border vesicles was inhibited by phlorizin but not phloretin or cytochalasin B. Our findings are consistent with the presence of a Na+-independent D-glucose transporter in the proximal tubular basolateral membrane with characteristics similar to those of transporters present in nonepithelial cells

  8. Amygdala lesions disrupt modulation of functional MRI activity evoked by facial expression in the monkey inferior temporal cortex

    Science.gov (United States)

    Hadj-Bouziane, Fadila; Liu, Ning; Bell, Andrew H.; Gothard, Katalin M.; Luh, Wen-Ming; Tootell, Roger B. H.; Murray, Elisabeth A.; Ungerleider, Leslie G.

    2012-01-01

    We previously showed that facial expressions modulate functional MRI activity in the face-processing regions of the macaque monkey’s amygdala and inferior temporal (IT) cortex. Specifically, we showed that faces expressing emotion yield greater activation than neutral faces; we term this difference the “valence effect.” We hypothesized that amygdala lesions would disrupt the valence effect by eliminating the modulatory feedback from the amygdala to the IT cortex. We compared the valence effects within the IT cortex in monkeys with excitotoxic amygdala lesions (n = 3) with those in intact control animals (n = 3) using contrast agent-based functional MRI at 3 T. Images of four distinct monkey facial expressions—neutral, aggressive (open mouth threat), fearful (fear grin), and appeasing (lip smack)—were presented to the subjects in a blocked design. Our results showed that in monkeys with amygdala lesions the valence effects were strongly disrupted within the IT cortex, whereas face responsivity (neutral faces > scrambled faces) and face selectivity (neutral faces > non-face objects) were unaffected. Furthermore, sparing of the anterior amygdala led to intact valence effects in the anterior IT cortex (which included the anterior face-selective regions), whereas sparing of the posterior amygdala led to intact valence effects in the posterior IT cortex (which included the posterior face-selective regions). Overall, our data demonstrate that the feedback projections from the amygdala to the IT cortex mediate the valence effect found there. Moreover, these modulatory effects are consistent with an anterior-to-posterior gradient of projections, as suggested by classical tracer studies. PMID:23184972

  9. Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex.

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    Guillaume Martel

    Full Text Available Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD. Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR. Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction.

  10. The central amygdala circuits in fear regulation

    Science.gov (United States)

    Li, Bo

    The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how the CeA contributes to the learning and expression of fear remains unclear. Our recent studies in mice indicate that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). In particular, this plasticity is cell-type specific and is required for the formation of fear memory. In addition, sensory cues that predict threat can cause activation of the somatostatin-positive CeL neurons, which is sufficient to drive freezing behavior. Here I will report our recent findings regarding the circuit and cellular mechanisms underlying CeL function in fear processing.

  11. Impaired Emotional Declarative Memory Following Unilateral Amygdala Damage

    OpenAIRE

    Adolphs, Ralph; Tranel, Daniel; Denburg, Natalie

    2000-01-01

    Case studies of patients with bilateral amygdala damage and functional imaging studies of normal individuals have demonstrated that the amygdala plays a critical role in encoding emotionally arousing stimuli into long-term declarative memory. However, several issues remain poorly understood: the separate roles of left and right amygdala, the time course over which the amygdala participates in memory consolidation, and the type of knowledge structures it helps consolidate. We investigated thes...

  12. The amygdala complex: multiple roles in associative learning and attention.

    OpenAIRE

    Gallagher, M; Holland, P C

    1994-01-01

    Although certain neurophysiological functions of the amygdala complex in learning seem well established, the purpose of this review is to propose that an additional conceptualization of amygdala function is now needed. The research we review provides evidence that a subsystem within the amygdala provides a coordinated regulation of attentional processes. An important aspect of this additional neuropsychology of the amygdala is that it may aid in understanding the importance of connections bet...

  13. Phosphate depletion in opossum kidney cells: apical but not basolateral or transepithelial adaptions of Pi transport.

    Science.gov (United States)

    Barac-Nieto, M; Alfred, M; Spitzer, A

    2001-01-01

    Monolayers of opossum kidney (OK) cells are widely used as models for the renal proximal tubule. OK cells adapt to phosphate (Pi) depletion by increasing their capacity for apical and basolateral Na+-dependent Pi uptake. Because NMR-visible cell Pi was found to be decreased in Pi-deprived kidney cells, we suggested that up-regulation of basolateral Pi efflux also occurs during adaptation to Pi deprivation [American Journal of Physiol 1994;267:C915-919]. In order to test this hypothesis, we measured the cell Pi pool, basolateral Pi efflux and transepithelial Pi fluxes in OK cells grown on permeable plastic filters, exposed overnight to solutions containing either 0.5 mM (deprived) or 2.0 mM (replete) Pi or 32Pi. Following steady state or acute loading with 32Pi, the specific activity (SA) of cell Pi, the cell Pi pool and the basolateral efflux of 32Pi were measured. In the steady state, a 2-fold increase in Pi uptake sustained the intracellular Pi pool at 85% of the control level (30 +/- 5 nmol/mg) in spite of a decrease in extracellular Pi from 2 to 0.5 mM. When the extracellular Pi was acutely (1 h) reduced to 0.1 mM, the cell Pi pool decreased (to 3 +/- 1 nmol/mg) both in cells previously adapted overnight to either 0.5 or to 2 mM Pi (p >0.3). The rates of absolute and fractional basolateral washout of cell 32Pi after 1 h loading with 0.1 mM 32Pi were similar in cells adapted to 0.5 compared to 2 mM Pi. This indicates that Pi depletion did not affect the effective permeability of the basolateral membranes to Pi. Adaptation for 16 h to 0.5 compared to 2 mM Pi did not alter the rate of net transepithelial transport of 0.1 mM Pi from the apical to the basal compartment but reduced (p OK cells grown on plastic support there are no adaptive increases in either basolateral Pi efflux, or in transcellular and paracellular Pi transport, in response to Pi depletion. Adaptations are limited to increases in apical and basolateral sodium-dependent Pi uptakes that can maintain

  14. Unsaturated fatty acids promote bioaccessibility and basolateral secretion of carotenoids and α-tocopherol by Caco-2 cells.

    Science.gov (United States)

    Failla, Mark L; Chitchumronchokchai, Chureeporn; Ferruzzi, Mario G; Goltz, Shellen R; Campbell, Wayne W

    2014-06-01

    Bioavailability of carotenoids and tocopherols from foods is determined by the efficiency of transfer from food/meal to mixed micelles during digestion, incorporation into chylomicrons for trans-epithelial transport to lymphatic/blood system, and distribution to target tissues. Fats and oils are important factors for facilitating the absorption of lipophilic compounds. However, dietary fats and oils are composed of various types of saturated and unsaturated fatty acids which may differentially impact the bioavailability of carotenoids and tocopherols from foods. We have investigated the effects of several common commercial lipids on bioavailability using an in vitro digestion model and Caco-2 human intestinal cells. Meals consisted of mixed salad vegetables containing a single test lipid. Micellarization and cellular uptake of β-carotene (βC) and lycopene (LYC) during small intestinal digestion was increased by lipids rich in unsaturated fatty acids: soybean oil > olive > canola > butter. In contrast, type of lipid minimally affected the bioaccessibility of lutein (LUT) and zeaxanthin (ZEA). To examine the influence of type of dietary triglyceride on uptake and basolateral secretion of carotenoids, Caco-2 cells grown on Transwell membranes were incubated with micellar mixtures of fatty acids (1.0 mM) mimicking the types and ratio of saturated to unsaturated (mono- + poly-unsaturated) fatty acids (FA) present in butter (70 : 30), olive oil (7 : 93) and soybean oil (11 : 89). Cells were exposed to micelles containing βC, LUT, α-tocopherol (α-TC) and a mixture of test fatty acids. Uptake and basolateral secretion of βC, LUT and α-TC were greater in cells pre-treated with mixtures enriched in unsaturated compared to saturated FA and these effects were mediated by increased assembly and secretion of chylomicrons. These results suggest that dietary fats/oils rich in unsaturated fatty acids promote carotenoid and α-TC bioavailability by enhancing their

  15. Mouse organic cation transporter 1 determines properties and regulation of basolateral organic cation transport in renal proximal tubules.

    Science.gov (United States)

    Schlatter, Eberhard; Klassen, Philipp; Massmann, Vivian; Holle, Svenja K; Guckel, Denise; Edemir, Bayram; Pavenstädt, Hermann; Ciarimboli, Giuliano

    2014-08-01

    The proximal tubule of mouse kidney expresses mouse organic cation transporter 1 (mOCT1), mOCT2, and much less mOCT3. Therefore, mOCT-mediated transport across the basolateral membrane of proximal tubules reflects properties of at least mOCT1 and mOCT2. Here, we unraveled substrate affinities and modulation of transport activity by acute regulation by protein kinases on mOCT1 and mOCT2 separately and compared these findings with those from isolated proximal tubules of male and female mOCT2−/− mice. These data are also compared to our recent reports on isolated tubules from wild-type and mOCT1/2 double knockout (mOCT1/2−/−) mice. OCT-mediated transport in proximal tubules of mOCT2−/− mice was only 20 % lower compared to those isolated from wild-type mice. While mOCT1 was regulated by all five pathways examined [protein kinase A (PKA), protein kinase C (PKC), p56lck, phosphoinositide 3-kinase (PI3K), and calmodulin (CaM)], mOCT2 activity was modulated by PKA, p56lck, and CaM only, however, in the same direction. As mOCT-mediated transport across the basolateral membrane of mOCT2−/− mice expressing only mOCT1 and to a small amount mOCT3 was identical to that observed for tubules isolated from wild-type mice and to that observed for human embryonic kidney 293 (HEK293) cells stably expressing mOCT1, mOCT1 represents the relevant paralog for OCT-dependent organic cation transport in the mouse kidney. Gender does not play a major role in expression and activity of renal OCT-mediated transport in the mouse. Properties of mouse OCT considerably differ from those of rat or human origin, and thus, observations made in these rodents cannot directly be transferred to the human situation

  16. A common polymorphism in a Williams syndrome gene predicts amygdala reactivity and extraversion in healthy adults

    Science.gov (United States)

    Swartz, Johnna R.; Waller, Rebecca; Bogdan, Ryan; Knodt, Annchen R.; Sabhlok, Aditi; Hyde, Luke W.; Hariri, Ahmad R.

    2015-01-01

    Background Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Recently, common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms will help advance our understanding not only of this specific genetic association but also the broader neurogenetic mechanisms of variability in socioemotional behavior. Methods Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional MRI (fMRI), assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students. Results The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men. Conclusions A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety. PMID:26853120

  17. Conditioned suppression and freezing as measures of aversive Pavlovian conditioning: effects of discrete amygdala lesions and overtraining.

    Science.gov (United States)

    Lee, Jonathan L C; Dickinson, Anthony; Everitt, Barry J

    2005-04-30

    Freezing and suppression are measures of conditioned fear that correlate in unlesioned animals. Both the basolateral (BLA) and central (CeN) nuclei of the amygdala are required for conditioned freezing, though there can be recovery with overtraining. The neuroanatomical substrates of conditioned suppression are less clear, with evidence both for a specific requirement of the CeN and for disruption by BLA lesions. The present study investigated the impact of selective excitotoxic lesions of the BLA and CeN upon the acquisition and expression of conditioned fear, measured by freezing and both on-baseline and off-baseline conditioned suppression in the same rats. BLA and CeN lesions both abolished all measures of conditioned fear after 9 trials of fear conditioning. However, when conditioning was extended to 33 trials, whereas rats with combined lesions of both the BLA and CeN continued to show no conditioned fear responses, there was a pattern of recovery observed after selective lesions. There was a partial recovery of freezing with both lesions, and full recovery of conditioned suppression, except for off-baseline suppression in CeN lesioned rats. These results indicate that with few conditioning trials, both the BLA and CeN are required in a serial manner for conditioned fear responses, but that overtraining can mitigate such impairments, likely involving parallel pathways in and through the amygdala.

  18. Optogenetic stimulation of lateral amygdala input to posterior piriform cortex modulates single-unit and ensemble odor processing

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    Benjamin eSadrian

    2015-12-01

    Full Text Available Olfactory information is synthesized within the olfactory cortex to provide not only an odor percept, but also a contextual significance that supports appropriate behavioral response to specific odor cues. The piriform cortex serves as a communication hub within this circuit by sharing reciprocal connectivity with higher processing regions, such as the lateral entorhinal cortex and amygdala. The functional significance of these descending inputs on piriform cortical processing of odorants is currently not well understood. We have employed optogenetic methods to selectively stimulate lateral and basolateral amygdala (BLA afferent fibers innervating the posterior piriform cortex (pPCX to quantify BLA modulation of pPCX odor-evoked activity. Single unit odor-evoked activity of anaesthetized BLA-infected animals was significantly modulated compared with control animal recordings, with individual cells displaying either enhancement or suppression of odor-driven spiking. In addition, BLA activation induced a decorrelation of odor-evoked pPCX ensemble activity relative to odor alone. Together these results indicate a modulatory role in pPCX odor processing for the BLA complex, which could contribute to learned changes in PCX activity following associative conditioning.

  19. Reversal of reduced parvalbumin neurons in hippocampus and amygdala of Angelman syndrome model mice by chronic treatment of fluoxetine.

    Science.gov (United States)

    Godavarthi, Swetha K; Sharma, Ankit; Jana, Nihar Ranjan

    2014-08-01

    Angelman syndrome (AS) is a neuropsychiatric disorder characterized by autism, intellectual disability and motor disturbances. The disease is primarily caused by the loss of function of maternally inherited UBE3A. Ube3a maternal-deficient mice recapitulates many essential feature of AS. These AS mice have been shown to be under chronic stress and exhibits anxiety-like behaviour because of defective glucocorticoid receptor signalling. Here, we demonstrate that chronic stress in these mice could lead to down-regulation of parvalbumin-positive interneurons in the hippocampus and basolateral amygdala from early post-natal days. Down-regulation of parvalbumin-positive interneurons number could be because of decrease in the expression of parvalbumin in these neurons. We also find that treatment with fluoxetine, a selective serotonin reuptake inhibitor, results in restoration of impaired glucocorticoid signalling, elevated serum corticosterone level, parvalbumin-positive interneurons and anxiety-like behaviours. Our findings suggest that impaired glucocorticod signalling in hippocampus and amygdala of AS mice is critical for the decrease in parvalbumin interneurons number, emergence of anxiety and other behavioural deficits and highlights the importance of fluoxetine in the recovery of these abnormalities. © 2014 International Society for Neurochemistry.

  20. Differential efferent projections of the anterior, posteroventral and posterodorsal subdivisions of the medial amygdala in mice

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    Cecília ePardo-Bellver

    2012-08-01

    Full Text Available The medial amygdaloid nucleus (Me is a key structure in the control of sociosexual behaviour in mice. It receives direct projections from the main and accessory olfactory bulbs, as well as an important hormonal input. To better understand its behavioural role, in this work we investigate the structures receiving information from the Me, by analysing the efferent projections from its anterior (MeA, posterodorsal (MePD and posteroventral (MePV subdivisions, using anterograde neuronal tracing with biotinylated and tetrametylrhodamine-conjugated dextranamines.The Me is strongly interconnected with the rest of the chemosensory amygdala, but shows only moderate projections to the central nucleus and light projections to the associative nuclei of the basolateral amygdaloid complex. In addition, the MeA originates a strong feedback projection to the deep mitral cell layer of the accessory olfactory bulb, whereas the MePV projects to its granule cell layer. The medial amygdaloid nucleus (especially the MeA has also moderate projections to different olfactory structures, including the piriform cortex. The densest outputs of the Me target the bed nucleus of the stria terminalis (BST and the hypothalamus. The MeA and MePV project to key structures of the circuit involved in the defensive response against predators (medial posterointermediate BST, anterior hypothalamic area, dorsomedial aspect of the ventromedial hypothalamic nucleus, although less dense projections also innervate reproductive-related nuclei. In contrast, the MePD projects mainly to structures that control reproductive behaviours (medial posteromedial BST, medial preoptic nucleus, and ventrolateral aspect of the ventromedial hypothalamic nucleus, although less dense projections to defensive-related nuclei also exist. These results confirm and extend previous results in other rodents and suggest that the medial amygdala is anatomically and functionally compartmentalized.

  1. Differential activation of amygdala, dorsal and ventral hippocampus following an exposure to a reminder ofunderwater trauma

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    Gilad eRitov

    2014-01-01

    Full Text Available Recollection of emotional memories is attributed in part to the activation of the amygdala and the hippocampus. Recent hypothesis suggest a pivotal role for the ventral hippocampus in traumatic stress processing and emotional memory retrieval. Persistent re-experiencing and intrusive recollections are core symptoms in acute and posttraumatic stress disorders (ASD; PTSD. Such intrusive recollections are often triggered by reminders associated with the trauma.We examined the impact of exposure to a trauma reminder (under water trauma on the activation of the basolateral amygdala (BLA, dorsal and ventral hippocampus. Rats were exposed to underwater trauma and 24 hours later were re-exposed to the context of the trauma. Phosphorylation of the extracellular signal-regulated kinase (ERK was used as a marker for level of activation of these regions. Significant increase in ERK activation was found in the ventral hippocampus and BLA. Such pattern of activation was not found in animals exposed only to the trauma or in animals exposed only to the trauma reminder. Additionally, the dissociative pattern of activation of the ventral hippocampus sub-regions positively correlated with the activation of the BLA.Our findings suggest a specific pattern of neural activation during recollection of a trauma reminder, with a unique contribution of the ventral hippocampus. Measured 24 hrs after the exposure to the traumatic experience, the current findings relate to relatively early stages of traumatic memory consolidation. Understanding the neural mechanisms underlying these initial stages may contribute to developing intervention strategies that could reduce the risk of eventually developing PTSD.

  2. Post-Acquisition Release of Glutamate and Norepinephrine in the Amygdala Is Involved in Taste-Aversion Memory Consolidation

    Science.gov (United States)

    Guzman-Ramos, Kioko; Osorio-Gomez, Daniel; Moreno-Castilla, Perla; Bermudez-Rattoni, Federico

    2012-01-01

    Amygdala activity mediates the acquisition and consolidation of emotional experiences; we have recently shown that post-acquisition reactivation of this structure is necessary for the long-term storage of conditioned taste aversion (CTA). However, the specific neurotransmitters involved in such reactivation are not known. The aim of the present…

  3. Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation within the Amygdala

    OpenAIRE

    Aubry, Antonio V.; Serrano, Peter A.; Burghardt, Nesha S.

    2016-01-01

    Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by w...

  4. Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation Within the Amygdala

    OpenAIRE

    Antonio Aubry; Antonio Aubry; Peter Serrano; Peter Serrano; Nesha Burghardt; Nesha Burghardt

    2016-01-01

    Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by...

  5. Local injection of d-lys-3-GHRP-6 in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation.

    Science.gov (United States)

    Beheshti, Siamak; Aslani, Neda

    2018-02-01

    It is well known that the hormone ghrelin affects learning and memory in different experimental models of learning. Though, the effect of antagonism of ghrelin receptor type 1a (GHS-R1a) in various regions of the brain and on different stages of learning has not been examined. In this study the effect of injection of a GHS-R1a selective antagonist (d-Lys-3-GHRP-6) into the basolateral amygdala, dentate gyrus or ventral tegmental area was examined on memory consolidation in the passive avoidance task. Adult male Wistar rats weighing 230-280g were used. Animals underwent stereotaxic surgery and cannulated in their amygdala, dentate gyrus or ventral tegmental area. One week after surgery, the rats received different doses of d-Lys-3-GHRP-6 (0.08, 0.8, and 8nM), immediately after training. The control groups received solvent of the drug. Twenty four hours later in the test day, memory retrieval was assessed. In all groups, post-training injection of d-Lys-3-GHRP-6 decreased step-through latency and increased entries into the dark compartment and time spent in the dark compartment, significantly and in a dose-dependent manner. The results indicate that antagonism of the GHS-R1a in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation and show that the ghrelin signaling has a widespread influence on cognitive performance. Copyright © 2017. Published by Elsevier Ltd.

  6. Differential Regulation of Apical-basolateral Dendrite Outgrowth by Activity in Hippocampal Neurons

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    Yang eYuan

    2015-08-01

    Full Text Available Hippocampal pyramidal neurons have characteristic dendrite asymmetry, characterized by structurally and functionally distinct apical and basolateral dendrites. The ability of the neuron to generate and maintain dendrite asymmetry is vital, since synaptic inputs received are critically dependent on dendrite architecture. Little is known about the role of neuronal activity in guiding maintainance of dendrite asymmetry. Our data indicate that dendrite asymmetry is established and maintained early during development. Further, our results indicate that cell intrinsic and global alterations of neuronal activity have differential effects on net extension of apical and basolateral dendrites. Thus, apical and basolateral dendrite extension may be independently regulated by cell intrinsic and network neuronal activity during development, suggesting that individual dendrites may have autonomous control over net extension. We propose that regulated individual dendrite extension in response to cell intrinsic and neuronal network activity may allow temporal control of synapse specificity in the developing hippocampus.

  7. Self-reported neglect, amygdala volume, and symptoms of anxiety in adolescent boys.

    Science.gov (United States)

    Roth, Marissa C; Humphreys, Kathryn L; King, Lucy S; Gotlib, Ian H

    2018-03-22

    Experiences of psychosocial neglect affect the developing brain and may place individuals at increased risk for anxiety. The majority of research in this area has focused on children who have experienced severe psychosocial deprivation; it is not clear whether typical variation in neglect experienced in community samples would have the same neurobiological consequences as those documented in extreme samples. The present study examined the associations among self-reported childhood neglect, amygdala volume, and anxiety symptoms in a community sample of 138 adolescents ages 9-15 years (43% male). Linear mixed modeling yielded a three-way interaction of neglect, sex, and brain hemisphere, reflecting a significant positive association between neglect and right amygdala volume in boys. Additional analyses indicated that right amygdala volume significantly mediated the association between neglect and anxiety symptoms in boys. These findings are consistent with previous reports of larger amygdala volumes in previously institutionalized children, and with documented associations between caregiving deprivation and anxiety symptoms. The results suggest that the effects of childhood neglect on limbic structures are sex-specific and lateralized, and provide support for a neural mechanism relating childhood neglect to later difficulties in emotional functioning. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. FMRI connectivity analysis of acupuncture effects on an amygdala-associated brain network

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    Zhao Baixiao

    2008-11-01

    Full Text Available Abstract Background Recently, increasing evidence has indicated that the primary acupuncture effects are mediated by the central nervous system. However, specific brain networks underpinning these effects remain unclear. Results In the present study using fMRI, we employed a within-condition interregional covariance analysis method to investigate functional connectivity of brain networks involved in acupuncture. The fMRI experiment was performed before, during and after acupuncture manipulations on healthy volunteers at an acupuncture point, which was previously implicated in a neural pathway for pain modulation. We first identified significant fMRI signal changes during acupuncture stimulation in the left amygdala, which was subsequently selected as a functional reference for connectivity analyses. Our results have demonstrated that there is a brain network associated with the amygdala during a resting condition. This network encompasses the brain structures that are implicated in both pain sensation and pain modulation. We also found that such a pain-related network could be modulated by both verum acupuncture and sham acupuncture. Furthermore, compared with a sham acupuncture, the verum acupuncture induced a higher level of correlations among the amygdala-associated network. Conclusion Our findings indicate that acupuncture may change this amygdala-specific brain network into a functional state that underlies pain perception and pain modulation.

  9. Extending the amygdala in theories of threat processing

    Science.gov (United States)

    Fox, Andrew S.; Oler, Jonathan A.; Tromp, Do P.M.; Fudge, Julie L.; Kalin, Ned H.

    2015-01-01

    The central extended amygdala is an evolutionarily conserved set of interconnected brain regions that play an important role in threat processing to promote survival. Two core components of the central extended amygdala, the central nucleus of the amygdala (Ce) and the lateral bed nucleus of the stria terminalis (BST) are highly similar regions that serve complimentary roles by integrating fear- and anxiety-relevant information. Survival depends on the central extended amygdala's ability to rapidly integrate and respond to threats that vary in their immediacy, proximity, and characteristics. Future studies will benefit from understanding alterations in central extended amygdala function in relation to stress-related psychopathology. PMID:25851307

  10. Iron repletion relocalizes hephaestin to a proximal basolateral compartment in polarized MDCK and Caco2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung-Min [Department of Biological Sciences, University of Columbia, NY (United States); Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States); Attieh, Zouhair K. [Department of Laboratory Science and Technology, American University of Science and Technology, Ashrafieh (Lebanon); Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States); Son, Hee Sook [Department of Food Science and Human Nutrition, College of Human Ecology, Chonbuk National University (Korea, Republic of); Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States); Chen, Huijun [Medical School, Nanjing University, Nanjing 210008, Jiangsu Province (China); Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States); Bacouri-Haidar, Mhenia [Department of Biology, Faculty of Sciences (I), Lebanese University, Hadath (Lebanon); Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States); Vulpe, Chris D., E-mail: vulpe@berkeley.edu [Department of Nutritional Science and Toxicology, University of California, Berkeley, CA (United States)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Hephaestin localizes in the perinuclear space in non-polarized cells. Black-Right-Pointing-Pointer Hephaestin localizes in the perinuclear space in iron deficient and polarized cells. Black-Right-Pointing-Pointer Hephaestin with apical iron moves near to basolateral membrane of polarized cells. Black-Right-Pointing-Pointer Peri-basolateral location of hephaestin is accessible to the extracellular space. Black-Right-Pointing-Pointer Hephaestin is involved in iron mobilization from the intestine to circulation. -- Abstract: While intestinal cellular iron entry in vertebrates employs multiple routes including heme and non-heme routes, iron egress from these cells is exclusively channeled through the only known transporter, ferroportin. Reduced intestinal iron export in sex-linked anemia mice implicates hephaestin, a ferroxidase, in this process. Polarized cells are exposed to two distinct environments. Enterocytes contact the gut lumen via the apical surface of the cell, and through the basolateral surface, to the body. Previous studies indicate both local and systemic control of iron uptake. We hypothesized that differences in iron availability at the apical and/or basolateral surface may modulate iron uptake via cellular localization of hephaestin. We therefore characterized the localization of hephaestin in two models of polarized epithelial cell lines, MDCK and Caco2, with varying iron availability at the apical and basolateral surfaces. Our results indicate that hephaestin is expressed in a supra-nuclear compartment in non-polarized cells regardless of the iron status of the cells and in iron deficient and polarized cells. In polarized cells, we found that both apical (as FeSO{sub 4}) and basolateral iron (as the ratio of apo-transferrin to holo-transferrin) affect mobilization of hephaestin from the supra-nuclear compartment. We find that the presence of apical iron is essential for relocalization of hephaestin to a

  11. Oxytocin in the amygdala and not the prefrontal cortex enhances fear and impairs extinction in the juvenile rat.

    Science.gov (United States)

    Kritman, Milly; Lahoud, Nisrine; Maroun, Mouna

    2017-05-01

    A growing body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT), aside from its central role in the regulation of social behavior, reduces fear and anxiety. The functional and opposing interactions of the medial prefrontal cortex (mPFC) and the amygdala in regulation of fear provide a unique experimental setting to examine the effects of OT on fear and extinction. Recent evidence suggests that in the adult animal OT can play a dual role in the regulation of fear leading to contrasting effects on fear depending on the manipulated brain region and the time of manipulations. The OT system is one of the systems that undergoes major changes throughout development, however, its role in regulating fear in young animals has not been widely explored. We recently showed that the mechanisms of extinction, and specifically engagement of the mPFC in extinction, are not identical in adult and juvenile animals. Thus, the purpose of this study was to elucidate the effects of OT on fear and extinction in juvenile animals. To that end, we determine extinction, by measuring freezing at different time points, following microinjection of the OT agonist, TGOT, into the mPFC, the basolateral and the central nuclei of the amygdala (BLA and CeA, respectively). The results show that whereas TGOT microinjections into the IL-mPFC did not affect extinction, microinjections into the amygdala were mainly associated with enhanced fear and impaired extinction. These results further emphasize the differences between adult and juvenile brains. Copyright © 2017. Published by Elsevier Inc.

  12. The delayed strengthening of synaptic connectivity in the amygdala depends on NMDA receptor activation during acute stress.

    Science.gov (United States)

    Yasmin, Farhana; Saxena, Kapil; McEwen, Bruce S; Chattarji, Sumantra

    2016-10-01

    There is growing evidence that stress leads to contrasting patterns of structural plasticity in the hippocampus and amygdala, two brain areas implicated in the cognitive and affective symptoms of stress-related psychiatric disorders. Acute stress has been shown to trigger a delayed increase in the density of dendritic spines in the basolateral amygdala (BLA) of rodents. However, the physiological correlates of this delayed spinogenesis in the BLA remain unexplored. Furthermore, NMDA receptors (NMDARs) have been known to underlie chronic stress-induced structural plasticity in the hippocampus, but nothing is known about the role of these receptors in the delayed spinogenesis, and its physiological consequences, in the BLA following acute stress. Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress enhances the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) recorded from principal neurons in the BLA 10 days later. This was also accompanied by faster use-dependent block of NMDA receptor currents during repeated stimulation of thalamic inputs to the BLA, which is indicative of higher presynaptic release probability at these inputs 10 days later. Furthermore, targeted in vivo infusion of the NMDAR-antagonist APV into the BLA during the acute stress prevents the increase in mEPSC frequency and spine density 10 days later. Together, these results identify a role for NMDARs during acute stress in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion. These findings also raise the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological

  13. Role and mechanisms of regulation of the basolateral Kir4.1/Kir5.1K+channels in the distal tubules.

    Science.gov (United States)

    Palygin, O; Pochynyuk, O; Staruschenko, A

    2017-01-01

    Epithelial K + channels are essential for maintaining electrolyte and fluid homeostasis in the kidney. It is recognized that basolateral inward-rectifying K + (K ir ) channels play an important role in the control of resting membrane potential and transepithelial voltage, thereby modulating water and electrolyte transport in the distal part of nephron and collecting duct. Monomeric K ir 4.1 (encoded by Kcnj10 gene) and heteromeric K ir 4.1/K ir 5.1 (K ir 4.1 together with K ir 5.1 (Kcnj16)) channels are abundantly expressed at the basolateral membranes of the distal convoluted tubule and the cortical collecting duct cells. Loss-of-function mutations in KCNJ10 cause EAST/SeSAME tubulopathy in humans associated with salt wasting, hypomagnesaemia, metabolic alkalosis and hypokalaemia. In contrast, mice lacking K ir 5.1 have severe renal phenotype that, apart from hypokalaemia, is the opposite of the phenotype seen in EAST/SeSAME syndrome. Experimental advances using genetic animal models provided critical insights into the physiological role of these channels in electrolyte homeostasis and the control of kidney function. Here, we discuss current knowledge about K + channels at the basolateral membrane of the distal tubules with specific focus on the homomeric K ir 4.1 and heteromeric K ir 4.1/K ir 5.1 channels. Recently identified molecular mechanisms regulating expression and activity of these channels, such as cell acidification, dopamine, insulin and insulin-like growth factor-1, Src family protein tyrosine kinases, as well as the role of these channels in NCC-mediated transport in the distal convoluted tubules, are also described. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  14. Basolateral localisation of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif

    DEFF Research Database (Denmark)

    Jespersen, Thomas; Rasmussen, Hanne B; Grunnet, Morten

    2004-01-01

    of the tyrosine residue at position 51 resulted in a non-polarized steady-state distribution of the channel. The importance of tyrosine 51 in basolateral localisation was emphasized by the fact that a short peptide comprising this tyrosine was able to redirect the p75 neurotrophin receptor, an otherwise apically......KCNQ1 potassium channels are expressed in many epithelial tissues as well as in the heart. In epithelia KCNQ1 channels play an important role in salt and water transport and the channel has been reported to be located apically in some cell types and basolaterally in others. Here we show that KCNQ1...... channels are located basolaterally when expressed in polarised MDCK cells. The basolateral localisation of KCNQ1 is not affected by co-expression of any of the five KCNE beta-subunits. We characterise two independent basolateral sorting signals present in the N-terminal tail of KCNQ1. Mutation...

  15. Afferent drive of medial prefrontal cortex by hippocampus and amygdala is altered in MAM-treated rats: evidence for interneuron dysfunction.

    Science.gov (United States)

    Esmaeili, Behnaz; Grace, Anthony A

    2013-09-01

    Evidence indicates that the prefrontal cortex and its regulation by afferent inputs are disrupted in schizophrenia. Using a validated rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM), we examined the convergent projections from the ventral hippocampus (vHipp) and the basolateral amygdala (BLA) in the medial prefrontal cortex (mPFC). In vivo extracellular recordings were done in anesthetized rats to assess how prior stimulation of the BLA or vHipp input to the mPFC affected mPFC responses to subsequent stimulation of these regions. The interstimulus interval (ISI) of the BLA and vHipp pulse stimulation was varied randomly between 0 and 130 ms, and the probability of evoked spike response in the mPFC measured. We found that BLA input increased vHipp-evoked spike probability at ISIs 40-130 ms, but decreased spike probability at ISIs 10-20 ms. This would be consistent with activation of inhibitory interneurons at shorter ISIs by BLA stimulation. In contrast, in MAM-treated rats BLA stimulation increased vHipp-evoked spike probability in mPFC at all ISIs tested. Given that interneurons are driven primarily by N-methyl-D-aspartate (NMDA) channel activation, the effects of the NMDA channel blocker, phencyclidine (PCP), were tested. PCP was found to completely attenuate the inhibitory effect of BLA input on vHipp-evoked responses in mPFC at shorter ISIs, causing the response in control rats treated with PCP to resemble that observed in the MAM rat. In contrast to the effects of BLA stimulation on vHipp-mPFC-evoked responses, there was no inhibitory period when examining the effects of vHipp stimulation on BLA-mPFC-evoked responses in control rats, but in MAM-treated rats there was a significant inhibition at short intervals. Thus, both affective input arising from the BLA and context-dependent input from the vHipp exert a modulatory effect on mPFC neural activity in response to these inputs. Whereas the

  16. Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning.

    Science.gov (United States)

    Rudebeck, Peter H; Ripple, Joshua A; Mitz, Andrew R; Averbeck, Bruno B; Murray, Elisabeth A

    2017-02-22

    Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC. SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed

  17. Amygdala Contributions to Stimulus–Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning

    Science.gov (United States)

    Averbeck, Bruno B.

    2017-01-01

    Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus–reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus–reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus–reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus–reward associations rapidly by shaping encoding within OFC and MFC. SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus–reward associations. MFC also

  18. Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome.

    Science.gov (United States)

    Huang, Wen-Chin; Chen, Youjun; Page, Damon T

    2016-11-15

    Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten +/- ), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten +/- mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits. The latter two phenotypes can be suppressed by pharmacological inhibition of S6K1 during early postnatal life or by reducing the activity of mPFC-BLA circuitry in adulthood. These findings identify a mechanism of altered connectivity that has potential relevance to the pathophysiology of macrocephaly/autism syndrome and autism spectrum disorders featuring dysregulated mTOR signalling.

  19. The Emotional Gatekeeper: A Computational Model of Attentional Selection and Suppression through the Pathway from the Amygdala to the Inhibitory Thalamic Reticular Nucleus

    Science.gov (United States)

    Bullock, Daniel; Barbas, Helen

    2016-01-01

    In a complex environment that contains both opportunities and threats, it is important for an organism to flexibly direct attention based on current events and prior plans. The amygdala, the hub of the brain's emotional system, is involved in forming and signaling affective associations between stimuli and their consequences. The inhibitory thalamic reticular nucleus (TRN) is a hub of the attentional system that gates thalamo-cortical signaling. In the primate brain, a recently discovered pathway from the amygdala sends robust projections to TRN. Here we used computational modeling to demonstrate how the amygdala-TRN pathway, embedded in a wider neural circuit, can mediate selective attention guided by emotions. Our Emotional Gatekeeper model demonstrates how this circuit enables focused top-down, and flexible bottom-up, allocation of attention. The model suggests that the amygdala-TRN projection can serve as a unique mechanism for emotion-guided selection of signals sent to cortex for further processing. This inhibitory selection mechanism can mediate a powerful affective ‘framing’ effect that may lead to biased decision-making in highly charged emotional situations. The model also supports the idea that the amygdala can serve as a relevance detection system. Further, the model demonstrates how abnormal top-down drive and dysregulated local inhibition in the amygdala and in the cortex can contribute to the attentional symptoms that accompany several neuropsychiatric disorders. PMID:26828203

  20. Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories.

    Science.gov (United States)

    Xue, Yan-Xue; Xue, Li-Fen; Liu, Jian-Feng; He, Jia; Deng, Jia-Hui; Sun, Shi-Chao; Han, Hai-Bin; Luo, Yi-Xiao; Xu, Ling-Zhi; Wu, Ping; Lu, Lin

    2014-05-07

    Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.

  1. Effects of electroconvulsive therapy on amygdala function in major depression - a longitudinal functional magnetic resonance imaging study.

    Science.gov (United States)

    Redlich, R; Bürger, C; Dohm, K; Grotegerd, D; Opel, N; Zaremba, D; Meinert, S; Förster, K; Repple, J; Schnelle, R; Wagenknecht, C; Zavorotnyy, M; Heindel, W; Kugel, H; Gerbaulet, M; Alferink, J; Arolt, V; Zwanzger, P; Dannlowski, U

    2017-09-01

    Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects. In a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained. Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = -0.48, p = 0.044), and by tendency also for the MED sample (r spearman = -0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample. In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.

  2. Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis.

    Science.gov (United States)

    Al-Hazza, Adel; Linley, John; Aziz, Qadeer; Hunter, Malcolm; Sandle, Geoffrey

    2016-02-05

    Basolateral K(+) channels hyperpolarize colonocytes to ensure Na(+) (and thus water) absorption. Small conductance basolateral (KCNQ1/KCNE3) K(+) channels have never been evaluated in human colon. We therefore evaluated KCNQ1/KCNE3 channels in distal colonic crypts obtained from normal and active ulcerative colitis (UC) patients. KCNQ1 and KCNE3 mRNA levels were determined by qPCR, and KCNQ1/KCNE3 channel activity in normal and UC crypts, and the effects of forskolin (activator of adenylate cyclase) and UC-related proinflammatory cytokines on normal crypts, studied by patch clamp recording. Whereas KCNQ1 and KCNE3 mRNA expression was similar in normal and UC crypts, single 6.8 pS channels were seen in 36% of basolateral patches in normal crypts, and to an even greater extent (74% of patches, P KCNQ1/KCNE3 channels make only a small contribution to basolateral conductance in normal colonic crypts, with increased channel activity in UC appearing insufficient to prevent colonic cell depolarization in this disease. This supports the proposal that defective Na(+) absorption rather than enhanced Cl(-) secretion, is the dominant pathophysiological mechanism of diarrhea in UC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Basolateral glycylsarcosine (Gly-Sar) transport in Caco-2 cell monolayers is pH dependent

    DEFF Research Database (Denmark)

    Berthelsen, Ragna; Nielsen, Carsten Uhd; Brodin, Birger

    2013-01-01

    Transepithelial di/tripeptide transport in enterocytes occurs via the apical proton-coupled peptide transporter, hPEPT1 (SLC15A1) and a basolateral peptide transporter, which has only been characterized functionally. In this study we examined the pH dependency, substrate uptake kinetics and subst...

  4. Postnatal maturation of GABAergic modulation of sensory inputs onto lateral amygdala principal neurons.

    Science.gov (United States)

    Bosch, Daniel; Ehrlich, Ingrid

    2015-10-01

    Throughout life, fear learning is indispensable for survival and neural plasticity in the lateral amygdala underlies this learning and storage of fear memories. During development, properties of fear learning continue to change into adulthood, but currently little is known about changes in amygdala circuits that enable these behavioural transitions. In recordings from neurons in lateral amygdala brain slices from infant up to adult mice, we show that spontaneous and evoked excitatory and inhibitory synaptic transmissions mature into adolescence. At this time, increased inhibitory activity and signalling has the ability to restrict the function of excitation by presynaptic modulation, and may thus enable precise stimulus associations to limit fear generalization from adolescence onward. Our results provide a basis for addressing plasticity mechanisms that underlie altered fear behaviour in young animals. Convergent evidence suggests that plasticity in the lateral amygdala (LA) participates in acquisition and storage of fear memory. Sensory inputs from thalamic and cortical areas activate principal neurons and local GABAergic interneurons, which provide feed-forward inhibition that tightly controls LA activity and plasticity via pre- and postsynaptic GABAA and GABAB receptors. GABAergic control is also critical during fear expression, generalization and extinction in adult animals. During rodent development, properties of fear and extinction learning continue to change into early adulthood. Currently, few studies have assessed physiological changes in amygdala circuits that may enable these behavioural transitions. To obtain first insights, we investigated changes in spontaneous and sensory input-evoked inhibition onto LA principal neurons and then focused on GABAB receptor-mediated modulation of excitatory sensory inputs in infant, juvenile, adolescent and young adult mice. We found that spontaneous and sensory-evoked inhibition increased during development

  5. Amygdala damage eliminates monetary loss aversion.

    Science.gov (United States)

    De Martino, Benedetto; Camerer, Colin F; Adolphs, Ralph

    2010-02-23

    Losses are a possibility in many risky decisions, and organisms have evolved mechanisms to evaluate and avoid them. Laboratory and field evidence suggests that people often avoid risks with losses even when they might earn a substantially larger gain, a behavioral preference termed "loss aversion." The cautionary brake on behavior known to rely on the amygdala is a plausible candidate mechanism for loss aversion, yet evidence for this idea has so far not been found. We studied two rare individuals with focal bilateral amygdala lesions using a series of experimental economics tasks. To measure individual sensitivity to financial losses we asked participants to play a variety of monetary gambles with possible gains and losses. Although both participants retained a normal ability to respond to changes in the gambles' expected value and risk, they showed a dramatic reduction in loss aversion compared to matched controls. The findings suggest that the amygdala plays a key role in generating loss aversion by inhibiting actions with potentially deleterious outcomes.

  6. Amygdala lesions in rhesus macaques decrease attention to threat

    Science.gov (United States)

    Dal Monte, Olga; Costa, Vincent D.; Noble, Pamela L.; Murray, Elisabeth A.; Averbeck, Bruno B.

    2015-01-01

    Evidence from animal and human studies has suggested that the amygdala plays a role in detecting threat and in directing attention to the eyes. Nevertheless, there has been no systematic investigation of whether the amygdala specifically facilitates attention to the eyes or whether other features can also drive attention via amygdala processing. The goal of the present study was to examine the effects of amygdala lesions in rhesus monkeys on attentional capture by specific facial features, as well as gaze patterns and changes in pupil dilation during free viewing. Here we show reduced attentional capture by threat stimuli, specifically the mouth, and reduced exploration of the eyes in free viewing in monkeys with amygdala lesions. Our findings support a role for the amygdala in detecting threat signals and in directing attention to the eye region of faces when freely viewing different expressions. PMID:26658670

  7. What, if anything, is the medial temporal lobe, and how can the amygdala be part of it if there is no such thing?

    Science.gov (United States)

    Murray, Elisabeth A; Wise, Steven P

    2004-11-01

    Should the medial temporal lobe (MTL) of primates--which includes allocortical structures such as the hippocampus, neocortical structures such as the parahippocampal cortex, and nuclear structures such as the basolateral amygdala--be considered a single "thing"? According to the prevailing view, here termed the reification theory, the answer is yes. According to this theory, the MTL functions as an amalgamated entity that provides the neuronal mechanisms for declarative memory; the greater the damage to the MTL or any of its components, the greater the deleterious effects on declarative memory. A countervailing view, here called the balkanization theory, holds that the various components of the MTL process and store different kinds of information. According to this theory, damage to each part of the MTL causes a unique set of behavioral deficits-some involving memory, others involving perception, and yet others involving response selection. The empirical neuropsychological evidence favors the balkanization theory, as do some new concepts in theoretical neuroanatomy.

  8. Fear and panic in humans with bilateral amygdala damage.

    Science.gov (United States)

    Feinstein, Justin S; Buzza, Colin; Hurlemann, Rene; Follmer, Robin L; Dahdaleh, Nader S; Coryell, William H; Welsh, Michael J; Tranel, Daniel; Wemmie, John A

    2013-03-01

    Decades of research have highlighted the amygdala's influential role in fear. We found that inhalation of 35% CO(2) evoked not only fear, but also panic attacks, in three rare patients with bilateral amygdala damage. These results indicate that the amygdala is not required for fear and panic, and make an important distinction between fear triggered by external threats from the environment versus fear triggered internally by CO(2).

  9. Temporary amygdala inhibition reduces stress effects in female mice

    OpenAIRE

    Dalooei, Jila Rezaeian; Sahraei, Hedayat; Meftahi, Gholam Hossein; Khosravi, Maryam; Bahari, Zahra; Hatef, Boshra; Mohammadi, Alireza; Nicaeili, Fateme; Eftekhari, Fateme; Ghamari, Fateme; Hadipour, Mohamadmehdi; Kaka, Gholamreza

    2016-01-01

    The current study investigated the effect of temporary inhibition of amygdala in response to metabolic changes caused by stress in female mice. Unilateral and bilateral amygdala cannulation was carried out, and after a week of recovery, 2% lidocaine hydrochloride was injected into the mice amygdalae five minutes before the induction of stress. A communication box was employed to induce stress for four consecutive days and plasma corticosterone, food and water intake, weight changes, and anore...

  10. Amygdala Functional Connectivity is Reduced After the Cold Pressor Task

    Science.gov (United States)

    Clewett, David; Schoeke, Andrej; Mather, Mara

    2013-01-01

    The amygdala forms a crucial link between central pain and stress systems. There is much evidence that psychological stress affects amygdala activity, but it is less clear how painful stressors influence subsequent amygdala functional connectivity. In the present study, we used pulsed arterial spin labeling (PASL) to investigate differences in healthy male adults’ resting-state amygdala functional connectivity following a cold pressor versus control task, with the stressor and control conditions conducted on different days. During the period of peak cortisol response to acute stress (approximately fifteen to thirty minutes after stressor onset), participants were asked to rest for six minutes with their eyes closed during a PASL scanning sequence. The cold pressor task led to reduced resting-state functional connectivity between the amygdalae and orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC), which occurred irrespective of cortisol release. The stressor also induced greater inverse connectivity between the left amygdala and dorsal anterior cingulate cortex (dACC), a brain region implicated in the down-regulation of amygdala responsivity. Furthermore, the degree of post-stressor left amygdala decoupling with the lateral OFC varied according to self-reported pain intensity during the cold pressor task. These findings indicate that the cold pressor task alters amygdala interactions with prefrontal and ACC regions 15–30 minutes after the stressor, and that these altered functional connectivity patterns are related to pain perception rather than cortisol feedback. PMID:23645370

  11. Surface morphology of amygdala is associated with trait anxiety.

    Directory of Open Access Journals (Sweden)

    Shuyu Li

    Full Text Available Previous neuroimaging studies have suggested a role of amygdala in trait anxiety level, in which amygdala was typically treated as a whole. To date, it remains unknown whether the morphology of specific subregions of amygdala are associated with trait anxiety. Here, we employed a shape analysis approach to locate the association between its morphology and trait anxiety on the surface of amygdala. 24 healthy young participants were included. The boundary of amygdala for each subject was first manually outlined using high-resolution magnetic resonance (MR image, followed by 3D surface reconstruction and parameterization using spherical harmonic description. Two point-wise metrics, direct displacement between the individual surface and atlas surface and its normal projection, were used to quantify the surface morphology of amygdala. Statistical analysis revealed significant correlations between the two surface metrics and trait anxiety levels, which were located around the lateral and central nucleus of right amygdala. Our results provided localized information for the association between amygdala and trait anxiety, and suggested a central role of the lateral and central nucleus of right amygdala on trait anxiety.

  12. Impact of family history and depression on amygdala volume.

    LENUS (Irish Health Repository)

    Saleh, Karim

    2012-07-30

    Family history of depression significantly impacts life-long depression risk. Family history could impact the stress and emotion regulation system that involves the amygdala. This study\\'s purpose was to investigate family history\\'s effect on amygdala volumes, and differences in first degree relatives with and without major depressive disorder (MDD). Participants, aged 18-65, were healthy volunteers (N=52) with (n=26) and without (n=26) first degree family history, and patients with MDD (N=48) with (n=27) and without (n=21)first-degree family history recruited for structural magnetic resonance imaging (MRI). Participants underwent clinical assessment followed by manual amygdala tracing. Patients with MDD without family history showed significantly larger right amygdala without a family history of MDD. These effects had larger right amygdala than healthy controls without MDD family history. These effects were pronounced in females. Family history and gender impacted amygdala volumes in all participants, providing a rationale for the inconsistent results in MDD amygdala studies. Higher familial risk in depression seems to be associated with smaller amygdala volumes, whereas depression alone is associated with larger amygdala volumes. Ultimately, these findings highlight consideration of family history and gender in research and treatment strategies.

  13. Altered Amygdala Development and Fear Processing in Prematurely Born Infants.

    Science.gov (United States)

    Cismaru, Anca Liliana; Gui, Laura; Vasung, Lana; Lejeune, Fleur; Barisnikov, Koviljka; Truttmann, Anita; Borradori Tolsa, Cristina; Hüppi, Petra S

    2016-01-01

    Prematurely born children have a high risk of developmental and behavioral disabilities. Cerebral abnormalities at term age have been clearly linked with later behavior alterations, but existing studies did not focus on the amygdala. Moreover, studies of early amygdala development after premature birth in humans are scarce. To compare amygdala volumes in very preterm infants at term equivalent age (TEA) and term born infants, and to relate premature infants' amygdala volumes with their performance on the Laboratory Temperament Assessment Battery (Lab-TAB) fear episode at 12 months. Eighty one infants born between 2008 and 2014 at the University Hospitals of Geneva and Lausanne, taking part in longitudinal and functional imaging studies, who had undergone a magnetic resonance imaging (MRI) scan at TEA enabling manual amygdala delineation. Amygdala volumes assessed by manual segmentation of MRI scans; volumes of cortical and subcortical gray matter, white matter and cerebrospinal fluid (CSF) automatically segmented in 66 infants; scores for the Lab-TAB fear episode for 42 premature infants at 12 months. Amygdala volumes were smaller in preterm infants at TEA than term infants (mean difference 138.03 mm(3), p motor activity in the fear episode. Our results indicate that premature birth is associated with a reduction in amygdala volumes and white matter volumes at TEA, suggesting that altered amygdala development might be linked to alterations in white matter connectivity reported in premature infants. Moreover, our data suggests that such alterations might affect infants' fear-processing capabilities.

  14. Dendritic morphology changes in neurons from the ventral hippocampus, amygdala and nucleus accumbens in rats with neonatal lesions into the prefrontal cortex.

    Science.gov (United States)

    Lazcano, Zayda; Solis, Oscar; Díaz, Alfonso; Brambila, Eduardo; Aguilar-Alonso, Patricia; Guevara, Jorge; Flores, Gonzalo

    2015-06-01

    Neonatal prefrontal cortex (nPFC) lesions in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the ventral hippocampus (VH) have been observed in post-mortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nPFC-lesions on the dendritic morphology of neurons from the VH, basolateral-amygdala (BLA) and the nucleus accumbens (NAcc) in rats. nPFC lesions were made on postnatal day 7 (PD7), after dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of PFC-lesions on locomotor activity caused by a novel environment. Adult animals with nPFC lesions showed a decreased spine density in pyramidal neurons from the VH and in medium spiny cells from the NAcc. An increased locomotion was observed in a novel environment for adult animals with a PFC-lesion. Our results indicate that PFC-lesions alter the neuronal dendrite morphology of the NAcc and the VH, suggesting a disconnection between these limbic structures. The locomotion paradigms suggest that dopaminergic transmission is altered in the PFC lesion model. This could help to understand the consequences of an earlier PFC dysfunction in schizophrenia. To evaluate possible dendritic changes in neonatal prefrontal cortex lesions in schizophrenia-related regions including nucleus accumbens, ventral hippocampus and basolateral amygdala, we used the Golgi-Cox stain samples at PD35 and PD70. Our results suggest that neonatal prefrontal cortex damage alters dendritic parameters in limbic regions, and this has potential implications for schizophrenia. © 2015 Wiley Periodicals, Inc.

  15. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users

    NARCIS (Netherlands)

    Crunelle, Cleo L.; Kaag, Anne Marije; van den Munkhof, Hanna E.; Reneman, Liesbeth; Homberg, Judith R.; Sabbe, Bernard; van den Brink, Wim; van Wingen, Guido

    2015-01-01

    Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal

  16. Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users

    NARCIS (Netherlands)

    Crunelle, C.L.; Kaag, A.M.; van den Munkhof, H.E.; Reneman, L.; Homberg, J.R.; Sabbe, B.; van den Brink, W.; van Wingen, G.

    2015-01-01

    OBJECTIVES: Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the

  17. Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice.

    Science.gov (United States)

    Liu, Zhi-Peng; He, Qing-Hai; Pan, Han-Qing; Xu, Xiao-Bin; Chen, Wen-Bing; He, Ye; Zhou, Jin; Zhang, Wen-Hua; Zhang, Jun-Yu; Ying, Xiao-Ping; Han, Ren-Wen; Li, Bao-Ming; Gao, Tian-Ming; Pan, Bing-Xing

    2017-06-15

    Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABA A R) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABA A R to amygdala inhibition and fear. By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABA A R (GABA A (δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA A (δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. In sharp contrast to the established role of synaptic GABA A R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA A (δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA A (δ)R. The disinhibition arose from IN-specific expression of GABA A (δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA A (δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA A (δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. Our findings suggest that GABA A (δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA A (δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the amygdala of the cynomolgus monkey.

    Science.gov (United States)

    Beattie, Matthew C; Maldonado-Devincci, Antoniette M; Porcu, Patrizia; O'Buckley, Todd K; Daunais, James B; Grant, Kathleen A; Morrow, A Leslie

    2017-03-01

    Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) enhance the gamma-aminobutyric acid (GABA)-ergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3α,5α-THP levels in human plasma, rat hippocampus and mouse limbic regions. We explored the relationship between 3α,5α-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to hypothalamic-pituitary-adrenal (HPA) axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 h/day over 12 months. Immunohistochemistry was performed using an anti-3α,5α-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 to 4.2 g/kg/day over 12 months. Prolonged ethanol consumption reduced cellular 3α,5α-THP immunoreactivity by 13 ± 2 percent (P amygdala and 17 ± 2 percent (P amygdala. The effect of ethanol was most pronounced in heavy drinkers that consumed ≥3 g/kg ≥ 20 percent of days. Consequently, 3α,5α-THP immunoreactivity in both the lateral and basolateral amygdala was inversely correlated with average daily ethanol intake (Spearman r = -0.87 and -0.72, respectively, P amygdala. 3α,5α-THP immunoreactivity following ethanol exposure was also correlated with HPA axis function prior to ethanol exposure. These data indicate that voluntary ethanol drinking reduces amygdala levels of 3α,5α-THP in non-human primates and that amygdala 3α,5α-THP levels may be linked to HPA axis function. © 2015 Society for the Study of Addiction.

  19. Reciprocal activation/inactivation of ERK in the amygdala and frontal cortex is correlated with the degree of novelty of an open-field environment.

    Science.gov (United States)

    Sanguedo, Frederico Velasco; Dias, Caio Vitor Bueno; Dias, Flavia Regina Cruz; Samuels, Richard Ian; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-03-01

    Phosphorylated extracellular signal-regulated kinase (ERK) has been used to identify brain areas activated by exogenous stimuli including psychostimulant drugs. Assess the role of the amygdala in emotional responses. Experimental manipulations were performed in which environmental familiarity was the variable. To provide the maximal degree of familiarity, ERK was measured after removal from the home cage and re-placement back into the same cage. To maximize exposure to an unfamiliar environment, ERK was measured following placement into a novel open field. To assess whether familiarity was the critical variable in the ERK response to the novel open field, ERK was also measured after either four or eight placements into the same environment. ERK quantification was carried out in the amygdala, frontal cortex, and the nucleus accumbens. After home cage re-placement, ERK activation was found in the frontal cortex and nucleus accumbens but was absent in the amygdala. Following placement in a novel environment, ERK activation was more prominent in the amygdala than the frontal cortex or nucleus accumbens. In contrast, with habituation to the novel environment, ERK phosphors declined markedly in the amygdala but increased in the frontal cortex and nucleus accumbens to the level observed following home cage re-placement. The differential responsiveness of the amygdala versus the frontal cortex and the nucleus accumbens to a novel versus a habituated environment is consistent with a reciprocal interaction between these neural systems and points to their important role in the mediation of behavioral activation to novelty and behavioral inactivation with habituation.

  20. Lifespan anxiety is reflected in human amygdala cortical connectivity.

    Science.gov (United States)

    He, Ye; Xu, Ting; Zhang, Wei; Zuo, Xi-Nian

    2016-03-01

    The amygdala plays a pivotal role in processing anxiety and connects to large-scale brain networks. However, intrinsic functional connectivity (iFC) between amygdala and these networks has rarely been examined in relation to anxiety, especially across the lifespan. We employed resting-state functional MRI data from 280 healthy adults (18-83.5 yrs) to elucidate the relationship between anxiety and amygdala iFC with common cortical networks including the visual network, somatomotor network, dorsal attention network, ventral attention network, limbic network, frontoparietal network, and default network. Global and network-specific iFC were separately computed as mean iFC of amygdala with the entire cerebral cortex and each cortical network. We detected negative correlation between global positive amygdala iFC and trait anxiety. Network-specific associations between amygdala iFC and anxiety were also detectable. Specifically, the higher iFC strength between the left amygdala and the limbic network predicted lower state anxiety. For the trait anxiety, left amygdala anxiety-connectivity correlation was observed in both somatomotor and dorsal attention networks, whereas the right amygdala anxiety-connectivity correlation was primarily distributed in the frontoparietal and ventral attention networks. Ventral attention network exhibited significant anxiety-gender interactions on its iFC with amygdala. Together with findings from additional vertex-wise analysis, these data clearly indicated that both low-level sensory networks and high-level associative networks could contribute to detectable predictions of anxiety behaviors by their iFC profiles with the amygdala. This set of systems neuroscience findings could lead to novel functional network models on neural correlates of human anxiety and provide targets for novel treatment strategies on anxiety disorders. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

  1. Lifespan anxiety is reflected in human amygdala cortical connectivity

    Science.gov (United States)

    He, Ye; Xu, Ting; Zhang, Wei

    2016-01-01

    Abstract The amygdala plays a pivotal role in processing anxiety and connects to large‐scale brain networks. However, intrinsic functional connectivity (iFC) between amygdala and these networks has rarely been examined in relation to anxiety, especially across the lifespan. We employed resting‐state functional MRI data from 280 healthy adults (18–83.5 yrs) to elucidate the relationship between anxiety and amygdala iFC with common cortical networks including the visual network, somatomotor network, dorsal attention network, ventral attention network, limbic network, frontoparietal network, and default network. Global and network‐specific iFC were separately computed as mean iFC of amygdala with the entire cerebral cortex and each cortical network. We detected negative correlation between global positive amygdala iFC and trait anxiety. Network‐specific associations between amygdala iFC and anxiety were also detectable. Specifically, the higher iFC strength between the left amygdala and the limbic network predicted lower state anxiety. For the trait anxiety, left amygdala anxiety–connectivity correlation was observed in both somatomotor and dorsal attention networks, whereas the right amygdala anxiety–connectivity correlation was primarily distributed in the frontoparietal and ventral attention networks. Ventral attention network exhibited significant anxiety–gender interactions on its iFC with amygdala. Together with findings from additional vertex‐wise analysis, these data clearly indicated that both low‐level sensory networks and high‐level associative networks could contribute to detectable predictions of anxiety behaviors by their iFC profiles with the amygdala. This set of systems neuroscience findings could lead to novel functional network models on neural correlates of human anxiety and provide targets for novel treatment strategies on anxiety disorders. Hum Brain Mapp 37:1178–1193, 2016. © 2015 The Authors Human Brain Mapping

  2. Is there a link between childhood trauma, cognition, and amygdala and hippocampus volume in first-episode psychosis?

    Science.gov (United States)

    Aas, Monica; Navari, Serena; Gibbs, Ayana; Mondelli, Valeria; Fisher, Helen L; Morgan, Craig; Morgan, Kevin; MacCabe, James; Reichenberg, Abraham; Zanelli, Jolanta; Fearon, Paul; Jones, Peter B; Murray, Robin M; Pariante, Carmine M; Dazzan, Paola

    2012-05-01

    Patients with psychosis have higher rates of childhood trauma, which is also associated with adverse effects on cognitive functions such as attention, concentration and mental speed, language, and verbal intelligence. Although the pathophysiological substrate for this association remains unclear, these cognitive deficits may represent the functional correlate of changes observed in relation to trauma exposure in structures such as the amygdala and the hippocampus. Interestingly, these structures are often reported as altered in psychosis. This study investigated the association between childhood trauma, cognitive function and amygdala and hippocampus volume, in first-episode psychosis. We investigated 83 patients with first-episode psychosis and 63 healthy controls. All participants underwent an MRI scan acquired with a GE Sigma 1.5-T system, and a standardized neuropsychological assessment of general cognition, memory, processing speed, executive function, visuo-spatial abilities, verbal intelligence, and language. In a subsample of the patients (N=45) information on childhood trauma was collected with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q). We found that amygdala, but not hippocampus, volume was significantly smaller (p=0.001) in patients compared to healthy controls. There was a trend level interaction for hippocampus volume between group and sex (p=0.056). A history of childhood trauma was associated with both worse cognitive performance and smaller amygdala volume. This smaller amygdala appeared to mediate the relationship between childhood trauma and performance on executive function, language and verbal intelligence in patients with psychosis. This points to a complex relationship between childhood trauma exposure, cognitive function and amygdala volume in first-episode psychosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Amygdala temporal dynamics: temperamental differences in the timing of amygdala response to familiar and novel faces

    Directory of Open Access Journals (Sweden)

    Shelton Richard C

    2009-12-01

    Full Text Available Abstract Background Inhibited temperament - the predisposition to respond to new people, places or things with wariness or avoidance behaviors - is associated with increased risk for social anxiety disorder and major depression. Although the magnitude of the amygdala's response to novelty has been identified as a neural substrate of inhibited temperament, there may also be differences in temporal dynamics (latency, duration, and peak. We hypothesized that persons with inhibited temperament would have faster responses to novel relative to familiar neutral faces compared to persons with uninhibited temperament. We used event-related functional magnetic resonance imaging to measure the temporal dynamics of the blood oxygen level dependent (BOLD response to both novel and familiar neutral faces in participants with inhibited or uninhibited temperament. Results Inhibited participants had faster amygdala responses to novel compared with familiar faces, and both longer and greater amygdala response to all faces. There were no differences in peak response. Conclusion Faster amygdala response to novelty may reflect a computational bias that leads to greater neophobic responses and represents a mechanism for the development of social anxiety.

  4. Amygdala involvement in self-blame regret

    OpenAIRE

    Nicolle, A.; Bach, D.R.; Frith, Chris D; Dolan, R.J.

    2011-01-01

    Regret-related brain activity is dependent on free choice, but it is unclear whether this activity is a function of more subtle differences in the degree of responsibility a decision-maker exerts over a regrettable outcome. In this experiment, we show that trial-by-trial subjective ratings of regret depend on a higher subjective sense of responsibility, as well as being dependent on objective responsibility. Using fMRI we show an enhanced amygdala response to regret-related outcomes when thes...

  5. Volume regulatory responses of basolateral membrane vesicles from Necturus enterocytes: Role of the cytoskeleton

    OpenAIRE

    Dubinsky, William P.; Mayorga-Wark, Otilia; Schultz, Stanley G.

    1999-01-01

    Previous studies from this laboratory have demonstrated that basolateral membrane vesicles isolated from Necturus maculosus small intestinal epithelial cells possess a K+ channel that is inhibited by ATP. In the present studies, we demonstrate that these vesicles, which are essentially devoid of soluble cytoplasmic contaminants, exhibit volume regulatory responses that parallel those of intact epithelial cells. Thus, suspension of these vesicles in a solution that is hypotonic to the intraves...

  6. Bicarbonate-dependent transport of acetate and butyrate across the basolateral membrane of sheep rumen epithelium.

    Science.gov (United States)

    Dengler, F; Rackwitz, R; Benesch, F; Pfannkuche, H; Gäbel, G

    2014-02-01

    This study aimed to assess the role of HCO₃⁻ in the transport of acetate and butyrate across the basolateral membrane of rumen epithelium and to identify transport proteins involved. The effects of basolateral variation in HCO₃⁻ concentrations on acetate and butyrate efflux out of the epithelium and the transepithelial flux of these short-chain fatty acids were tested in Ussing chamber experiments using (14)C-labelled substrates. HCO₃⁻-dependent transport mechanisms were characterized by adding specific inhibitors of candidate proteins to the serosal side. Effluxes of acetate and butyrate out of the epithelium were higher to the serosal side than to the mucosal side. Acetate and butyrate effluxes to both sides of rumen epithelium consisted of HCO₃⁻-independent and -dependent parts. HCO₃⁻-dependent transport across the basolateral membrane was confirmed in studies of transepithelial fluxes. Mucosal to serosal fluxes of acetate and butyrate decreased with lowering serosal HCO₃⁻ concentrations. In the presence of 25 mm HCO₃⁻, transepithelial flux of acetate was inhibited effectively by p-hydroxymercuribenzoic acid or α-cyano-4-hydroxycinnamic acid, while butyrate flux was unaffected by the blockers. Fluxes of both acetate and butyrate from the serosal to the mucosal side were diminished largely by the addition of NO₃⁻ to the serosal side, with this effect being more pronounced for acetate. Our results indicate the existence of a basolateral short-chain fatty acid/HCO₃⁻ exchanger, with monocarboxylate transporter 1 as a primary candidate for acetate transfer. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  7. Basolateral potassium channel in turtle colon. Evidence for single-file ion flow

    OpenAIRE

    1983-01-01

    Treatment of the apical surface of the isolated, ouabain-inhibited turtle colon with the polyene antibiotic amphotericin B permitted the properties of a barium-sensitive potassium conductance in the basolateral membrane to be discerned from the measurements of transepithelial fluxes and electrical currents. Simultaneous measurements of potassium currents and 42K fluxes showed that the movement of potassium was not in accord with simple diffusion. Two other cations, thallium and rubidium, were...

  8. Ventral striatum and amygdala activity as convergence sites for early adversity and conduct disorder.

    Science.gov (United States)

    Holz, Nathalie E; Boecker-Schlier, Regina; Buchmann, Arlette F; Blomeyer, Dorothea; Jennen-Steinmetz, Christine; Baumeister, Sarah; Plichta, Michael M; Cattrell, Anna; Schumann, Gunter; Esser, Günter; Schmidt, Martin; Buitelaar, Jan; Meyer-Lindenberg, Andreas; Banaschewski, Tobias; Brandeis, Daniel; Laucht, Manfred

    2017-02-01

    Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associated with alterations in regions of affective processing like ventral striatum (VS) and amygdala. However, no study so far has demonstrated neural converging effects of CFA and CD in the same sample. At age 25 years, functional MRI data during two affective tasks, i.e. a reward (N = 171) and a face-matching paradigm (N = 181) and anatomical scans (N = 181) were acquired in right-handed currently healthy participants of an epidemiological study followed since birth. CFA during childhood was determined using a standardized parent interview. Disruptive behaviors and CD diagnoses during childhood and adolescence were obtained by diagnostic interview (2-19 years), temperamental reward dependence was assessed by questionnaire (15 and 19 years).CFA predicted increased CD and amygdala volume. Both exposure to CFA and CD were associated with a decreased VS response during reward anticipation and blunted amygdala activity during face-matching. CD mediated the effect of CFA on brain activity. Temperamental reward dependence was negatively correlated with CFA and CD and positively with VS activity. These findings underline the detrimental effects of CFA on the offspring's affective processing and support the importance of early postnatal intervention programs aiming to reduce childhood adversity factors. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  9. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis.

    Science.gov (United States)

    Munafò, Marcus R; Brown, Sarah M; Hariri, Ahmad R

    2008-05-01

    We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship. We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry. Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes. Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.

  10. Amygdala response to self-critical stimuli and symptom improvement in psychotherapy for depression.

    Science.gov (United States)

    Doerig, Nadja; Krieger, Tobias; Altenstein, David; Schlumpf, Yolanda; Spinelli, Simona; Späti, Jakub; Brakowski, Janis; Quednow, Boris B; Seifritz, Erich; Holtforth, Martin Grosse

    2016-02-01

    Cognitive-behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory. To better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment. Functional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self-critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients. Patients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association. Amygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition. © The Royal College of Psychiatrists 2016.

  11. Amygdala reactivity to fearful faces correlates positively with impulsive aggression

    DEFF Research Database (Denmark)

    da Cunha-Bang, Sofi; Fisher, Patrick M; Hjordt, Liv V

    2018-01-01

    Facial expressions robustly activate the amygdala, a brain structure playing a critical role in aggression. Whereas previous studies suggest that amygdala reactivity is related to various measures of impulsive aggression, we here estimate a composite measure of impulsive aggression and evaluate...... whether it is associated with amygdala reactivity to angry and fearful faces. We estimated amygdala reactivity with functional magnetic resonance imaging in 47 men with varying degree of aggressive traits (19 incarcerated violent offenders and 28 healthy controls). We modeled a composite "impulsive...... aggression" trait construct (LVagg) using a linear structural equation model, with a single latent variable capturing the shared correlation between five self-report measures of trait aggression, anger and impulsivity. We tested for associations between amygdala reactivity and the LVagg, adjusting for age...

  12. Amygdala signals subjective appetitiveness and aversiveness of mixed gambles

    DEFF Research Database (Denmark)

    Gelskov, Sofie V.; Henningsson, Susanne; Madsen, Kristoffer Hougaard

    2015-01-01

    People are more sensitive to losses than to equivalent gains when making financial decisions. We used functional magnetic resonance imaging (fMRI) to illuminate how the amygdala contributes to loss aversion. The blood oxygen level dependent (BOLD) response of the amygdala was mapped while healthy...... individuals were responding to 50/50 gambles with varying potential gain and loss amounts. Overall, subjects demanded twice as high potential gain as loss to accept a gamble. The individual level of loss aversion was expressed by the decision boundary, i.e., the gain-loss ratio at which subjects accepted...... and rejected gambles with equal probability. Amygdala activity increased the more the gain-loss ratio deviated from the individual decision boundary showing that the amygdala codes action value. This response pattern was more strongly expressed in loss aversive individuals, linking amygdala activity...

  13. Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala

    Science.gov (United States)

    2012-01-01

    Background Research into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward. Findings We used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants. Conclusions These findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward. PMID:23151390

  14. Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder.

    Science.gov (United States)

    Kleinhans, Natalia M; Reiter, Maya A; Neuhaus, Emily; Pauley, Greg; Martin, Nathalie; Dager, Stephen; Estes, Annette

    2016-07-01

    The amygdala is a complex structure with distinct subregions and dissociable functional networks. The laterobasal subregion of the amygdala is hypothesized to mediate the presentation and severity of autism symptoms, although very little data are available regarding amygdala dysfunction at the subregional level. In this study, we investigated the relationship between abnormal amygdalar intrinsic connectivity, autism symptom severity, and anxiety and depressive symptoms. We collected resting state fMRI data on 31 high functioning adolescents and adults with autism spectrum disorder and 38 typically developing (TD) controls aged 14-45. Twenty-five participants with ASD and 28 TD participants were included in the final analyses. ASD participants were administered the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. Adult participants were administered the Beck Depression Inventory II and the Beck Anxiety Inventory. Functional connectivity analyses were conducted from three amygdalar subregions: centromedial (CM), laterobasal (LB) and superficial (SF). In addition, correlations with the behavioral measures were tested in the adult participants. In general, the ASD group showed significantly decreased connectivity from the LB subregion and increased connectivity from the CM and SF subregions compared to the TD group. We found evidence that social symptoms are primarily associated with under-connectivity from the LB subregion whereas over-connectivity and under-connectivity from the CM, SF and LB subregions are related to co-morbid depression and anxiety in ASD, in brain regions that were distinct from those associated with social dysfunction, and in different patterns than were observed in mildly symptomatic TD participants. Our findings provide new evidence for functional subregional differences in amygdala pathophysiology in ASD. Autism Res 2016, 9: 760-772. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  15. An Appetitive Experience after Fear Memory Destabilization Attenuates Fear Retention: Involvement GluN2B-NMDA Receptors in the Basolateral Amygdala Complex

    Science.gov (United States)

    Ferrer Monti, Roque I.; Giachero, Marcelo; Alfei, Joaquín M.; Bueno, Adrián M.; Cuadra, Gabriel; Molina, Victor A.

    2016-01-01

    It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear…

  16. Medial amygdala lesions selectively block aversive Pavlovian-instrumental transfer in rats.

    Directory of Open Access Journals (Sweden)

    Margaret Grace McCue

    2014-09-01

    Full Text Available Pavlovian conditioned stimuli (CSs play an important role in the reinforcement and motivation of instrumental active avoidance (AA. Conditioned threats can also invigorate ongoing AA responding (aversive Pavlovian-instrumental transfer or PIT. The neural circuits mediating AA are poorly understood, although lesion studies suggest that lateral, basal and central amygdala nuclei, as well as infralimbic prefrontal cortex, make key, and sometimes opposing, contributions. We recently completed an extensive analysis of brain c-Fos expression in good vs. poor avoiders following an AA test (Martinez et al 2013, Learning and Memory. This analysis identified medial amygdala (MeA as a potentially important region for Pavlovian motivation of instrumental actions. MeA is known to mediate defensive responding to innate threats as well as social behaviors, but its role in mediating aversive Pavlovian-instrumental interactions is unknown. We evaluated the effect of MeA lesions on Pavlovian conditioning, Sidman two-way AA conditioning (shuttling and aversive PIT in rats. Mild footshocks served as the unconditioned stimulus in all conditioning phases. MeA lesions had no effect on AA but blocked the expression of aversive PIT and 22 kHz ultrasonic vocalizations in the AA context. Interestingly, MeA lesions failed to affect Pavlovian freezing to discrete threats but reduced freezing to contextual threats when assessed outside of the AA chamber. These findings differentiate MeA from lateral and central amygdala, as lesions of these nuclei disrupt Pavlovian freezing and aversive PIT, but have opposite effects on AA performance. Taken together, these results suggest that MeA plays a selective role in the motivation of instrumental avoidance by general or uncertain Pavlovian threats.

  17. Amygdala involvement in self-blame regret.

    Science.gov (United States)

    Nicolle, Antoinette; Bach, Dominik R; Frith, Chris; Dolan, Raymond J

    2011-01-01

    Regret-related brain activity is dependent on free choice, but it is unclear whether this activity is a function of more subtle differences in the degree of responsibility a decision-maker exerts over a regrettable outcome. In this experiment, we show that trial-by-trial subjective ratings of regret depend on a higher subjective sense of responsibility, as well as being dependent on objective responsibility. Using fMRI we show an enhanced amygdala response to regret-related outcomes when these outcomes are associated with high, as compared to low, responsibility. This enhanced response was maximal in participants who showed a greater level of enhancement in their subjective ratings of regret engendered by an objective increase in responsibility. Orbitofrontal and cingulate cortex showed opposite effects, with an enhanced response for regret-related outcomes when participants were not objectively responsible. The findings indicate that the way the brain processes regret-related outcomes depends on both objective and subjective aspects of responsibility, highlighting the critical importance of the amygdala. © 2010 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business

  18. Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

    International Nuclear Information System (INIS)

    Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.; Areso, P.; Hauptmann, M.; Frazer, A.

    1991-01-01

    This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125 I-iodopindolol ( 125 I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125 I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125 I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125 I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125 I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125 I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus

  19. Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress

    Directory of Open Access Journals (Sweden)

    Justin P. Smith

    2014-04-01

    Full Text Available In a newly developed conceptual model of stressful social decision making, the Stress-Alternatives Model (SAM; used for the 1st time in mice elicits two types of response: escape or remain submissively. Daily (4d aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS. Although escape holes (only large enough for smaller test animals are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala, gene expression of BDNF was diminished, but NPS expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala, which coincided with decreased BDNF expression. Reduced expression of BDNF is only in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma

  20. Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory.

    Science.gov (United States)

    Sui, Li; Huang, SiJia; Peng, BinBin; Ren, Jie; Tian, FuYing; Wang, Yan

    2014-07-01

    Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical-amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical-amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.

  1. Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala.

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    Timothy J Jarome

    Full Text Available Protein degradation through the ubiquitin-proteasome system [UPS] plays a critical role in some forms of synaptic plasticity. However, its role in memory formation in the amygdala, a site critical for the formation of fear memories, currently remains unknown. Here we provide the first evidence that protein degradation through the UPS is critically engaged at amygdala synapses during memory formation and retrieval. Fear conditioning results in NMDA-dependent increases in degradation-specific polyubiquitination in the amygdala, targeting proteins involved in translational control and synaptic structure and blocking the degradation of these proteins significantly impairs long-term memory. Furthermore, retrieval of fear memory results in a second wave of NMDA-dependent polyubiquitination that targets proteins involved in translational silencing and synaptic structure and is critical for memory updating following recall. These results indicate that UPS-mediated protein degradation is a major regulator of synaptic plasticity necessary for the formation and stability of long-term memories at amygdala synapses.

  2. Differential Patterns of Amygdala and Ventral Striatum Activation Predict Gender-Specific Changes in Sexual Risk Behavior

    Science.gov (United States)

    Sansosti, Alexandra A.; Bowman, Hilary C.; Hariri, Ahmad R.

    2015-01-01

    Although the initiation of sexual behavior is common among adolescents and young adults, some individuals express this behavior in a manner that significantly increases their risk for negative outcomes including sexually transmitted infections. Based on accumulating evidence, we have hypothesized that increased sexual risk behavior reflects, in part, an imbalance between neural circuits mediating approach and avoidance in particular as manifest by relatively increased ventral striatum (VS) activity and relatively decreased amygdala activity. Here, we test our hypothesis using data from seventy 18- to 22-year-old university students participating in the Duke Neurogenetics Study. We found a significant three-way interaction between amygdala activation, VS activation, and gender predicting changes in the number of sexual partners over time. Although relatively increased VS activation predicted greater increases in sexual partners for both men and women, the effect in men was contingent on the presence of relatively decreased amygdala activation and the effect in women was contingent on the presence of relatively increased amygdala activation. These findings suggest unique gender differences in how complex interactions between neural circuit function contributing to approach and avoidance may be expressed as sexual risk behavior in young adults. As such, our findings have the potential to inform the development of novel, gender-specific strategies that may be more effective at curtailing sexual risk behavior. PMID:26063921

  3. When vocal processing gets emotional: on the role of social orientation in relevance detection by the human amygdala.

    Science.gov (United States)

    Schirmer, Annett; Escoffier, Nicolas; Zysset, Stefan; Koester, Dirk; Striano, Tricia; Friederici, Angela D

    2008-04-15

    Previous work on vocal emotional processing provided little evidence for involvement of emotional processing areas such as the amygdala or the orbitofrontal cortex (OFC). Here, we sought to specify whether involvement of these areas depends on how relevant vocal expressions are for the individual. To this end, we assessed participants' social orientation--a measure of the interest and concern for other individuals and hence the relevance of social signals. We then presented task-irrelevant syllable sequences that contained rare changes in tone of voice that could be emotional or neutral. Processing differences between emotional and neutral vocal change in the right amygdala and the bilateral OFC were significantly correlated with the social orientation measure. Specifically, higher social orientation scores were associated with enhanced amygdala and OFC activity to emotional as compared to neutral change. Given the presumed role of the amygdala in the detection of emotionally relevant information, our results suggest that social orientation enhances this detection process and the activation of emotional representations mediated by the OFC. Moreover, social orientation may predict listener responses to vocal emotional cues and explain interindividual variability in vocal emotional processing.

  4. Functional anatomy of 5-HT2A receptors in the amygdala and hippocampal complex: relevance to memory functions.

    Science.gov (United States)

    Bombardi, Cristiano; Di Giovanni, Giuseppe

    2013-10-01

    The amygdaloid complex and hippocampal region contribute to emotional activities, learning, and memory. Mounting evidence suggests a primary role for serotonin (5-HT) in the physiological basis of memory and its pathogenesis by modulating directly the activity of these two areas and their cross-talk. Indeed, both the amygdala and the hippocampus receive remarkably dense serotoninergic inputs from the dorsal and median raphe nuclei. Anatomical, behavioral and electrophysiological evidence indicates the 5-HT2A receptor as one of the principal postsynaptic targets mediating 5-HT effects. In fact, the 5-HT2A receptor is the most abundant 5-HT receptor expressed in these brain structures and is expressed on both amygdalar and hippocampal pyramidal glutamatergic neurons as well as on γ-aminobutyric acid (GABA)-containing interneurons. 5-HT2A receptors on GABAergic interneurons stimulate GABA release, and thereby have an important role in regulating network activity and neural oscillations in the amygdala and hippocampal region. This review will focus on the distribution and physiological functions of the 5-HT2A receptor in the amygdala and hippocampal region. Taken together the results discussed here suggest that 5-HT2A receptor may be a potential therapeutic target for those disorders related to hippocampal and amygdala dysfunction.

  5. Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

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    Onozawa Kitaro

    2011-11-01

    Full Text Available Abstract Background We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC. The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS delivered to the BLA on nociceptive responses in the rat PFC. Results HFS induced long lasting suppression (LLS of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA receptor antagonists (2-amino-5-phosphonovaleric acid (APV, dizocilpine (MK-801 and also metabotropic glutamate receptor (mGluR group antagonists (α-methyl-4-carboxyphenylglycine (MCPG, and 2-[(1S,2S-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl-D-alanine (LY341495, prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride and D4 (3-{[4-(4-chlorophenyl piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870, microinjected into the PFC, inhibited LLS of nociceptive responses. Conclusions Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

  6. Prenatal stress alters amygdala functional connectivity in preterm neonates.

    Science.gov (United States)

    Scheinost, Dustin; Kwon, Soo Hyun; Lacadie, Cheryl; Sze, Gordon; Sinha, Rajita; Constable, R Todd; Ment, Laura R

    2016-01-01

    Exposure to prenatal and early-life stress results in alterations in neural connectivity and an increased risk for neuropsychiatric disorders. In particular, alterations in amygdala connectivity have emerged as a common effect across several recent studies. However, the impact of prenatal stress exposure on the functional organization of the amygdala has yet to be explored in the prematurely-born, a population at high risk for neuropsychiatric disorders. We test the hypothesis that preterm birth and prenatal exposure to maternal stress alter functional connectivity of the amygdala using two independent cohorts. The first cohort is used to establish the effects of preterm birth and consists of 12 very preterm neonates and 25 term controls, all without prenatal stress exposure. The second is analyzed to establish the effects of prenatal stress exposure and consists of 16 extremely preterm neonates with prenatal stress exposure and 10 extremely preterm neonates with no known prenatal stress exposure. Standard resting-state functional magnetic resonance imaging and seed connectivity methods are used. When compared to term controls, very preterm neonates show significantly reduced connectivity between the amygdala and the thalamus, the hypothalamus, the brainstem, and the insula (p amygdala and the thalamus, the hypothalamus, and the peristriate cortex (p amygdala connectivity associated with preterm birth. Functional connectivity from the amygdala to other subcortical regions is decreased in preterm neonates compared to term controls. In addition, these data, for the first time, suggest that prenatal stress exposure amplifies these decreases.

  7. Altered amygdala-prefrontal connectivity during emotion perception in schizophrenia.

    Science.gov (United States)

    Bjorkquist, Olivia A; Olsen, Emily K; Nelson, Brady D; Herbener, Ellen S

    2016-08-01

    Individuals with schizophrenia evidence impaired emotional functioning. Abnormal amygdala activity has been identified as an etiological factor underlying affective impairment in this population, but the exact nature remains unclear. The current study utilized psychophysiological interaction analyses to examine functional connectivity between the amygdala and medial prefrontal cortex (mPFC) during an emotion perception task. Participants with schizophrenia (SZ) and healthy controls (HC) viewed and rated positive, negative, and neutral images while undergoing functional neuroimaging. Results revealed a significant group difference in right amygdala-mPFC connectivity during perception of negative versus neutral images. Specifically, HC participants demonstrated positive functional coupling between the amygdala and mPFC, consistent with co-active processing of salient information. In contrast, SZ participants evidenced negative functional coupling, consistent with top-down inhibition of the amygdala by the mPFC. A significant positive correlation between connectivity strength during negative image perception and clinician-rated social functioning was also observed in SZ participants, such that weaker right amygdala-mPFC coupling during negative compared to neutral image perception was associated with poorer social functioning. Overall, results suggest that emotional dysfunction and associated deficits in functional outcome in schizophrenia may relate to abnormal interactions between the amygdala and mPFC during perception of emotional stimuli. This study adds to the growing literature on abnormal functional connections in schizophrenia and supports the functional disconnection hypothesis of schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Amygdala hyperactivation to angry faces in intermittent explosive disorder.

    Science.gov (United States)

    McCloskey, Michael S; Phan, K Luan; Angstadt, Mike; Fettich, Karla C; Keedy, Sarah; Coccaro, Emil F

    2016-08-01

    Individuals with intermittent explosive disorder (IED) were previously found to exhibit amygdala hyperactivation and relatively reduced orbital medial prefrontal cortex (OMPFC) activation to angry faces while performing an implicit emotion information processing task during functional magnetic resonance imaging (fMRI). This study examines the neural substrates associated with explicit encoding of facial emotions among individuals with IED. Twenty unmedicated IED subjects and twenty healthy, matched comparison subjects (HC) underwent fMRI while viewing blocks of angry, happy, and neutral faces and identifying the emotional valence of each face (positive, negative or neutral). We compared amygdala and OMPFC reactivity to faces between IED and HC subjects. We also examined the relationship between amygdala/OMPFC activation and aggression severity. Compared to controls, the IED group exhibited greater amygdala response to angry (vs. neutral) facial expressions. In contrast, IED and control groups did not differ in OMPFC activation to angry faces. Across subjects amygdala activation to angry faces was correlated with number of prior aggressive acts. These findings extend previous evidence of amygdala dysfunction in response to the identification of an ecologically-valid social threat signal (processing angry faces) among individuals with IED, further substantiating a link between amygdala hyperactivity to social signals of direct threat and aggression. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Temporary amygdala inhibition reduces stress effects in female mice

    Directory of Open Access Journals (Sweden)

    Jila Rezaeian Dalooei

    2016-09-01

    Full Text Available The current study investigated the effect of temporary inhibition of amygdala in response to metabolic changes caused by stress in female mice. Unilateral and bilateral amygdala cannulation was carried out, and after a week of recovery, 2% lidocaine hydrochloride was injected into the mice amygdalae five minutes before the induction of stress. A communication box was employed to induce stress for four consecutive days and plasma corticosterone, food and water intake, weight changes, and anorexia were measured as stress-induced metabolic changes. Results demonstrated that stress, increases stress, increased plasma corticosterone concentrations, weight, food, and water intake. Temporary inhibition of the amygdala slightly decreased plasma corticosterone concentrations, but did not fully reduce the effect of stress. The bilateral injection of lidocaine hydrochloride to the amygdala reduced the effect of stress and reduced water intake and weight. Unilateral injection of lidocaine hydrochloride into the left and right amygdala reduced food intake. In conclusion, the present study demonstrated that the left side and right side of amygdala nuclei play a different role in metabolic responses in stress.

  10. Impaired recognition of social emotions following amygdala damage.

    Science.gov (United States)

    Adolphs, Ralph; Baron-Cohen, Simon; Tranel, Daniel

    2002-11-15

    Lesion, functional imaging, and single-unit studies in human and nonhuman animals have demonstrated a role for the amygdala in processing stimuli with emotional and social significance. We investigated the recognition of a wide variety of facial expressions, including basic emotions (e.g., happiness, anger) and social emotions (e.g., guilt, admiration, flirtatiousness). Prior findings with a standardized set of stimuli indicated that recognition of social emotions can be signaled by the eye region of the face and is disproportionately impaired in autism (Baron-Cohen, Wheelwright, & Jolliffe, 1997). To test the hypothesis that the recognition of social emotions depends on the amygdala, we administered the same stimuli to 30 subjects with unilateral amygdala damage (16 left, 14 right), 2 with bilateral amygdala damage, 47 brain-damaged controls, and 19 normal controls. Compared with controls, subjects with unilateral or bilateral amygdala damage were impaired when recognizing social emotions; moreover, they were more impaired in recognition of social emotions than in recognition of basic emotions, and, like previously described patients with autism, they were impaired also when asked to recognize social emotions from the eye region of the face alone. The findings suggest that the human amygdala is relatively specialized to process stimuli with complex social significance. The results also provide further support for the idea that some of the impairments in social cognition seen in patients with autism may result from dysfunction of the amygdala.

  11. Preoperative amygdala fMRI in temporal lobe epilepsy.

    Science.gov (United States)

    Bonelli, Silvia B; Powell, Robert; Yogarajah, Mahinda; Thompson, Pamela J; Symms, Mark R; Koepp, Matthias J; Duncan, John S

    2009-02-01

    Anterior temporal lobe resections (ATLR) benefit 70% of patients with refractory mesial temporal lobe epilepsy (TLE), but may be complicated by emotional disturbances. We used functional magnetic resonance imaging (fMRI) to investigate the role of the amygdala in processing emotions in TLE and whether this may be a potential preoperative predictive marker for emotional disturbances following surgery. We studied 54 patients with refractory mesial TLE due to hippocampal sclerosis (28 right, 26 left) and 21 healthy controls using a memory encoding fMRI paradigm, which included viewing fearful and neutral faces. Twenty-one TLE patients (10 left, 11 right) subsequently underwent ATLR. Anxiety and depression were assessed preoperatively and 4 months postoperatively using the Hospital Anxiety and Depression Scale. On viewing fearful faces, healthy controls demonstrated left lateralized, while right TLE patients showed bilateral amygdala activation. Left TLE patients had significantly reduced activation in left and right amygdalae compared to controls and right TLE patients. In right TLE patients, left and right amygdala activation was significantly related to preoperative anxiety and depression levels, and preoperative right amygdala activation correlated significantly with postoperative change of anxiety and depression scores, characterized by greater increases in anxiety and depression in patients with greater preoperative activation. No such correlations were seen for left TLE patients. The fearful face fMRI paradigm is a reliable method for visualizing amygdala activation in controls and patients with mesial TLE. Activation of the right amygdala preoperatively was predictive of emotional disturbances following right ATLR.

  12. Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement.

    Science.gov (United States)

    Stringfield, S J; Higginbotham, J A; Wang, R; Berger, A L; McLaughlin, R J; Fuchs, R A

    2017-09-01

    The basolateral amygdala (BLA) is a critical site for the reconsolidation of labile contextual cocaine memories following retrieval-induced reactivation/destabilization. Here, we examined whether glucocorticoid receptors (GR), which are abundant in the BLA, mediate this phenomenon. Rats were trained to lever press for cocaine reinforcement in a distinct environmental context, followed by extinction training in a different context. Rats were then briefly exposed to the cocaine-paired context (to elicit memory reactivation and reconsolidation) or their home cages (no reactivation control). Exposure to the cocaine-paired context elicited greater serum corticosterone concentrations than home cage stay. Interestingly, the GR antagonist, mifepristone (3-10 ng/hemisphere), administered into the BLA after memory reactivation produced a further, dose-dependent increase in serum corticosterone concentrations during the putative time of cocaine-memory reconsolidation but produced an inverted U-shaped dose-effect curve on subsequent cocaine-seeking behavior 72 h later. This effect was anatomically selective, dependent on memory reactivation (i.e., not observed after home cage exposure), and did not reflect protracted hyperactivity. However, the effect was also observed when mifepristone was administered after novelty stress that mimics drug context-induced hypothalamic-pituitary-adrenal (HPA) axis activation without explicit memory reactivation. Together, these findings suggest that, similar to explicit memory retrieval, a stressful event is sufficient to destabilize cocaine memories and permit their manipulation. Furthermore, BLA GR stimulation exerts inhibitory feedback upon HPA axis activation and thus suppresses cocaine-memory reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Connections of the corticomedial amygdala in the golden hamster. I. Efferents of the ''vomeronasal amygdala''

    International Nuclear Information System (INIS)

    Kevetter, G.A.; Winans, S.S.

    1981-01-01

    The medial (M) an posteromedial cortical (C3) amygdaloid nuclei and the nucleus of the accessory olfactory tract (NAOT) are designated the ''vomeronasal amygdala'' because they are the only components of the amygdala to receive a direct projection from the accessory olfactory bulb (AOB). The efferents of M and C3 were traced after injections of 3 H-proline into the amygdala in male golden hamsters. Frozen sections of the brains were processed for autoradiography. The efferents of the ''vomeronasal amygdala'' are largely to areas which are primary and secondary terminal areas along the vomeronasal pathway, although the efferents from C3 and M terminate in different layers in these areas than do the projections from the vomeronasal nerve or the AOB. Specifically, C3 projects ipsilaterally to the internal granule cell layer of the AOB, the cellular layer of NAOT, and layer Ib of M. Additional fibers from C3 terminate in a retrocommissural component of the bed nucleus of the strain terminalis (BNST) bilaterally, and in the cellular layers of the contralateral C3. The medial nucleus projects to the cellular layer of the ipsilateral NAOT, layer Ib of C3, and bilaterally to the medial component of BNST. Projections from M to non-vomeronasal areas terminate in the medial preoptic area-anterior hypothalamic junction, ventromedial nucleus of the hypothalamus, ventral premammillary nucleus and possibly in the ventral subiculum. These results demonstrate reciprocal connections between primary and secondary vomeronasal areas between the secondary areas themselves. They suggest that M, but not C3, projects to areas outside this vomeronasal network. The medial amygdaloid nucleus is therefore an important link between the vomeronasal organ and areas of the brain not receiving direct vomeronasal input

  14. Amygdala response to emotional faces in seasonal affective disorder

    DEFF Research Database (Denmark)

    Borgsted, Camilla; Ozenne, Brice; Mc Mahon, Brenda

    2018-01-01

    emotional faces BOLD-fMRI paradigm during summer and winter. We computed amygdala activation (SPM5) to an aversive contrast (angry & fearful minus neutral) and angry, fearful and neutral faces, separately. Season-by-group and main effects were evaluated using Generalized Least Squares. In SAD individuals...... individuals showed significantly lower amygdala activation to all faces compared to healthy controls, with no evidence for a season-by-group interaction. Seasonal change in amygdala activation was unrelated to change in SIGH-SAD. LIMITATIONS: Small sample size, lack of positive valence stimuli. CONCLUSIONS...

  15. Pre-Training Reversible Inactivation of the Basal Amygdala (BA Disrupts Contextual, but Not Auditory, Fear Conditioning, in Rats.

    Directory of Open Access Journals (Sweden)

    Elisa Mari Akagi Jordão

    Full Text Available The basolateral amygdala complex (BLA, including the lateral (LA, basal (BA and accessory basal (AB nuclei, is involved in acquisition of contextual and auditory fear conditioning. The BA is one of the main targets for hippocampal information, a brain structure critical for contextual learning, which integrates several discrete stimuli into a single configural representation. Congruent with the hodology, selective neurotoxic damage to the BA results in impairments in contextual, but not auditory, fear conditioning, similarly to the behavioral impairments found after hippocampal damage. This study evaluated the effects of muscimol-induced reversible inactivation of the BA during a simultaneous contextual and auditory fear conditioning training on later fear responses to both the context and the tone, tested separately, without muscimol administration. As compared to control rats micro-infused with vehicle, subjects micro-infused with muscimol before training exhibited, during testing without muscimol, significant reduction of freezing responses to the conditioned context, but not to the conditioned tone. Therefore, reversible inactivation of the BA during training impaired contextual, but not auditory fear conditioning, thus confirming and extending similar behavioral observations following selective neurotoxic damage to the BA and, in addition, revealing that this effect is not related to the lack of a functional BA during testing.

  16. Age-related individual variability in memory performance is associated with amygdala-hippocampal circuit function and emotional pattern separation.

    Science.gov (United States)

    Leal, Stephanie L; Noche, Jessica A; Murray, Elizabeth A; Yassa, Michael A

    2017-01-01

    While aging is generally associated with episodic memory decline, not all older adults exhibit memory loss. Furthermore, emotional memories are not subject to the same extent of forgetting and appear preserved in aging. We conducted high-resolution fMRI during a task involving pattern separation of emotional information in older adults with and without age-related memory impairment (characterized by performance on a word-list learning task: low performers: LP vs. high performers: HP). We found signals consistent with emotional pattern separation in hippocampal dentate (DG)/CA3 in HP but not in LP individuals, suggesting a deficit in emotional pattern separation. During false recognition, we found increased DG/CA3 activity in LP individuals, suggesting that hyperactivity may be associated with overgeneralization. We additionally observed a selective deficit in basolateral amygdala-lateral entorhinal cortex-DG/CA3 functional connectivity in LP individuals during pattern separation of negative information. During negative false recognition, LP individuals showed increased medial temporal lobe functional connectivity, consistent with overgeneralization. Overall, these results suggest a novel mechanistic account of individual differences in emotional memory alterations exhibited in aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Large basolateral processes on type II hair cells comprise a novel processing unit in mammalian vestibular organs

    Science.gov (United States)

    Pujol, Rémy; Pickett, Sarah B.; Nguyen, Tot Bui; Stone, Jennifer S.

    2014-01-01

    Sensory receptors in the vestibular system (hair cells) encode head movements and drive central motor reflexes that control gaze, body movements, and body orientation. In mammals, type I and II vestibular hair cells are defined by their shape, contacts with vestibular afferent nerves, and membrane conductance. Here, we describe unique morphological features of type II vestibular hair cells in mature rodents (mice and gerbils) and bats. These features are cytoplasmic processes that extend laterally from the hair cell’s base and project under type I hair cells. Closer analysis of adult mouse utricles demonstrated that the basolateral processes of type II hair cells range in shape, size, and branching, with the longest processes extending 3–4 hair cell widths. The hair cell basolateral processes synapse upon vestibular afferent nerves and receive inputs from vestibular efferent nerves. Further, some basolateral processes make physical contacts with the processes of other type II hair cells, forming some sort of network amongst type II hair cells. Basolateral processes are rare in perinatal mice and do not attain their mature form until 3–6 weeks of age. These observations demonstrate that basolateral processes are significant signaling regions of type II vestibular hair cells, and they suggest type II hair cells may directly communicate with each other, which has not been described in vertebrates. PMID:24825750

  18. Occupancy of serotonin transporters in the amygdala by paroxetine in association with attenuation of left amygdala activation by negative faces in major depressive disorder

    NARCIS (Netherlands)

    Ruhe, Henricus G.; Koster, Michiel; Booij, Jan; van Herk, Marcel; Veltman, Dick J.; Schene, Aart H.

    2014-01-01

    Amygdala hyperactivation in major depressive disorder (MDD) might be attenuated by selective serotonin reuptake inhibitors (SSRls), but the working mechanism remains unclear. We hypothesized that higher amygdala serotonin transporter (SERT) occupancy by paroxetine results in greater attenuation of

  19. Occupancy of serotonin transporters in the amygdala by paroxetine in association with attenuation of left amygdala activation by negative faces in major depressive disorder

    NARCIS (Netherlands)

    Ruhé, Henricus G.; Koster, Michiel; Booij, Jan; van Herk, Marcel; Veltman, Dick J.; Schene, Aart H.

    2014-01-01

    Amygdala hyperactivation in major depressive disorder (MDD) might be attenuated by selective serotonin reuptake inhibitors (SSRIs), but the working mechanism remains unclear. We hypothesized that higher amygdala serotonin transporter (SERT) occupancy by paroxetine results in greater attenuation of

  20. Altered task-based and resting-state amygdala functional connectivity following real-time fMRI amygdala neurofeedback training in major depressive disorder

    Directory of Open Access Journals (Sweden)

    Kymberly D. Young

    2018-01-01

    Conclusions: Neurofeedback training to increase amygdala hemodynamic activity during positive AM recall increased amygdala connectivity with regions involved in self-referential, salience, and reward processing. Results suggest future targets for neurofeedback interventions, particularly interventions involving the precuneus.

  1. Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age.

    Science.gov (United States)

    Graham, Alice M; Rasmussen, Jerod M; Rudolph, Marc D; Heim, Christine M; Gilmore, John H; Styner, Martin; Potkin, Steven G; Entringer, Sonja; Wadhwa, Pathik D; Fair, Damien A; Buss, Claudia

    2018-01-15

    Maternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans. Participants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks' gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants' amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control. Higher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control. These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts. Copyright © 2017 Society of Biological Psychiatry

  2. Associations between the size of the amygdala in infancy and language abilities during the preschool years in normally developing children.

    Science.gov (United States)

    Ortiz-Mantilla, Silvia; Choe, Myong-sun; Flax, Judy; Grant, P Ellen; Benasich, April A

    2010-02-01

    Recently, structural MRI studies in children have been used to examine relations between brain volume and behavioral measures. However, most of these studies have been done in children older than 2 years of age. Obtaining volumetric measures in infants is considerably more difficult, as structures are less well defined and largely unmyelinated, making segmentation challenging. Moreover, it is still unclear whether individual anatomic variation across development, in healthy, normally developing infants, is reflected in the configuration and function of the mature brain and, as importantly, whether variation in infant brain structure might be related to later cognitive and linguistic abilities. In this longitudinal study, using T1 structural MRI, we identified links between amygdala volume in normally developing, naturally sleeping, 6-month infants and their subsequent language abilities at 2, 3 and 4 years. The images were processed and manually segmented using Cardviews to extract volumetric measures. Intra-rater reliability for repeated segmentation was 87.73% of common voxel agreement. Standardized language assessments were administered at 6 and 12 months and at 2, 3 and 4 years. Significant and consistent correlations were found between amygdala size and language abilities. Children with larger right amygdalae at 6 months had lower scores on expressive and receptive language measures at 2, 3, and 4 years. Associations between amygdala size and language outcomes have been reported in children with autism. The findings presented here extend this association to normally developing children, supporting the idea that the amygdalae might play an important but as yet unspecified role in mediating language acquisition. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  3. Intracellular calcium modulates basolateral K(+)-permeability in frog skin epithelium

    DEFF Research Database (Denmark)

    Brodin, Birger; Rytved, K A; Nielsen, R

    1994-01-01

    Cytosolic calcium ([Ca2+]i) has been suggested as a key modulator in the regulation of active sodium transport across electrically "tight" (high resistance) epithelia. In this study we investigated the effects of calcium on cellular electrophysiological parameters in a classical model tissue, the......, the frog skin. [Ca2+]i was measured with fura-2 in an epifluorescence microscope setup. An inhibition of basolateral potassium permeability was observed when cytosolic calcium was increased. This inhibition was reversible upon removal of calcium from the serosal solution....

  4. Pre-treatment amygdala volume predicts electroconvulsive therapy response

    NARCIS (Netherlands)

    ten Doesschate, Freek; van Eijndhoven, Philip; Tendolkar, Indira; van Wingen, Guido A.; van Waarde, Jeroen A.

    2014-01-01

    Electroconvulsive therapy (ECT) is an effective treatment for patients with severe depression. Knowledge on factors predicting therapeutic response may help to identify patients who will benefit most from the intervention. Based on the neuroplasticity hypothesis, volumes of the amygdala and

  5. Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala

    DEFF Research Database (Denmark)

    Jensen, Morten; Ratner, Cecilia; Rudenko, Olga

    2016-01-01

    BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previ......BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has...... not previously been addressed directly. METHOD: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration...... overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. RESULTS: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff induced stress...

  6. Human Amygdala Represents the Complete Spectrum of Subjective Valence

    Science.gov (United States)

    Jin, Jingwen; Zelano, Christina; Gottfried, Jay A.

    2015-01-01

    Although the amygdala is a major locus for hedonic processing, how it encodes valence information is poorly understood. Given the hedonic potency of odor stimuli and the amygdala's anatomical proximity to the peripheral olfactory system, we combined high-resolution fMRI with pattern-based multivariate techniques to examine how valence information is encoded in the amygdala. Ten human subjects underwent fMRI scanning while smelling 9 odorants that systematically varied in perceived valence. Representational similarity analyses showed that amygdala codes the entire dimension of valence, ranging from pleasantness to unpleasantness. This unidimensional representation significantly correlated with self-reported valence ratings but not with intensity ratings. Furthermore, within-trial valence representations evolved over time, prioritizing earlier differentiation of unpleasant stimuli. Together, these findings underscore the idea that both spatial and temporal features uniquely encode pleasant and unpleasant odor valence in the amygdala. The availability of a unidimensional valence code in the amygdala, distributed in both space and time, would create greater flexibility in determining the pleasantness or unpleasantness of stimuli, providing a mechanism by which expectation, context, attention, and learning could influence affective boundaries for guiding behavior. SIGNIFICANCE STATEMENT Our findings elucidate the mechanisms of affective processing in the amygdala by demonstrating that this brain region represents the entire valence dimension from pleasant to unpleasant. An important implication of this unidimensional valence code is that pleasant and unpleasant valence cannot coexist in the amygdale because overlap of fMRI ensemble patterns for these two valence extremes obscures their unique content. This functional architecture, whereby subjective valence maps onto a pattern continuum between pleasant and unpleasant poles, offers a robust mechanism by which context

  7. Amygdala Volume and Social Network Size in Humans

    OpenAIRE

    Bickart, Kevin C.; Wright, Christopher I.; Dautoff, Rebecca J.; Dickerson, Bradford C.; Barrett, Lisa Feldman

    2010-01-01

    We demonstrated that amygdala volume (corrected for total intracranial volume) positively correlated with the size and complexity of social networks in adult humans ranging in age from 19 to 83 years. This relationship was specific to the amygdala as compared to other subcortical structures. An exploratory analysis of the entire cortical mantle also revealed an association between social network variables and cortical thickness in three cortical areas, two of which share dense connectivity wi...

  8. Clinical neuroprediction: Amygdala reactivity predicts depressive symptoms 2 years later.

    Science.gov (United States)

    Mattson, Whitney I; Hyde, Luke W; Shaw, Daniel S; Forbes, Erika E; Monk, Christopher S

    2016-06-01

    Depression is linked to increased amygdala activation to neutral and negatively valenced facial expressions. Amygdala activation may be predictive of changes in depressive symptoms over time. However, most studies in this area have focused on small, predominantly female and homogenous clinical samples. Studies are needed to examine how amygdala reactivity relates to the course of depressive symptoms dimensionally, prospectively and in populations diverse in gender, race and socioeconomic status. A total of 156 men from predominately low-income backgrounds completed an fMRI task where they viewed emotional facial expressions. Left and right amygdala reactivity to neutral, but not angry or fearful, facial expressions relative to a non-face baseline at age 20 predicted greater depressive symptoms 2 years later, controlling for age 20 depressive symptoms. Heightened bilateral amygdala reactivity to neutral facial expressions predicted increases in depressive symptoms 2 years later in a large community sample. Neutral facial expressions are affectively ambiguous and a tendency to interpret these stimuli negatively may reflect to cognitive biases that lead to increases in depressive symptoms over time. Individual differences in amygdala reactivity to neutral facial expressions appear to identify those at most risk for a more problematic course of depressive symptoms across time. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  9. Growth hormone biases amygdala network activation after fear learning.

    Science.gov (United States)

    Gisabella, B; Farah, S; Peng, X; Burgos-Robles, A; Lim, S H; Goosens, K A

    2016-11-29

    Prolonged stress exposure is a risk factor for developing posttraumatic stress disorder, a disorder characterized by the 'over-encoding' of a traumatic experience. A potential mechanism by which this occurs is through upregulation of growth hormone (GH) in the amygdala. Here we test the hypotheses that GH promotes the over-encoding of fearful memories by increasing the number of neurons activated during memory encoding and biasing the allocation of neuronal activation, one aspect of the process by which neurons compete to encode memories, to favor neurons that have stronger inputs. Viral overexpression of GH in the amygdala increased the number of amygdala cells activated by fear memory formation. GH-overexpressing cells were especially biased to express the immediate early gene c-Fos after fear conditioning, revealing strong autocrine actions of GH in the amygdala. In addition, we observed dramatically enhanced dendritic spine density in GH-overexpressing neurons. These data elucidate a previously unrecognized autocrine role for GH in the regulation of amygdala neuron function and identify specific mechanisms by which chronic stress, by enhancing GH in the amygdala, may predispose an individual to excessive fear memory formation.

  10. Diazepam reduces excitability of amygdala and further influences auditory cortex following sodium salicylate treatment in rats.

    Science.gov (United States)

    Song, Yu; Liu, Junxiu; Ma, Furong; Mao, Lanqun

    2016-12-01

    Diazepam can reduce the excitability of lateral amygdala and eventually suppress the excitability of the auditory cortex in rats following salicylate treatment, indicating the regulating effect of lateral amygdala to the auditory cortex in the tinnitus procedure. To study the spontaneous firing rates (SFR) of the auditory cortex and lateral amygdala regulated by diazepam in the tinnitus rat model induced by sodium salicylate. This study first created a tinnitus rat modal induced by sodium salicylate, and recorded SFR of both auditory cortex and lateral amygdala. Then diazepam was intraperitoneally injected and the SFR changes of lateral amygdala recorded. Finally, diazepam was microinjected on lateral amygdala and the SFR changes of the auditory cortex recorded. Both SFRs of the auditory cortex and lateral amygdala increased after salicylate treatment. SFR of lateral amygdala decreased after intraperitoneal injection of diazepam. Microinjecting diazepam to lateral amygdala decreased SFR of the auditory cortex ipsilaterally and contralaterally.

  11. Measuring localization and diffusion coefficients of basolateral proteins in lateral versus basal membranes using functionalized substrates and kICS analysis

    DEFF Research Database (Denmark)

    Marlar, Saw; Christensen, Eva Arnspang; Pedersen, Gitte Albinus

    2014-01-01

    Micropatterning enabled semiquantitation of basolateral proteins in lateral and basal membranes of the same cell. Lateral diffusion coefficients of basolateral aquaporin-3 (AQP3-EGFP) and EGFP-AQP4 were extracted from “lateral” and “basal” membranes using identical live-cell imaging and k...

  12. Subregional differences in intrinsic amygdala hyper and hypo connectivity in autism spectrum disorder

    Science.gov (United States)

    Kleinhans, Natalia M.; Reiter, Maya A.; Neuhaus, Emily; Pauley, Greg; Martin, Nathalie; Dager, Stephen; Estes, Annette

    2015-01-01

    LAY ABSTRACT Autism research indicates that there may be similar brain circuits affected in both individuals with autism and individuals with mood disorders such as major depression. However, psychotropic medications, while widely prescribed in individuals with autism, have been largely unsuccessful in treating core autism symptoms, indicating that etiology of co-existing psychiatric and autism symptoms may differ. In this fMRI study, the relationship between brain activity in the amygdala, a small, almond-shaped structure located deep within the brain, and activity in other parts of the brain were examined in 25 individuals with autism and 28 individuals without autism, during rest. This study provides the first evidence that connections between the amygdala and other brain regions are not uniformly atypical in autism, but differ depending on the subregion under investigation. In autism we observed weaker connections from the laterobasal subregion of the amygdala, a group of nuclei involved in social behavior and emotion, and, stronger connections from the centromedial and superficial subregions, which are involved in emotional arousal and olfaction. Additionally, we found that connectivity patterns related to autism symptoms were different from connectivity patterns related to mood symptoms. This finding suggests that despite occurring frequently in individuals with autism, mood disorders may involve separate neural mechanisms. This finding may also help explain why psychotropic medications are generally ineffective at treating autism symptoms. SCIENTIFIC ABSTRACT Background The amygdala is a complex structure with distinct subregions and dissociable functional networks. The laterobasal subregion of the amygdala is hypothesized to mediate the presentation and severity of autism symptoms, although very little data are available regarding amygdala dysfunction at the subregional level. Methods In this study, we investigated the relationship between abnormal

  13. The extended amygdala and salt appetite

    Science.gov (United States)

    Johnson, A. K.; de Olmos, J.; Pastuskovas, C. V.; Zardetto-Smith, A. M.; Vivas, L.

    1999-01-01

    Both chemo- and mechanosensitive receptors are involved in detecting changes in the signals that reflect the status of body fluids and of blood pressure. These receptors are located in the systemic circulatory system and in the sensory circumventricular organs of the brain. Under conditions of body fluid deficit or of marked changes in fluid distribution, multiple inputs derived from these humoral and neural receptors converge on key areas of the brain where the information is integrated. The result of this central processing is the mobilization of homeostatic behaviors (thirst and salt appetite), hormone release, autonomic changes, and cardiovascular adjustments. This review discusses the current understanding of the nature and role of the central and systemic receptors involved in the facilitation and inhibition of thirst and salt appetite and on particular components of the central neural network that receive and process input derived from fluid- and cardiovascular-related sensory systems. Special attention is paid to the structures of the lamina terminalis, the area postrema, the lateral parabrachial nucleus, and their association with the central nucleus of the amygdala and the bed nucleus of the stria terminalis in controlling the behaviors that participate in maintaining body fluid and cardiovascular homeostasis.

  14. Depression/anxiety disorder and amygdala

    International Nuclear Information System (INIS)

    Iidaka, Tetsuya

    2007-01-01

    Described and discussed are neuro-imaging studies on the amygdala (Am) concerning its volume, neuro-active drug effect on it and its response to repulsive and attractive stress-evoked character/temperament tests in patients mainly with major depression (MD) and anxiety disorder (AD), by functional MRI (fMRI) and positron emission tomography (PET). A recent trend of volumetry of Am is the voxel-based morphometry by MRI, of which results are still controversial in MD. In contrast, many studies by PET and fMRI using neuro-active drugs have revealed that Am activity in MD is stimulated, and this hyperactivity can be improved by anti-depressive drugs. In addition, difference of activities is suggested in Am left and right hemispheres. The hyperactivity in Am has been reported also in AD and phobic disorders, of which symptoms are conceivably expressed by the sensitivity changes in the cerebral limbic system involving Am. The author considers the central region responsible for the depressive mood is present around cortex of anteroinferior genu of corpus callosum where neuro-network with Am is dense. (R.T.)

  15. Abnormal amygdala activation profile in pedophilia.

    Science.gov (United States)

    Sartorius, Alexander; Ruf, Matthias; Kief, Christine; Demirakca, Traute; Bailer, Josef; Ende, Gabriele; Henn, Fritz A; Meyer-Lindenberg, Andreas; Dressing, Harald

    2008-08-01

    Despite considerable public interest research in neurobiological correlates of pedophilia is scarce. Since amygdala activation is central for emotional valuation, arousal, and salience, we investigated the activation profile of this structure in 10 male subjects with pedophilia (exclusively attracted to boys), all convicted sex-offenders and sentenced to forensic psychiatric treatment along with ten male heterosexual matched controls. We used a sexually non-explicit functional Magnetic Resonance Imaging (fMRI) paradigm with images of men, women, boys or girls randomly embedded in neutral target/non-target geometrical symbols. We applied statistical parametric mapping (SPM2) and SPSS 14 for image processing and analysis. While controls activated significantly less to pictures of children compared to adults, the activation profile was reversed in subjects with pedophilia, who exhibited significantly more activation to children than adults. The highest activation was observed for boys in the patient group, and for women in control participants. Our data show enhanced activation to children's pictures even in an incidental context and suggest the provocative hypothesis that a normally present mechanism for reduced emotional arousal for children relative to adults is reversed in pedophilia, suggesting a neural substrate associated with deviant sexual preference in this condition. More extensive research in this field would be of benefit for both the victims and the offenders.

  16. Kisspeptin signaling in the amygdala modulates reproductive hormone secretion.

    Science.gov (United States)

    Comninos, Alexander N; Anastasovska, Jelena; Sahuri-Arisoylu, Meliz; Li, Xiaofeng; Li, Shengyun; Hu, Minghan; Jayasena, Channa N; Ghatei, Mohammad A; Bloom, Stephen R; Matthews, Paul M; O'Byrne, Kevin T; Bell, Jimmy D; Dhillo, Waljit S

    2016-05-01

    Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a 'master regulator' of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.

  17. Ensemble coding of context-dependent fear memory in the amygdala

    Directory of Open Access Journals (Sweden)

    Caitlin A Orsini

    2013-12-01

    Full Text Available After fear conditioning, presenting the conditioned stimulus (CS alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex and amygdala. In the present work, we sought to determine at what level of this circuit context-dependent representations of the CS emerge. To explore this question, we used cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH. This method exploits the intracellular expression profile of the immediate early gene, Arc, to visualize neuronal activation patterns to two different behavioral experiences. Rats were fear conditioned in one context and extinguished in another; twenty-four hours later, they were sequentially exposed to the CS in the extinction context and another context. Control rats were also tested in each context, but were never extinguished. We assessed Arc mRNA expression within the basal amygdala (BA, lateral amygdala (LA, ventral hippocampus (VH, prelimbic cortex (PL and infralimbic cortex (IL. We observed that the sequential retention tests induced context-dependent patterns of Arc expression in the BA, LA, and IL of extinguished rats; this was not observed in non-extinguished controls. In general, non-extinguished animals had proportionately greater numbers of non-selective (double-labeled neurons than extinguished animals. Collectively, these findings suggest that extinction learning results in pattern separation, particularly within the BA, in which unique neuronal ensembles represent fear memories after extinction.

  18. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

    Science.gov (United States)

    Sosulina, L.; Strippel, C.; Romo-Parra, H.; Walter, A. L.; Kanyshkova, T.; Sartori, S. B.; Lange, M. D.; Singewald, N.

    2015-01-01

    Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at −101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K+ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar9,Met(O2)11]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. PMID:26334021

  19. Anti-inflammatory activity of the basolateral fraction of Caco-2 cells exposed to a rosemary supercritical extract

    NARCIS (Netherlands)

    Arranz, E.; Mes, J.J.; Wichers, H.J.; Jaime, L.; Reglero, G.; Santoyo, S.

    2015-01-01

    The anti-inflammatory activity of the basolateral fraction of Caco-2 cells exposed to a rosemary supercritical extract was examined. Uptake of rosemary extract fractions was tested on Caco-2 cell monolayers (2–12 h incubation times) and the quantification of carnosic acid and carnosol was performed

  20. Modulation of amygdala response to task-irrelevant emotion.

    Science.gov (United States)

    Sebastian, Catherine L; McCrory, Eamon J; De Brito, Stephane A; Viding, Essi

    2017-04-01

    It has been shown that as cognitive demands of a non-emotional task increase, amygdala response to task-irrelevant emotional stimuli is reduced. However, it remains unclear whether effects are due to altered task demands, or altered perceptual input associated with task demands. Here, we present fMRI data from 20 adult males during a novel cognitive conflict task in which the requirement to scan emotional information was necessary for task performance and held constant across levels of cognitive conflict. Response to fearful facial expressions was attenuated under high (vs low) conflict conditions, as indexed by both slower reaction times and reduced right amygdala response. Psychophysiological interaction analysis showed that increased amygdala response to fear in the low conflict condition was accompanied by increased functional coupling with middle frontal gyrus, a prefrontal region previously associated with emotion regulation during cognitive task performance. These data suggest that amygdala response to emotion is modulated as a function of task demands, even when perceptual inputs are closely matched across load conditions. PPI data also show that, in particular emotional contexts, increased functional coupling of amygdala with prefrontal cortex can paradoxically occur when executive demands are lower. © The Author (2017). Published by Oxford University Press.

  1. Serotonin transporter genotype modulates amygdala activity during mood regulation.

    Science.gov (United States)

    Gillihan, Seth J; Rao, Hengyi; Wang, Jiongjiong; Detre, John A; Breland, Jessica; Sankoorikal, Geena Mary V; Brodkin, Edward S; Farah, Martha J

    2010-03-01

    Recent studies have implicated the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) in depression vulnerability, particularly in the context of stress. Several neuroimaging studies have shown that 5-HTTLPR genotype predicts amygdala reactivity to negatively valenced stimuli, suggesting a mechanism whereby the short allele confers depression risk. The current study investigated whether 5-HTTLPR genotype similarly affects neural activity during an induced sad mood and during recovery from sad mood. Participants were 15 homozygous short (S) and 15 homozygous long (L) individuals. Regional cerebral blood flow was measured with perfusion functional magnetic resonance imaging during four scanning blocks: baseline, sad mood, mood recovery and following return to baseline. Comparing mood recovery to baseline, both whole brain analyses and template-based region-of-interest analyses revealed greater amygdala activity for the S vs the L-group. There were no significant amygdala differences found during the induced sad mood. These results demonstrate the effect of the S allele on amygdala activity during intentional mood regulation and suggest that amygdala hyperactivity during recovery from a sad mood may be one mechanism by which the S allele confers depression risk.

  2. Diverting attention suppresses human amygdala responses to faces

    Directory of Open Access Journals (Sweden)

    Carmen eMorawetz

    2010-12-01

    Full Text Available Recent neuroimaging studies disagree as to whether the processing of emotion-laden visual stimuli is dependent upon the availability of attentional resources or entirely capacity-free. Two main factors have been proposed to be responsible for the discrepancies: the differences in the perceptual attentional demands of the tasks used to divert attentional resources from emotional stimuli and the spatial location of the affective stimuli in the visual field. To date, no neuroimaging report addressed these two issues in the same set of subjects. Therefore, the aim of the study was to investigate the effects of high and low attentional load as well as different stimulus locations on face processing in the amygdala using fMRI to provide further evidence for one of the two opposing theories. We were able for the first time to directly test the interaction of attentional load and spatial location. The results revealed a strong attenuation of amygdala activity when the attentional load was high. The eccentricity of the emotional stimuli did not affect responses in the amygdala and no interaction effect between attentional load and spatial location was found. We conclude that the processing of emotional stimuli in the amygdala is strongly dependent on the availability of attentional resources without a preferred processing of stimuli presented in the periphery and provide firm evidence for the concept of the attentional load theory of emotional processing in the amygdala.

  3. The amygdala in schizophrenia: a trimodal magnetic resonance imaging study.

    Science.gov (United States)

    Kalus, Peter; Slotboom, Johannes; Gallinat, Jürgen; Wiest, Roland; Ozdoba, Christoph; Federspiel, Andrea; Strik, Werner K; Buri, Caroline; Schroth, Gerhard; Kiefer, Claus

    2005-03-03

    In schizophrenic psychoses, structural and functional alterations of the amygdala have been demonstrated by several neuroimaging studies. However, postmortem examinations on the brains of schizophrenics did not confirm the volume changes reported by volumetric magnetic resonance imaging (MRI) studies. In order to address these contradictory findings and to further elucidate the possibly underlying pathophysiological process of the amygdala, we employed a trimodal MRI design including high-resolution volumetry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) in a sample of 14 schizophrenic patients and 14 matched controls. Three-dimensional MRI volumetry revealed a significant reduction of amygdala raw volumes in the patient group, while amygdala volumes normalized for intracranial volume did not differ between the two groups. The regional diffusional anisotropy of the amygdala, expressed as inter-voxel coherence (COH), showed a marked and significant reduction in schizophrenics. Assessment of qMTI parameters yielded significant group differences for the T2 time of the bound proton pool and the T1 time of the free proton pool, while the semi-quantitative magnetization transfer ratio (MTR) did not differ between the groups. The application of multimodal MRI protocols is diagnostically relevant for the differentiation between schizophrenic patients and controls and provides a new strategy for the detection and characterization of subtle structural alterations in defined regions of the living brain.

  4. The association between perceived social support and amygdala structure.

    Science.gov (United States)

    Sato, Wataru; Kochiyama, Takanori; Kubota, Yasutaka; Uono, Shota; Sawada, Reiko; Yoshimura, Sayaka; Toichi, Motomi

    2016-05-01

    The subjective perception of social support plays a crucial role in human well-being. However, its structural neural substrates remain unknown. We hypothesized that the amygdala, specifically its laterobasal and superficial subregions, which have been suggested to serve social functions, could be associated with the level of perceived social support. To test this hypothesis, we assessed perceived social support using the Multidimensional Scale of Perceived Social Support. In addition, we measured the volume and shape of the amygdala using structural magnetic resonance imaging in 49 healthy participants. Global amygdala volume in the left hemisphere was positively associated with the perceived social support score after adjusting for total cerebral volume, sex, age, intelligence, and five-factor personality domains. The local shape of the laterobasal and superficial subregions of the left amygdala showed the same association with perceived social support. These data suggest that the social subregions of the left amygdala are associated with the implementation of perceived social support. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Interplay of Amygdala and Cingulate Plasticity in Emotional Fear

    Directory of Open Access Journals (Sweden)

    Hiroki Toyoda

    2011-01-01

    Full Text Available The amygdala is known to be a critical brain region for emotional fear. It is believed that synaptic plasticity within the amygdala is the cellular basis of fear memory. Recent studies demonstrate that cortical areas such as the prefrontal cortex (PFC and anterior cingulate cortex (ACC may also contribute to the formation of fear memory, including trace fear memory and remote fear memory. At synaptic level, fear conditioning also triggers plastic changes within the cortical areas immediately after the condition. These results raise the possibility that certain forms of synaptic plasticity may occur within the cortex while synaptic potentiation takes place within synapses in the hippocampus and amygdala. This hypothesis is supported by electrophysiological evidence obtained from freely moving animals that neurons in the hippocampus/amygdala fire synchronous activities with cortical neurons during the learning. To study fear-related synaptic plasticity in the cortex and its functional connectivity with neurons in the amygdala and hippocampus will help us understand brain mechanisms of fear and improve clinical treatment of emotional disorders in patients.

  6. Volumetric associations between uncinate fasciculus, amygdala, and trait anxiety

    Directory of Open Access Journals (Sweden)

    Baur Volker

    2012-01-01

    Full Text Available Abstract Background Recent investigations of white matter (WM connectivity suggest an important role of the uncinate fasciculus (UF, connecting anterior temporal areas including the amygdala with prefrontal-/orbitofrontal cortices, for anxiety-related processes. Volume of the UF, however, has rarely been investigated, but may be an important measure of structural connectivity underlying limbic neuronal circuits associated with anxiety. Since UF volumetric measures are newly applied measures, it is necessary to cross-validate them using further neural and behavioral indicators of anxiety. Results In a group of 32 subjects not reporting any history of psychiatric disorders, we identified a negative correlation between left UF volume and trait anxiety, a finding that is in line with previous results. On the other hand, volume of the left amygdala, which is strongly connected with the UF, was positively correlated with trait anxiety. In addition, volumes of the left UF and left amygdala were inversely associated. Conclusions The present study emphasizes the role of the left UF as candidate WM fiber bundle associated with anxiety-related processes and suggests that fiber bundle volume is a WM measure of particular interest. Moreover, these results substantiate the structural relatedness of UF and amygdala by a non-invasive imaging method. The UF-amygdala complex