Optimal and Local Connectivity Between Neuron and Synapse Array in the Quantum Dot/Silicon Brain

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Duong, Tuan A.; Assad, Christopher; Thakoor, Anikumar P.

2010-01-01

This innovation is used to connect between synapse and neuron arrays using nanowire in quantum dot and metal in CMOS (complementary metal oxide semiconductor) technology to enable the density of a brain-like connection in hardware. The hardware implementation combines three technologies: 1. Quantum dot and nanowire-based compact synaptic cell (50x50 sq nm) with inherently low parasitic capacitance (hence, low dynamic power approx.l0(exp -11) watts/synapse), 2. Neuron and learning circuits implemented in 50-nm CMOS technology, to be integrated with quantum dot and nanowire synapse, and 3. 3D stacking approach to achieve the overall numbers of high density O(10(exp 12)) synapses and O(10(exp 8)) neurons in the overall system. In a 1-sq cm of quantum dot layer sitting on a 50-nm CMOS layer, innovators were able to pack a 10(exp 6)-neuron and 10(exp 10)-synapse array; however, the constraint for the connection scheme is that each neuron will receive a non-identical 10(exp 4)-synapse set, including itself, via its efficacy of the connection. This is not a fully connected system where the 100x100 synapse array only has a 100-input data bus and 100-output data bus. Due to the data bus sharing, it poses a great challenge to have a complete connected system, and its constraint within the quantum dot and silicon wafer layer. For an effective connection scheme, there are three conditions to be met: 1. Local connection. 2. The nanowire should be connected locally, not globally from which it helps to maximize the data flow by sharing the same wire space location. 3. Each synapse can have an alternate summation line if needed (this option is doable based on the simple mask creation). The 10(exp 3)x10(exp 3)-neuron array was partitioned into a 10-block, 10(exp 2)x10(exp 3)-neuron array. This building block can be completely mapped within itself (10,000 synapses to a neuron).

Neural circuit rewiring: insights from DD synapse remodeling.

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Kurup, Naina; Jin, Yishi

2016-01-01

Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

Multiple cell adhesion molecules shaping a complex nicotinic synapse on neurons.

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Triana-Baltzer, Gallen B; Liu, Zhaoping; Gounko, Natalia V; Berg, Darwin K

2008-09-01

Neuroligin, SynCAM, and L1-CAM are cell adhesion molecules with synaptogenic roles in glutamatergic pathways. We show here that SynCAM is expressed in the chick ciliary ganglion, embedded in a nicotinic pathway, and, as shown previously for neuroligin and L1-CAM, acts transcellularly to promote synaptic maturation on the neurons in culture. Moreover, we show that electroporation of chick embryos with dominant negative constructs disrupting any of the three molecules in vivo reduces the total amount of presynaptic SV2 overlaying the neurons expressing the constructs. Only disruption of L1-CAM and neuroligin, however, reduces the number of SV2 puncta specifically overlaying nicotinic receptor clusters. Disrupting L1-CAM and neuroligin together produces no additional decrement, indicating that they act on the same subset of synapses. SynCAM may affect synaptic maturation rather than synapse formation. The results indicate that individual neurons can express multiple synaptogenic molecules with different effects on the same class of nicotinic synapses.

Impact of delays on the synchronization transitions of modular neuronal networks with hybrid synapses

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Liu, Chen; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xile; Tsang, Kaiming; Chan, Wailok

2013-09-01

The combined effects of the information transmission delay and the ratio of the electrical and chemical synapses on the synchronization transitions in the hybrid modular neuronal network are investigated in this paper. Numerical results show that the synchronization of neuron activities can be either promoted or destroyed as the information transmission delay increases, irrespective of the probability of electrical synapses in the hybrid-synaptic network. Interestingly, when the number of the electrical synapses exceeds a certain level, further increasing its proportion can obviously enhance the spatiotemporal synchronization transitions. Moreover, the coupling strength has a significant effect on the synchronization transition. The dominated type of the synapse always has a more profound effect on the emergency of the synchronous behaviors. Furthermore, the results of the modular neuronal network structures demonstrate that excessive partitioning of the modular network may result in the dramatic detriment of neuronal synchronization. Considering that information transmission delays are inevitable in intra- and inter-neuronal networks communication, the obtained results may have important implications for the exploration of the synchronization mechanism underlying several neural system diseases such as Parkinson's Disease.

Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

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Qian-Kun Yang

2013-01-01

Full Text Available NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

A Neuron- and a Synapse Chip for Artificial Neural Networks

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Lansner, John; Lehmann, Torsten

1992-01-01

A cascadable, analog, CMOS chip set has been developed for hardware implementations of artificial neural networks (ANN's):I) a neuron chip containing an array of neurons with hyperbolic tangent activation functions and adjustable gains, and II) a synapse chip (or a matrix-vector multiplier) where...

Motor Neurons

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Hounsgaard, Jorn

2017-01-01

Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

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Luis B Tovar-y-Romo

2014-02-01

Full Text Available Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF, glial-derived neurotrophic factor (GDNF, ciliary neurotrophic factor (CNTF and insulin-like growth factor 1 (IGF-1. Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this review we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.

Neuron array with plastic synapses and programmable dendrites.

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Ramakrishnan, Shubha; Wunderlich, Richard; Hasler, Jennifer; George, Suma

2013-10-01

We describe a novel neuromorphic chip architecture that models neurons for efficient computation. Traditional architectures of neuron array chips consist of large scale systems that are interfaced with AER for implementing intra- or inter-chip connectivity. We present a chip that uses AER for inter-chip communication but uses fast, reconfigurable FPGA-style routing with local memory for intra-chip connectivity. We model neurons with biologically realistic channel models, synapses and dendrites. This chip is suitable for small-scale network simulations and can also be used for sequence detection, utilizing directional selectivity properties of dendrites, ultimately for use in word recognition.

The interplay between neurons and glia in synapse development and plasticity

OpenAIRE

Stogsdill, Jeff A; Eroglu, Cagla

2016-01-01

In the brain, the formation of complex neuronal networks amenable to experience-dependent remodeling is complicated by the diversity of neurons and synapse types. The establishment of a functional brain depends not only on neurons, but also non-neuronal glial cells. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This article reviews important findings, which uncovered cellular and molecular aspects of the neuro...

Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

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Pamphlett, Roger; Kum Jew, Stephen

2013-12-12

The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

Heavy metals in locus ceruleus and motor neurons in motor neuron disease

Science.gov (United States)

2013-01-01

Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

Spinal cord: motor neuron diseases.

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Rezania, Kourosh; Roos, Raymond P

2013-02-01

Spinal cord motor neuron diseases affect lower motor neurons in the ventral horn. This article focuses on the most common spinal cord motor neuron disease, amyotrophic lateral sclerosis, which also affects upper motor neurons. Also discussed are other motor neuron diseases that only affect the lower motor neurons. Despite the identification of several genes associated with familial amyotrophic lateral sclerosis, the pathogenesis of this complex disease remains elusive. Copyright © 2013 Elsevier Inc. All rights reserved.

Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

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Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

2011-01-01

SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS.

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Lalancette-Hebert, Melanie; Sharma, Aarti; Lyashchenko, Alexander K; Shneider, Neil A

2016-12-20

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (I A ) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced I A activation by targeted reduction of γ-MNs in SOD1 G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.

How to make spinal motor neurons.

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Davis-Dusenbery, Brandi N; Williams, Luis A; Klim, Joseph R; Eggan, Kevin

2014-02-01

All muscle movements, including breathing, walking, and fine motor skills rely on the function of the spinal motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary motor neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of motor neurons in vitro. In this Primer, we discuss how the logic of spinal motor neuron development has been applied to allow generation of motor neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of motor neurons generated through each of these techniques.

Pathogenesis of motor neuron disease

Institute of Scientific and Technical Information of China (English)

Xuefei Wang

2006-01-01

OBJECTIVE: To summarize and analyze the factors and theories related to the attack of motor neuron disease, and comprehensively investigate the pathogenesis of motor neuron disease.DATA SOURCES: A search of Pubmed database was undertaken to identify articles about motor neuron disease published in English from January 1994 to June 2006 by using the keywords of "neurodegenerative diseases". Other literatures were collected by retrieving specific journals and articles.STUDY SELECTION: The data were checked primarily, articles related to the pathogenesis of motor neuron disease were involved, and those obviously irrelated to the articles were excluded.DATA EXTRACTION: Totally 54 articles were collected, 30 of them were involved, and the other 24 were excluded.DATA SYNTHESIS: The pathogenesis of motor neuron disease has multiple factors, and the present related theories included free radical oxidation, excitotoxicity, genetic and immune factors, lack of neurotrophic factor,injury of neurofilament, etc. The studies mainly come from transgenic animal models, cell culture in vitro and patients with familial motor neuron disease, but there are still many restrictions and disadvantages.CONCLUSION: It is necessary to try to find whether there is internal association among different mechanisms,comprehensively investigate the pathogenesis of motor neuron diseases, in order to provide reliable evidence for the clinical treatment.

GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction.

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Saha, Rinki; Knapp, Stephanie; Chakraborty, Darpan; Horovitz, Omer; Albrecht, Anne; Kriebel, Martin; Kaphzan, Hanoch; Ehrlich, Ingrid; Volkmer, Hansjürgen; Richter-Levin, Gal

2017-01-01

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Spinal Accessory Motor Neurons in the Mouse: A Special Type of Branchial Motor Neuron?

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Watson, Charles; Tvrdik, Petr

2018-04-16

The spinal accessory nerve arises from motor neurons in the upper cervical spinal cord. The axons of these motor neurons exit dorsal to the ligamentum denticulatum and form the spinal accessory nerve. The nerve ascends in the spinal subarachnoid space to enter the posterior cranial fossa through the foramen magnum. The spinal accessory nerve then turns caudally to exit through the jugular foramen alongside the vagus and glossopharyngeal nerves, and then travels to supply the sternomastoid and trapezius muscles in the neck. The unusual course of the spinal accessory nerve has long prompted speculation that it is not a typical spinal motor nerve and that it might represent a caudal remnant of the branchial motor system. Our cell lineage tracing data, combined with images from public databases, show that the spinal accessory motor neurons in the mouse transiently express Phox2b, a transcription factor that is required for development of brain stem branchial motor nuclei. While this is strong prima facie evidence that the spinal accessory motor neurons should be classified as branchial motor, the evolutionary history of these motor neurons in anamniote vertebrates suggests that they may be considered to be an atypical branchial group that possesses both branchial and somatic characteristics. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Retrogradely Transported TrkA Endosomes Signal Locally within Dendrites to Maintain Sympathetic Neuron Synapses

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Kathryn M. Lehigh

2017-04-01

Full Text Available Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies translocate into dendrites, where they are signaling competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially confined inhibition of TrkA kinase activity, we found that distal-axon-derived TrkA signaling endosomes are necessary within sympathetic neuron dendrites for maintenance of synapses. Thus, TrkA signaling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome signaling within dendrites to promote aggregation of postsynaptic protein complexes.

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment.

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MacNamee, Sarah E; Liu, Kendra E; Gerhard, Stephan; Tran, Cathy T; Fetter, Richard D; Cardona, Albert; Tolbert, Leslie P; Oland, Lynne A

2016-07-01

Anatomical, molecular, and physiological interactions between astrocytes and neuronal synapses regulate information processing in the brain. The fruit fly Drosophila melanogaster has become a valuable experimental system for genetic manipulation of the nervous system and has enormous potential for elucidating mechanisms that mediate neuron-glia interactions. Here, we show the first electrophysiological recordings from Drosophila astrocytes and characterize their spatial and physiological relationship with particular synapses. Astrocyte intrinsic properties were found to be strongly analogous to those of vertebrate astrocytes, including a passive current-voltage relationship, low membrane resistance, high capacitance, and dye-coupling to local astrocytes. Responses to optogenetic stimulation of glutamatergic premotor neurons were correlated directly with anatomy using serial electron microscopy reconstructions of homologous identified neurons and surrounding astrocytic processes. Robust bidirectional communication was present: neuronal activation triggered astrocytic glutamate transport via excitatory amino acid transporter 1 (Eaat1), and blocking Eaat1 extended glutamatergic interneuron-evoked inhibitory postsynaptic currents in motor neurons. The neuronal synapses were always located within 1 μm of an astrocytic process, but none were ensheathed by those processes. Thus, fly astrocytes can modulate fast synaptic transmission via neurotransmitter transport within these anatomical parameters. J. Comp. Neurol. 524:1979-1998, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Differential regulation of polarized synaptic vesicle trafficking and synapse stability in neural circuit rewiring in Caenorhabditis elegans.

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Naina Kurup

2017-06-01

Full Text Available Neural circuits are dynamic, with activity-dependent changes in synapse density and connectivity peaking during different phases of animal development. In C. elegans, young larvae form mature motor circuits through a dramatic switch in GABAergic neuron connectivity, by concomitant elimination of existing synapses and formation of new synapses that are maintained throughout adulthood. We have previously shown that an increase in microtubule dynamics during motor circuit rewiring facilitates new synapse formation. Here, we further investigate cellular control of circuit rewiring through the analysis of mutants obtained in a forward genetic screen. Using live imaging, we characterize novel mutations that alter cargo binding in the dynein motor complex and enhance anterograde synaptic vesicle movement during remodeling, providing in vivo evidence for the tug-of-war between kinesin and dynein in fast axonal transport. We also find that a casein kinase homolog, TTBK-3, inhibits stabilization of nascent synapses in their new locations, a previously unexplored facet of structural plasticity of synapses. Our study delineates temporally distinct signaling pathways that are required for effective neural circuit refinement.

Effects of dynamic synapses on noise-delayed response latency of a single neuron

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Uzuntarla, M.; Ozer, M.; Ileri, U.; Calim, A.; Torres, J. J.

2015-12-01

The noise-delayed decay (NDD) phenomenon emerges when the first-spike latency of a periodically forced stochastic neuron exhibits a maximum for a particular range of noise intensity. Here, we investigate the latency response dynamics of a single Hodgkin-Huxley neuron that is subject to both a suprathreshold periodic stimulus and a background activity arriving through dynamic synapses. We study the first-spike latency response as a function of the presynaptic firing rate f . This constitutes a more realistic scenario than previous works, since f provides a suitable biophysically realistic parameter to control the level of activity in actual neural systems. We first report on the emergence of classical NDD behavior as a function of f for the limit of static synapses. Second, we show that when short-term depression and facilitation mechanisms are included at the synapses, different NDD features can be found due to their modulatory effect on synaptic current fluctuations. For example, an intriguing double NDD (DNDD) behavior occurs for different sets of relevant synaptic parameters. Moreover, depending on the balance between synaptic depression and synaptic facilitation, single NDD or DNDD can prevail, in such a way that synaptic facilitation favors the emergence of DNDD whereas synaptic depression favors the existence of single NDD. Here we report the existence of the DNDD effect in the response latency dynamics of a neuron.

Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

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Kim, Jeong-Ki; Caine, Charlotte; Awano, Tomoyuki; Herbst, Ruth; Monani, Umrao R

2017-07-01

Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus.

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Matías A Goldin

2017-08-01

Full Text Available Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the "breaking" of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which

Repetitive activation of the corticospinal pathway by means of rTMS may reduce the efficiency of corticomotoneuronal synapses

DEFF Research Database (Denmark)

Taube, Wolfgang; Leukel, Christian; Nielsen, Jens Bo

2015-01-01

Low-frequency rTMS applied to the primary motor cortex (M1) may produce depression of motor-evoked potentials (MEPs). This depression is commonly assumed to reflect changes in cortical circuits. However, little is known about rTMS-induced effects on subcortical circuits. Therefore, the present st......-either at M1 and/or the CM synapse. As the early facilitation reflects activation of direct CM projections, the most likely site of action is the synapse of the CM neurons onto spinal motoneurons....

Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease

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Fisher, Karen M.; Zaaimi, Boubker; Williams, Timothy L.; Baker, Stuart N.

2012-01-01

In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15–30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15–30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

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Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

2017-03-01

The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation.

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Seven, Yasin B; Perim, Raphael R; Hobson, Orinda R; Simon, Alec K; Tadjalli, Arash; Mitchell, Gordon S

2018-04-15

Although adenosine 2A (A 2A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A 2A receptor siRNA injections. A 2A receptor siRNA injections selectively knocked down A 2A receptors in cholera toxin B-subunit-identified phrenic motor neurons, sparing cervical non-phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A 2A receptors relevant to A 2A receptor-induced phrenic motor facilitation. Upregulation of A 2A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A 2A receptors for pMF are unknown. This is an important question since the physiological outcome of A 2A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A 2A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A 2A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 ± 2%). Intrapleural siRNA injections were used to selectively knock down A 2A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A 2A receptor knock-down was verified by a ∼45% decrease in A 2A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, p

Cux1 and Cux2 regulate dendritic branching, spine morphology and synapses of the upper layer neurons of the cortex

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Cubelos, Beatriz; Sebastián-Serrano, Alvaro; Beccari, Leonardo; Calcagnotto, Maria Elisa; Cisneros, Elsa; Kim, Seonhee; Dopazo, Ana; Alvarez-Dolado, Manuel; Redondo, Juan Miguel; Bovolenta, Paola; Walsh, Christopher A.; Nieto, Marta

2010-01-01

Summary Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development and synapse formation in layer II–III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits. PMID:20510857

Gap junctions and motor behavior

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Kiehn, Ole; Tresch, Matthew C.

2002-01-01

The production of any motor behavior requires coordinated activity in motor neurons and premotor networks. In vertebrates, this coordination is often assumed to take place through chemical synapses. Here we review recent data suggesting that electrical gap-junction coupling plays an important role...... in coordinating and generating motor outputs in embryonic and early postnatal life. Considering the recent demonstration of a prevalent expression of gap-junction proteins and gap-junction structures in the adult mammalian spinal cord, we suggest that neuronal gap-junction coupling might also contribute...... to the production of motor behavior in adult mammals....

Contextual Learning Requires Functional Diversity at Excitatory and Inhibitory Synapses onto CA1 Pyramidal Neurons

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Dai Mitsushima

2015-01-01

Full Text Available Although the hippocampus is processing temporal and spatial information in particular context, the encoding rule creating memory is completely unknown. To examine the mechanism, we trained rats on an inhibitory avoidance (IA task, a hippocampus-dependent rapid one-trial contextual learning paradigm. By combining Herpes virus-mediated in vivo gene delivery with in vitro patch-clamp recordings, I reported contextual learning drives GluR1-containing AMPA receptors into CA3-CA1 synapses. The molecular event is required for contextual memory, since bilateral expression of delivery blocker in CA1 successfully blocked IA learning. Moreover, I found a logarithmic correlation between the number of delivery blocking cells and learning performance. Considering that one all-or-none device can process 1-bit of data per clock (Nobert Wiener 1961, the logarithmic correlation may provides evidence that CA1 neurons transmit essential data of contextual information. Further, I recently reported critical role of acetylcholine as an intrinsic trigger of learning-dependent synaptic plasticity. IA training induced ACh release in CA1 that strengthened not only AMPA receptor-mediated excitatory synapses, but also GABAA receptor-mediated inhibitory synapses on each CA1 neuron. More importantly, IA-trained rats showed individually different excitatory and inhibitory synaptic inputs with wide variation on each CA1 neuron. Here I propose a new hypothesis that the diversity of synaptic inputs on CA1 neurons may depict cell-specific outputs processing experienced episodes after training.

Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons.

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Machado, Carolina Barcellos; Kanning, Kevin C; Kreis, Patricia; Stevenson, Danielle; Crossley, Martin; Nowak, Magdalena; Iacovino, Michelina; Kyba, Michael; Chambers, David; Blanc, Eric; Lieberam, Ivo

2014-02-01

Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations.

IL-10 Promotes Neurite Outgrowth and Synapse Formation in Cultured Cortical Neurons after the Oxygen-Glucose Deprivation via JAK1/STAT3 Pathway.

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Chen, Hongbin; Lin, Wei; Zhang, Yixian; Lin, Longzai; Chen, Jianhao; Zeng, Yongping; Zheng, Mouwei; Zhuang, Zezhong; Du, Houwei; Chen, Ronghua; Liu, Nan

2016-07-26

As a classic immunoregulatory and anti-inflammatory cytokine, interleukin-10 (IL-10) provides neuroprotection in cerebral ischemia in vivo or oxygen-glucose deprivation (OGD)-induced injury in vitro. However, it remains blurred whether IL-10 promotes neurite outgrowth and synapse formation in cultured primary cortical neurons after OGD injury. In order to evaluate its effect on neuronal apoptosis, neurite outgrowth and synapse formation, we administered IL-10 or IL-10 neutralizing antibody (IL-10NA) to cultured rat primary cortical neurons after OGD injury. We found that IL-10 treatment activated the Janus kinase 1 (JAK1)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. Moreover, IL-10 attenuated OGD-induced neuronal apoptosis by down-regulating the Bax expression and up-regulating the Bcl-2 expression, facilitated neurite outgrowth by increasing the expression of Netrin-1, and promoted synapse formation in cultured primary cortical neurons after OGD injury. These effects were partly abolished by JAK1 inhibitor GLPG0634. Contrarily, IL-10NA produced opposite effects on the cultured cortical neurons after OGD injury. Taken together, our findings suggest that IL-10 not only attenuates neuronal apoptosis, but also promotes neurite outgrowth and synapse formation via the JAK1/STAT3 signaling pathway in cultured primary cortical neurons after OGD injury.

Estradiol pretreatment ameliorates impaired synaptic plasticity at synapses of insulted CA1 neurons after transient global ischemia

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Takeuchi, Koichi; Yang, Yupeng; Takayasu, Yukihiro; Gertner, Michael; Hwang, Jee-Yeon; Aromolaran, Kelly; Bennett, Michael V.L.; Zukin, R. Suzanne

2015-01-01

Global ischemia in humans or induced experimentally in animals causes selective and delayed neuronal death in pyramidal neurons of the hippocampal CA1. The ovarian hormone estradiol administered before or immediately after insult affords histological protection in experimental models of focal and global ischemia and ameliorates the cognitive deficits associated with ischemic cell death. However, the impact of estradiol on the functional integrity of Schaffer collateral to CA1 (Sch-CA1) pyramidal cell synapses following global ischemia is not clear. Here we show that long term estradiol treatment initiated 14 days prior to global ischemia in ovariectomized female rats acts via the IGF-1 receptor to protect the functional integrity of CA1 neurons. Global ischemia impairs basal synaptic transmission, assessed by the input/output relation at Sch-CA1 synapses, and NMDA receptor (NMDAR)-dependent long term potentiation (LTP), assessed at 3 days after surgery. Presynaptic function, assessed by fiber volley and paired pulse facilitation, is unchanged. To our knowledge, our results are the first to demonstrate that estradiol at near physiological concentrations enhances basal excitatory synaptic transmission and ameliorates deficits in LTP at synapses onto CA1 neurons in a clinically-relevant model of global ischemia. Estradiol-induced rescue of LTP requires the IGF-1 receptor, but not the classical estrogen receptors (ER)-α or β. These findings support a model whereby estradiol acts via the IGF-1 receptor to maintain the functional integrity of hippocampal CA1 synapses in the face of global ischemia. PMID:25463028

Microorganism and filamentous fungi drive evolution of plant synapses.

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Baluška, František; Mancuso, Stefano

2013-01-01

In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

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Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

2009-01-01

Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

Synchronization of motor neurons during locomotion in the neonatal rat

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Tresch, Matthew C.; Kiehn, Ole

2002-01-01

We describe here the robust synchronization of motor neurons at a millisecond time scale during locomotor activity in the neonatal rat. Action potential activity of motor neuron pairs was recorded extracellularly using tetrodes during locomotor activity in the in vitro neonatal rat spinal cord....... Approximately 40% of motor neuron pairs recorded in the same spinal segment showed significant synchronization, with the duration of the central peak in cross-correlograms between motor neurons typically ranging between ∼ 30 and 100 msec. The percentage of synchronized motor neuron pairs was considerably higher...... between motor neurons persisted. On the other hand, both local and distant coupling between motor neurons were preserved after antagonism of gap junction coupling between motor neurons. These results demonstrate that motor neuron activity is strongly synchronized at a millisecond time scale during...

A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia.

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Lee, Sue-Hyun; Kwak, Chuljung; Shim, Jaehoon; Kim, Jung-Eun; Choi, Sun-Lim; Kim, Hyoung F; Jang, Deok-Jin; Lee, Jin-A; Lee, Kyungmin; Lee, Chi-Hoon; Lee, Young-Don; Miniaci, Maria Concetta; Bailey, Craig H; Kandel, Eric R; Kaang, Bong-Kiun

2012-08-28

The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill- and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, long-term facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval.

FIB/SEM technology and high-throughput 3D reconstruction of dendritic spines and synapses in GFP-labeled adult-generated neurons

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Carles eBosch

2015-05-01

Full Text Available The fine analysis of synaptic contacts is usually performed using transmission electron microscopy (TEM and its combination with neuronal labeling techniques. However, the complex 3D architecture of neuronal samples calls for their reconstruction from serial sections. Here we show that focused ion beam/scanning electron microscopy (FIB/SEM allows efficient, complete, and automatic 3D reconstruction of identified dendrites, including their spines and synapses, from GFP/DAB-labeled neurons, with a resolution comparable to that of TEM. We applied this technology to analyze the synaptogenesis of labeled adult-generated granule cells (GCs in mice. 3D reconstruction of spines in GCs aged 3–4 and 8–9 weeks revealed two different stages of spine development and unexpected features of synapse formation, including vacant and branched spines and presynaptic terminals establishing synapses with up to 10 spines. Given the reliability, efficiency, and high resolution of FIB/SEM technology and the wide use of DAB in conventional EM, we consider FIB/SEM fundamental for the detailed characterization of identified synaptic contacts in neurons in a high-throughput manner.

Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons.

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Bello, Sanusi M; Millo, Hadas; Rajebhosale, Manisha; Price, Stephen R

2012-01-11

Motor neurons that control limb movements are organized as a neuronal nucleus in the developing ventral horn of the spinal cord called the lateral motor column. Neuronal migration segregates motor neurons into distinct lateral and medial divisions within the lateral motor column that project axons to dorsal or ventral limb targets, respectively. This migratory phase is followed by an aggregation phase whereby motor neurons within a division that project to the same muscle cluster together. These later phases of motor neuron organization depend on limb-regulated differential cadherin expression within motor neurons. Initially, all motor neurons display the same cadherin expression profile, which coincides with the migratory phase of motor neuron segregation. Here, we show that this early, pan-motor neuron cadherin function drives the divisional segregation of spinal motor neurons in the chicken embryo by controlling motor neuron migration. We manipulated pan-motor neuron cadherin function through dissociation of cadherin binding to their intracellular partners. We found that of the major intracellular transducers of cadherin signaling, γ-catenin and α-catenin predominate in the lateral motor column. In vivo manipulations that uncouple cadherin-catenin binding disrupt divisional segregation via deficits in motor neuron migration. Additionally, reduction of the expression of cadherin-7, a cadherin predominantly expressed in motor neurons only during their migration, also perturbs divisional segregation. Our results show that γ-catenin-dependent cadherin function is required for spinal motor neuron migration and divisional segregation and suggest a prolonged role for cadherin expression in all phases of motor neuron organization.

Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication.

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Rozanski, Gabriela M; Li, Qi; Stanley, Elise F

2013-04-01

The dorsal root ganglion (DRG) contains a subset of closely-apposed neuronal somata (NS) separated solely by a thin satellite glial cell (SGC) membrane septum to form an NS-glial cell-NS trimer. We recently reported that stimulation of one NS with an impulse train triggers a delayed, noisy and long-lasting response in its NS pair via a transglial signaling pathway that we term a 'sandwich synapse' (SS). Transmission could be unidirectional or bidirectional and facilitated in response to a second stimulus train. We have shown that in chick or rat SS the NS-to-SGC leg of the two-synapse pathway is purinergic via P2Y2 receptors but the second SGC-to-NS synapse mechanism remained unknown. A noisy evoked current in the target neuron, a reversal potential close to 0 mV, and insensitivity to calcium scavengers or G protein block favored an ionotropic postsynaptic receptor. Selective block by D-2-amino-5-phosphonopentanoate (AP5) implicated glutamatergic transmission via N-methyl-d-aspartate receptors. This agent also blocked NS responses evoked by puff of UTP, a P2Y2 agonist, directly onto the SGC cell, confirming its action at the second synapse of the SS transmission pathway. The N-methyl-d-aspartate receptor NR2B subunit was implicated by block of transmission with ifenprodil and by its immunocytochemical localization to the NS membrane, abutting the glial septum P2Y2 receptor. Isolated DRG cell clusters exhibited daisy-chain and branching NS-glial cell-NS contacts, suggestive of a network organization within the ganglion. The identification of the glial-to-neuron transmitter and receptor combination provides further support for transglial transmission and completes the DRG SS molecular transmission pathway. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

The immunological synapse

DEFF Research Database (Denmark)

Klemmensen, Thomas; Pedersen, Lars Ostergaard; Geisler, Carsten

2003-01-01

. A distinct 3-dimensional supramolecular structure at the T cell/APC interface has been suggested to be involved in the information transfer. Due to its functional analogy to the neuronal synapse, the structure has been termed the "immunological synapse" (IS). Here, we review molecular aspects concerning...

On-chip photonic synapse.

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Cheng, Zengguang; Ríos, Carlos; Pernice, Wolfram H P; Wright, C David; Bhaskaran, Harish

2017-09-01

The search for new "neuromorphic computing" architectures that mimic the brain's approach to simultaneous processing and storage of information is intense. Because, in real brains, neuronal synapses outnumber neurons by many orders of magnitude, the realization of hardware devices mimicking the functionality of a synapse is a first and essential step in such a search. We report the development of such a hardware synapse, implemented entirely in the optical domain via a photonic integrated-circuit approach. Using purely optical means brings the benefits of ultrafast operation speed, virtually unlimited bandwidth, and no electrical interconnect power losses. Our synapse uses phase-change materials combined with integrated silicon nitride waveguides. Crucially, we can randomly set the synaptic weight simply by varying the number of optical pulses sent down the waveguide, delivering an incredibly simple yet powerful approach that heralds systems with a continuously variable synaptic plasticity resembling the true analog nature of biological synapses.

Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice.

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Turner, Bradley J; Alfazema, Neza; Sheean, Rebecca K; Sleigh, James N; Davies, Kay E; Horne, Malcolm K; Talbot, Kevin

2014-04-01

Spinal muscular atrophy results from diminished levels of survival motor neuron (SMN) protein in spinal motor neurons. Low levels of SMN also occur in models of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1) and genetic reduction of SMN levels exacerbates the phenotype of transgenic SOD1(G93A) mice. Here, we demonstrate that SMN protein is significantly reduced in the spinal cords of patients with sporadic ALS. To test the potential of SMN as a modifier of ALS, we overexpressed SMN in 2 different strains of SOD1(G93A) mice. Neuronal overexpression of SMN significantly preserved locomotor function, rescued motor neurons, and attenuated astrogliosis in spinal cords of SOD1(G93A) mice. Despite this, survival was not prolonged, most likely resulting from SMN mislocalization and depletion of gems in motor neurons of symptomatic mice. Our results reveal that SMN upregulation slows locomotor deficit onset and motor neuron loss in this mouse model of ALS. However, disruption of SMN nuclear complexes by high levels of mutant SOD1, even in the presence of SMN overexpression, might limit its survival promoting effects in this specific mouse model. Studies in emerging mouse models of ALS are therefore warranted to further explore the potential of SMN as a modifier of ALS. Copyright © 2014 Elsevier Inc. All rights reserved.

Evolution and Development of the Inner Ear Efferent System: Transforming a Motor Neuron Population to Connect to the Most Unusual Motor Protein via Ancient Nicotinic Receptors

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Bernd Fritzsch

2017-04-01

Full Text Available All craniate chordates have inner ears with hair cells that receive input from the brain by cholinergic centrifugal fibers, the so-called inner ear efferents (IEEs. Comparative data suggest that IEEs derive from facial branchial motor (FBM neurons that project to the inner ear instead of facial muscles. Developmental data showed that IEEs develop adjacent to FBMs and segregation from IEEs might depend on few transcription factors uniquely associated with IEEs. Like other cholinergic terminals in the peripheral nervous system (PNS, efferent terminals signal on hair cells through nicotinic acetylcholine channels, likely composed out of alpha 9 and alpha 10 units (Chrna9, Chrna10. Consistent with the evolutionary ancestry of IEEs is the even more conserved ancestry of Chrna9 and 10. The evolutionary appearance of IEEs may reflect access of FBMs to a novel target, possibly related to displacement or loss of mesoderm-derived muscle fibers by the ectoderm-derived ear vesicle. Experimental transplantations mimicking this possible aspect of ear evolution showed that different motor neurons of the spinal cord or brainstem form cholinergic synapses on hair cells when ears replace somites or eyes. Transplantation provides experimental evidence in support of the evolutionary switch of FBM neurons to become IEEs. Mammals uniquely evolved a prestin related motor system to cause shape changes in outer hair cells regulated by the IEEs. In summary, an ancient motor neuron population drives in craniates via signaling through highly conserved Chrna receptors a uniquely derived cellular contractility system that is essential for hearing in mammals.

A reconfigurable on-line learning spiking neuromorphic processor comprising 256 neurons and 128K synapses.

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Qiao, Ning; Mostafa, Hesham; Corradi, Federico; Osswald, Marc; Stefanini, Fabio; Sumislawska, Dora; Indiveri, Giacomo

2015-01-01

Implementing compact, low-power artificial neural processing systems with real-time on-line learning abilities is still an open challenge. In this paper we present a full-custom mixed-signal VLSI device with neuromorphic learning circuits that emulate the biophysics of real spiking neurons and dynamic synapses for exploring the properties of computational neuroscience models and for building brain-inspired computing systems. The proposed architecture allows the on-chip configuration of a wide range of network connectivities, including recurrent and deep networks, with short-term and long-term plasticity. The device comprises 128 K analog synapse and 256 neuron circuits with biologically plausible dynamics and bi-stable spike-based plasticity mechanisms that endow it with on-line learning abilities. In addition to the analog circuits, the device comprises also asynchronous digital logic circuits for setting different synapse and neuron properties as well as different network configurations. This prototype device, fabricated using a 180 nm 1P6M CMOS process, occupies an area of 51.4 mm(2), and consumes approximately 4 mW for typical experiments, for example involving attractor networks. Here we describe the details of the overall architecture and of the individual circuits and present experimental results that showcase its potential. By supporting a wide range of cortical-like computational modules comprising plasticity mechanisms, this device will enable the realization of intelligent autonomous systems with on-line learning capabilities.

Hereditary motor neuropathies and motor neuron diseases: which is which.

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Hanemann, Clemens O; Ludolph, Albert C

2002-12-01

When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.

Retrograde Neuroanatomical Tracing of Phrenic Motor Neurons in Mice.

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Vandeweerd, Jean-Michel; Hontoir, Fanny; De Knoop, Alexis; De Swert, Kathleen; Nicaise, Charles

2018-02-22

Phrenic motor neurons are cervical motor neurons originating from C3 to C6 levels in most mammalian species. Axonal projections converge into phrenic nerves innervating the respiratory diaphragm. In spinal cord slices, phrenic motor neurons cannot be identified from other motor neurons on morphological or biochemical criteria. We provide the description of procedures for visualizing phrenic motor neuron cell bodies in mice, following intrapleural injections of cholera toxin subunit beta (CTB) conjugated to a fluorophore. This fluorescent neuroanatomical tracer has the ability to be caught up at the diaphragm neuromuscular junction, be carried retrogradely along the phrenic axons and reach the phrenic cell bodies. Two methodological approaches of intrapleural CTB delivery are compared: transdiaphragmatic versus transthoracic injections. Both approaches are successful and result in similar number of CTB-labeled phrenic motor neurons. In conclusion, these techniques can be applied to visualize or quantify the phrenic motor neurons in various experimental studies such as those focused on the diaphragm-phrenic circuitry.

Progranulin is expressed within motor neurons and promotes neuronal cell survival

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Kay Denis G

2009-10-01

Full Text Available Abstract Background Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival. Results In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months. This is mediated at least in part through

Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.

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Thibault, Dominic; Giguère, Nicolas; Loustalot, Fabien; Bourque, Marie-Josée; Ducrot, Charles; El Mestikawy, Salah; Trudeau, Louis-Éric

2016-05-01

Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.

Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

Science.gov (United States)

Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

2014-05-01

Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology. Copyright © 2014 Elsevier Inc. All rights reserved.

Organization of central synapses by adhesion molecules

OpenAIRE

Tallafuss, Alexandra; Constable, John R.L.; Washbourne, Philip

2010-01-01

Synapses are the primary means for transmitting information from one neuron to the next. They are formed during development of the nervous system, and formation of appropriate synapses is crucial for establishment of neuronal circuits that underlie behavior and cognition. Understanding how synapses form and are maintained will allow us to address developmental disorders such as autism, mental retardation and possibly also psychological disorders. A number of biochemical and proteomic studies ...

A Re-configurable On-line Learning Spiking Neuromorphic Processor comprising 256 neurons and 128K synapses

Directory of Open Access Journals (Sweden)

Ning eQiao

2015-04-01

Full Text Available Implementing compact, low-power artificial neural processing systems with real-time on-line learning abilities is still an open challenge. In this paper we present a full-custom mixed-signal VLSI device with neuromorphic learning circuits that emulate the biophysics of real spiking neurons and dynamic synapses for exploring the properties of computational neuroscience models and for building brain-inspired computing systems. The proposed architecture allows the on-chip configuration of a wide range of network connectivities, including recurrent and deep networks with short-term and long-term plasticity. The device comprises 128 K analog synapse and 256 neuron circuits with biologically plausible dynamics and bi-stable spike-based plasticity mechanisms that endow it with on-line learning abilities. In addition to the analog circuits, the device comprises also asynchronous digital logic circuits for setting different synapse and neuron properties as well as different network configurations. This prototype device, fabricated using a 180 nm 1P6M CMOS process, occupies an area of 51.4 mm 2 , and consumes approximately 4 mW for typical experiments, for example involving attractor networks. Here we describe the details of the overall architecture and of the individual circuits and present experimental results that showcase its potential. By supporting a wide range of cortical-like computational modules comprising plasticity mechanisms, this device will enable the realization of intelligent autonomous systems with on-line learning capabilities.

Inference of topology and the nature of synapses, and the flow of information in neuronal networks

Science.gov (United States)

Borges, F. S.; Lameu, E. L.; Iarosz, K. C.; Protachevicz, P. R.; Caldas, I. L.; Viana, R. L.; Macau, E. E. N.; Batista, A. M.; Baptista, M. S.

2018-02-01

The characterization of neuronal connectivity is one of the most important matters in neuroscience. In this work, we show that a recently proposed informational quantity, the causal mutual information, employed with an appropriate methodology, can be used not only to correctly infer the direction of the underlying physical synapses, but also to identify their excitatory or inhibitory nature, considering easy to handle and measure bivariate time series. The success of our approach relies on a surprising property found in neuronal networks by which nonadjacent neurons do "understand" each other (positive mutual information), however, this exchange of information is not capable of causing effect (zero transfer entropy). Remarkably, inhibitory connections, responsible for enhancing synchronization, transfer more information than excitatory connections, known to enhance entropy in the network. We also demonstrate that our methodology can be used to correctly infer directionality of synapses even in the presence of dynamic and observational Gaussian noise, and is also successful in providing the effective directionality of intermodular connectivity, when only mean fields can be measured.

Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration

Science.gov (United States)

Alves, Chrystian J.; Dariolli, Rafael; Jorge, Frederico M.; Monteiro, Matheus R.; Maximino, Jessica R.; Martins, Roberto S.; Strauss, Bryan E.; Krieger, José E.; Callegaro, Dagoberto; Chadi, Gerson

2015-01-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS

Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: A clinical and brain imaging review

NARCIS (Netherlands)

van der Graaff, M. M.; de Jong, J. M. B. V.; Baas, F.; de Visser, M.

2009-01-01

There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary

Coexisting chaotic attractors in a single neuron model with adapting feedback synapse

International Nuclear Information System (INIS)

Li Chunguang; Chen Guanrong

2005-01-01

In this paper, we consider the nonlinear dynamical behavior of a single neuron model with adapting feedback synapse, and show that chaotic behaviors exist in this model. In some parameter domain, we observe two coexisting chaotic attractors, switching from the coexisting chaotic attractors to a connected chaotic attractor, and then switching back to the two coexisting chaotic attractors. We confirm the chaoticity by simulations with phase plots, waveform plots, and power spectra

Axonal regeneration and neuronal function are preserved in motor neurons lacking ß-actin in vivo.

Directory of Open Access Journals (Sweden)

Thomas R Cheever

2011-03-01

Full Text Available The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA, suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo.

Synchrony detection and amplification by silicon neurons with STDP synapses.

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Bofill-i-petit, Adria; Murray, Alan F

2004-09-01

Spike-timing dependent synaptic plasticity (STDP) is a form of plasticity driven by precise spike-timing differences between presynaptic and postsynaptic spikes. Thus, the learning rules underlying STDP are suitable for learning neuronal temporal phenomena such as spike-timing synchrony. It is well known that weight-independent STDP creates unstable learning processes resulting in balanced bimodal weight distributions. In this paper, we present a neuromorphic analog very large scale integration (VLSI) circuit that contains a feedforward network of silicon neurons with STDP synapses. The learning rule implemented can be tuned to have a moderate level of weight dependence. This helps stabilise the learning process and still generates binary weight distributions. From on-chip learning experiments we show that the chip can detect and amplify hierarchical spike-timing synchrony structures embedded in noisy spike trains. The weight distributions of the network emerging from learning are bimodal.

Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

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Schwab, Andrew J; Ebert, Allison D

2014-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

Intercellular protein-protein interactions at synapses.

Science.gov (United States)

Yang, Xiaofei; Hou, Dongmei; Jiang, Wei; Zhang, Chen

2014-06-01

Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer's disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.

Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

Science.gov (United States)

Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

2016-01-01

Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

Neuromodulation of vertebrate motor neuron membrane properties

DEFF Research Database (Denmark)

Hultborn, Hans; Kiehn, Ole

1992-01-01

The short-term function of motor neurons is to integrate synaptic inputs converging onto the somato-dendritic membrane and to transform the net synaptic drive into spike trains. A set of voltage-gated ion channels determines the electro-responsiveness and thereby the motor neuron's input-output f...

Current status of gene therapy for motor neuron disease

Institute of Scientific and Technical Information of China (English)

Xingkai An; Rong Peng; Shanshan Zhao

2006-01-01

OBJECTIVE: Although the etiology and pathogenesis of motor neuron disease is still unknown, there are many hypotheses on motor neuron mitochondrion, cytoskeleton structure and functional injuries. Thus, gene therapy of motor neuron disease has become a hot topic to apply in viral vector, gene delivery and basic gene techniques.DATA SOURCES: The related articles published between January 2000 and October 2006 were searched in Medline database and ISl database by computer using the keywords "motor neuron disease, gene therapy", and the language is limited to English. Meanwhile, the related references of review were also searched by handiwork. STUDY SELECTION: Original articles and referred articles in review were chosen after first hearing, then the full text which had new ideas were found, and when refer to the similar study in the recent years were considered first.DATA EXTRACTION: Among the 92 related articles, 40 ones were accepted, and 52 were excluded because of repetitive study or reviews.DATA SYNTHESIS: The viral vectors of gene therapy for motor neuron disease include adenoviral, adeno-associated viral vectors, herpes simplex virus type 1 vectors and lentiviral vectors. The delivery of them can be achieved by direct injection into the brain, or by remote delivery after injection vectors into muscle or peripheral nerves, or by ex vivo gene transfer. The viral vectors of gene therapy for motor neuron disease have been successfully developed, but the gene delivery of them is hampered by some difficulties. The RNA interference and neuroprotection are the main technologies for gene-based therapy in motor neuron disease. CONCLUSION : The RNA interference for motor neuron disease has succeeded in animal models, and the neuroprotection also does. But, there are still a lot of questions for gene therapy in the clinical treatment of motor neuron disease.

Presynaptic proteoglycans: sweet organizers of synapse development.

Science.gov (United States)

Song, Yoo Sung; Kim, Eunjoon

2013-08-21

Synaptic adhesion molecules control neuronal synapse development. In this issue of Neuron, Siddiqui et al. (2013) and de Wit et al. (2013) demonstrate that LRRTM4, a postsynaptic adhesion molecule, trans-synaptically interacts with presynaptic heparan sulfate proteoglycans (HSPGs) to promote synapse development. Copyright © 2013 Elsevier Inc. All rights reserved.

GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

Science.gov (United States)

Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

2011-09-22

The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

ALS and other motor neuron diseases.

Science.gov (United States)

Tiryaki, Ezgi; Horak, Holli A

2014-10-01

This review describes the most common motor neuron disease, ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its pathophysiology, including new genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews how to distinguish them from ALS, and discusses their pathophysiology. In this article, the spectrum of cognitive involvement in ALS, new concepts about protein synthesis pathology in the etiology of ALS, and new genetic associations will be covered. This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a "medical home" for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them.

Cell adhesion and matricellular support by astrocytes of the tripartite synapse

NARCIS (Netherlands)

Hillen, Anne E J; Burbach, J Peter H; Hol, Elly M

2018-01-01

Astrocytes contribute to the formation, function, and plasticity of synapses. Their processes enwrap the neuronal components of the tripartite synapse, and due to this close interaction they are perfectly positioned to modulate neuronal communication. The interaction between astrocytes and synapses

A VLSI recurrent network of integrate-and-fire neurons connected by plastic synapses with long-term memory.

Science.gov (United States)

Chicca, E; Badoni, D; Dante, V; D'Andreagiovanni, M; Salina, G; Carota, L; Fusi, S; Del Giudice, P

2003-01-01

Electronic neuromorphic devices with on-chip, on-line learning should be able to modify quickly the synaptic couplings to acquire information about new patterns to be stored (synaptic plasticity) and, at the same time, preserve this information on very long time scales (synaptic stability). Here, we illustrate the electronic implementation of a simple solution to this stability-plasticity problem, recently proposed and studied in various contexts. It is based on the observation that reducing the analog depth of the synapses to the extreme (bistable synapses) does not necessarily disrupt the performance of the device as an associative memory, provided that 1) the number of neurons is large enough; 2) the transitions between stable synaptic states are stochastic; and 3) learning is slow. The drastic reduction of the analog depth of the synaptic variable also makes this solution appealing from the point of view of electronic implementation and offers a simple methodological alternative to the technological solution based on floating gates. We describe the full custom analog very large-scale integration (VLSI) realization of a small network of integrate-and-fire neurons connected by bistable deterministic plastic synapses which can implement the idea of stochastic learning. In the absence of stimuli, the memory is preserved indefinitely. During the stimulation the synapse undergoes quick temporary changes through the activities of the pre- and postsynaptic neurons; those changes stochastically result in a long-term modification of the synaptic efficacy. The intentionally disordered pattern of connectivity allows the system to generate a randomness suited to drive the stochastic selection mechanism. We check by a suitable stimulation protocol that the stochastic synaptic plasticity produces the expected pattern of potentiation and depression in the electronic network.

Reward-modulated motor information in identified striatum neurons.

Science.gov (United States)

Isomura, Yoshikazu; Takekawa, Takashi; Harukuni, Rie; Handa, Takashi; Aizawa, Hidenori; Takada, Masahiko; Fukai, Tomoki

2013-06-19

It is widely accepted that dorsal striatum neurons participate in either the direct pathway (expressing dopamine D1 receptors) or the indirect pathway (expressing D2 receptors), controlling voluntary movements in an antagonistically balancing manner. The D1- and D2-expressing neurons are activated and inactivated, respectively, by dopamine released from substantia nigra neurons encoding reward expectation. However, little is known about the functional representation of motor information and its reward modulation in individual striatal neurons constituting the two pathways. In this study, we juxtacellularly recorded the spike activity of single neurons in the dorsolateral striatum of rats performing voluntary forelimb movement in a reward-predictable condition. Some of these neurons were identified morphologically by a combination of juxtacellular visualization and in situ hybridization for D1 mRNA. We found that the striatal neurons exhibited distinct functional activations before and during the forelimb movement, regardless of the expression of D1 mRNA. They were often positively, but rarely negatively, modulated by expecting a reward for the correct motor response. The positive reward modulation was independent of behavioral differences in motor performance. In contrast, regular-spiking and fast-spiking neurons in any layers of the motor cortex displayed only minor and unbiased reward modulation of their functional activation in relation to the execution of forelimb movement. Our results suggest that the direct and indirect pathway neurons cooperatively rather than antagonistically contribute to spatiotemporal control of voluntary movements, and that motor information is subcortically integrated with reward information through dopaminergic and other signals in the skeletomotor loop of the basal ganglia.

Neuroglial plasticity at striatal glutamatergic synapses in Parkinson's disease

Directory of Open Access Journals (Sweden)

Rosa M Villalba

2011-08-01

Full Text Available Striatal dopamine denervation is the pathological hallmark of Parkinson’s disease (PD. Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba et al., 2011. The concept of tripartite synapses (TS was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a. Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia-neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD

A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

Science.gov (United States)

Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

2014-01-01

SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

A computational model of motor neuron degeneration.

Science.gov (United States)

Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

2014-08-20

To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional neuromuscular junctions formed by embryonic stem cell-derived motor neurons.

Directory of Open Access Journals (Sweden)

Joy A Umbach

Full Text Available A key objective of stem cell biology is to create physiologically relevant cells suitable for modeling disease pathologies in vitro. Much progress towards this goal has been made in the area of motor neuron (MN disease through the development of methods to direct spinal MN formation from both embryonic and induced pluripotent stem cells. Previous studies have characterized these neurons with respect to their molecular and intrinsic functional properties. However, the synaptic activity of stem cell-derived MNs remains less well defined. In this study, we report the development of low-density co-culture conditions that encourage the formation of active neuromuscular synapses between stem cell-derived MNs and muscle cells in vitro. Fluorescence microscopy reveals the expression of numerous synaptic proteins at these contacts, while dual patch clamp recording detects both spontaneous and multi-quantal evoked synaptic responses similar to those observed in vivo. Together, these findings demonstrate that stem cell-derived MNs innervate muscle cells in a functionally relevant manner. This dual recording approach further offers a sensitive and quantitative assay platform to probe disorders of synaptic dysfunction associated with MN disease.

Non-viral gene therapy that targets motor neurons in vivo

Directory of Open Access Journals (Sweden)

Mary-Louise eRogers

2014-10-01

Full Text Available A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS. We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by ‘immunogene’ nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12 as DNA carrier was conjugated to an antibody (MLR2 to the neurotrophin receptor p75 (p75NTR. We used a plasmid (pVIVO2 designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP. MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0 % of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo.

Control of bursting synchronization in networks of Hodgkin-Huxley-type neurons with chemical synapses.

Science.gov (United States)

Batista, C A S; Viana, R L; Ferrari, F A S; Lopes, S R; Batista, A M; Coninck, J C P

2013-04-01

Thermally sensitive neurons present bursting activity for certain temperature ranges, characterized by fast repetitive spiking of action potential followed by a short quiescent period. Synchronization of bursting activity is possible in networks of coupled neurons, and it is sometimes an undesirable feature. Control procedures can suppress totally or partially this collective behavior, with potential applications in deep-brain stimulation techniques. We investigate the control of bursting synchronization in small-world networks of Hodgkin-Huxley-type thermally sensitive neurons with chemical synapses through two different strategies. One is the application of an external time-periodic electrical signal and another consists of a time-delayed feedback signal. We consider the effectiveness of both strategies in terms of protocols of applications suitable to be applied by pacemakers.

REM sleep selectively prunes and maintains new synapses in development and learning.

Science.gov (United States)

Li, Wei; Ma, Lei; Yang, Guang; Gan, Wen-Biao

2017-03-01

The functions and underlying mechanisms of rapid eye movement (REM) sleep remain unclear. Here we show that REM sleep prunes newly formed postsynaptic dendritic spines of layer 5 pyramidal neurons in the mouse motor cortex during development and motor learning. This REM sleep-dependent elimination of new spines facilitates subsequent spine formation during development and when a new motor task is learned, indicating a role for REM sleep in pruning to balance the number of new spines formed over time. Moreover, REM sleep also strengthens and maintains newly formed spines, which are critical for neuronal circuit development and behavioral improvement after learning. We further show that dendritic calcium spikes arising during REM sleep are important for pruning and strengthening new spines. Together, these findings indicate that REM sleep has multifaceted functions in brain development, learning and memory consolidation by selectively eliminating and maintaining newly formed synapses via dendritic calcium spike-dependent mechanisms.

Isl1 is required for multiple aspects of motor neuron development.

Science.gov (United States)

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L; Evans, Sylvia M; Sun, Yunfu

2011-07-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Developmental Connectivity and Molecular Phenotypes of Unique Cortical Projection Neurons that Express a Synapse-Associated Receptor Tyrosine Kinase.

Science.gov (United States)

Kast, Ryan J; Wu, Hsiao-Huei; Levitt, Pat

2017-11-28

The complex circuitry and cell-type diversity of the cerebral cortex are required for its high-level functions. The mechanisms underlying the diversification of cortical neurons during prenatal development have received substantial attention, but understanding of neuronal heterogeneity is more limited during later periods of cortical circuit maturation. To address this knowledge gap, connectivity analysis and molecular phenotyping of cortical neuron subtypes that express the developing synapse-enriched MET receptor tyrosine kinase were performed. Experiments used a MetGFP transgenic mouse line, combined with coexpression analysis of class-specific molecular markers and retrograde connectivity mapping. The results reveal that MET is expressed by a minor subset of subcerebral and a larger number of intratelencephalic projection neurons. Remarkably, MET is excluded from most layer 6 corticothalamic neurons. These findings are particularly relevant for understanding the maturation of discrete cortical circuits, given converging evidence that MET influences dendritic elaboration and glutamatergic synapse maturation. The data suggest that classically defined cortical projection classes can be further subdivided based on molecular characteristics that likely influence synaptic maturation and circuit wiring. Additionally, given that MET is classified as a high confidence autism risk gene, the data suggest that projection neuron subpopulations may be differentially vulnerable to disorder-associated genetic variation. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Presynaptic learning and memory with a persistent firing neuron and a habituating synapse: a model of short term persistent habituation.

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Ramanathan, Kiruthika; Ning, Ning; Dhanasekar, Dhiviya; Li, Guoqi; Shi, Luping; Vadakkepat, Prahlad

2012-08-01

Our paper explores the interaction of persistent firing axonal and presynaptic processes in the generation of short term memory for habituation. We first propose a model of a sensory neuron whose axon is able to switch between passive conduction and persistent firing states, thereby triggering short term retention to the stimulus. Then we propose a model of a habituating synapse and explore all nine of the behavioral characteristics of short term habituation in a two neuron circuit. We couple the persistent firing neuron to the habituation synapse and investigate the behavior of short term retention of habituating response. Simulations show that, depending on the amount of synaptic resources, persistent firing either results in continued habituation or maintains the response, both leading to longer recovery times. The effectiveness of the model as an element in a bio-inspired memory system is discussed.

What is happening to motor neuron disease in Nigeria? | Imam ...

African Journals Online (AJOL)

Background: Systematic studies of motor neuron disease were last reported from Ibadan, Nigeria, more than two decades ago. Since then, information about motor neuron disease has become limited making it necessary to review the current status of the disease. Methods: The clinical records of all cases of motor neuron ...

Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae.

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Sebastian Hückesfeld

Full Text Available Motor systems can be functionally organized into effector organs (muscles and glands, the motor neurons, central pattern generators (CPG and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium-imaging to monitor the neural activity of motor neurons within the central nervous system (CNS that drive food intake. Simultaneous nerve- and muscle-recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ. Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system.

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

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Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J; Brown, Robert H

2014-01-28

ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development.

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Matthew J Fogarty

Full Text Available Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E day 13 and birth (postnatal day 0. Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study. For respiratory-based motor neurons (hypoglossal and phrenic motor pools, we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic and muscle innervations (55% decrease. By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase and muscle innervations (99% increase; however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to

Motor neuron disease associated with carcinoma | Gritzman | South ...

African Journals Online (AJOL)

Paraneoplastic complications are obscure and difficult to understand. The association of motor neuron disease and carcinoma may sometimes be more than coincidental, and 2 cases are described. One patient had motor neuron disease, limbic encephalitis (a recognized paraneoplastic disorder) and carcinoma of the ...

[The mirror neuron system in motor and sensory rehabilitation].

Science.gov (United States)

Oouchida, Yutaka; Izumi, Shinichi

2014-06-01

The discovery of the mirror neuron system has dramatically changed the study of motor control in neuroscience. The mirror neuron system provides a conceptual framework covering the aspects of motor as well as sensory functions in motor control. Previous studies of motor control can be classified as studies of motor or sensory functions, and these two classes of studies appear to have advanced independently. In rehabilitation requiring motor learning, such as relearning movement after limb paresis, however, sensory information of feedback for motor output as well as motor command are essential. During rehabilitation from chronic pain, motor exercise is one of the most effective treatments for pain caused by dysfunction in the sensory system. In rehabilitation where total intervention unifying the motor and sensory aspects of motor control is important, learning through imitation, which is associated with the mirror neuron system can be effective and suitable. In this paper, we introduce the clinical applications of imitated movement in rehabilitation from motor impairment after brain damage and phantom limb pain after limb amputation.

Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons.

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Fallini, Claudia; Donlin-Asp, Paul G; Rouanet, Jeremy P; Bassell, Gary J; Rossoll, Wilfried

2016-03-30

Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels ofGAP43mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restoresGAP43mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA. The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays a key role in assembling RNA/protein complexes that are essential for mRNA splicing. It remains unclear whether defects in this well characterized housekeeping function cause the specific degeneration of spinal motor neurons observed in SMA. Here, we describe an additional role of SMN in regulating the axonal localization and local translation of the mRNA encoding growth-associated protein 43 (GAP43). This study supports a model whereby SMN deficiency impedes transport and local translation of mRNAs important for neurite outgrowth and stabilization

High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

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Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

2018-04-30

Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

Reinforcement learning of targeted movement in a spiking neuronal model of motor cortex.

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George L Chadderdon

Full Text Available Sensorimotor control has traditionally been considered from a control theory perspective, without relation to neurobiology. In contrast, here we utilized a spiking-neuron model of motor cortex and trained it to perform a simple movement task, which consisted of rotating a single-joint "forearm" to a target. Learning was based on a reinforcement mechanism analogous to that of the dopamine system. This provided a global reward or punishment signal in response to decreasing or increasing distance from hand to target, respectively. Output was partially driven by Poisson motor babbling, creating stochastic movements that could then be shaped by learning. The virtual forearm consisted of a single segment rotated around an elbow joint, controlled by flexor and extensor muscles. The model consisted of 144 excitatory and 64 inhibitory event-based neurons, each with AMPA, NMDA, and GABA synapses. Proprioceptive cell input to this model encoded the 2 muscle lengths. Plasticity was only enabled in feedforward connections between input and output excitatory units, using spike-timing-dependent eligibility traces for synaptic credit or blame assignment. Learning resulted from a global 3-valued signal: reward (+1, no learning (0, or punishment (-1, corresponding to phasic increases, lack of change, or phasic decreases of dopaminergic cell firing, respectively. Successful learning only occurred when both reward and punishment were enabled. In this case, 5 target angles were learned successfully within 180 s of simulation time, with a median error of 8 degrees. Motor babbling allowed exploratory learning, but decreased the stability of the learned behavior, since the hand continued moving after reaching the target. Our model demonstrated that a global reinforcement signal, coupled with eligibility traces for synaptic plasticity, can train a spiking sensorimotor network to perform goal-directed motor behavior.

Reinforcement learning of targeted movement in a spiking neuronal model of motor cortex.

Science.gov (United States)

Chadderdon, George L; Neymotin, Samuel A; Kerr, Cliff C; Lytton, William W

2012-01-01

Sensorimotor control has traditionally been considered from a control theory perspective, without relation to neurobiology. In contrast, here we utilized a spiking-neuron model of motor cortex and trained it to perform a simple movement task, which consisted of rotating a single-joint "forearm" to a target. Learning was based on a reinforcement mechanism analogous to that of the dopamine system. This provided a global reward or punishment signal in response to decreasing or increasing distance from hand to target, respectively. Output was partially driven by Poisson motor babbling, creating stochastic movements that could then be shaped by learning. The virtual forearm consisted of a single segment rotated around an elbow joint, controlled by flexor and extensor muscles. The model consisted of 144 excitatory and 64 inhibitory event-based neurons, each with AMPA, NMDA, and GABA synapses. Proprioceptive cell input to this model encoded the 2 muscle lengths. Plasticity was only enabled in feedforward connections between input and output excitatory units, using spike-timing-dependent eligibility traces for synaptic credit or blame assignment. Learning resulted from a global 3-valued signal: reward (+1), no learning (0), or punishment (-1), corresponding to phasic increases, lack of change, or phasic decreases of dopaminergic cell firing, respectively. Successful learning only occurred when both reward and punishment were enabled. In this case, 5 target angles were learned successfully within 180 s of simulation time, with a median error of 8 degrees. Motor babbling allowed exploratory learning, but decreased the stability of the learned behavior, since the hand continued moving after reaching the target. Our model demonstrated that a global reinforcement signal, coupled with eligibility traces for synaptic plasticity, can train a spiking sensorimotor network to perform goal-directed motor behavior.

Dynamic Information Encoding With Dynamic Synapses in Neural Adaptation

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Li, Luozheng; Mi, Yuanyuan; Zhang, Wenhao; Wang, Da-Hui; Wu, Si

2018-01-01

Adaptation refers to the general phenomenon that the neural system dynamically adjusts its response property according to the statistics of external inputs. In response to an invariant stimulation, neuronal firing rates first increase dramatically and then decrease gradually to a low level close to the background activity. This prompts a question: during the adaptation, how does the neural system encode the repeated stimulation with attenuated firing rates? It has been suggested that the neural system may employ a dynamical encoding strategy during the adaptation, the information of stimulus is mainly encoded by the strong independent spiking of neurons at the early stage of the adaptation; while the weak but synchronized activity of neurons encodes the stimulus information at the later stage of the adaptation. The previous study demonstrated that short-term facilitation (STF) of electrical synapses, which increases the synchronization between neurons, can provide a mechanism to realize dynamical encoding. In the present study, we further explore whether short-term plasticity (STP) of chemical synapses, an interaction form more common than electrical synapse in the cortex, can support dynamical encoding. We build a large-size network with chemical synapses between neurons. Notably, facilitation of chemical synapses only enhances pair-wise correlations between neurons mildly, but its effect on increasing synchronization of the network can be significant, and hence it can serve as a mechanism to convey the stimulus information. To read-out the stimulus information, we consider that a downstream neuron receives balanced excitatory and inhibitory inputs from the network, so that the downstream neuron only responds to synchronized firings of the network. Therefore, the response of the downstream neuron indicates the presence of the repeated stimulation. Overall, our study demonstrates that STP of chemical synapse can serve as a mechanism to realize dynamical neural

Optogenetically enhanced axon regeneration: motor versus sensory neuron-specific stimulation.

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Ward, Patricia J; Clanton, Scott L; English, Arthur W

2018-02-01

Brief neuronal activation in injured peripheral nerves is both necessary and sufficient to enhance motor axon regeneration, and this effect is specific to the activated motoneurons. It is less clear whether sensory neurons respond in a similar manner to neuronal activation following peripheral axotomy. Further, it is unknown to what extent enhancement of axon regeneration with increased neuronal activity relies on a reflexive interaction within the spinal circuitry. We used mouse genetics and optical tools to evaluate the precision and selectivity of system-specific neuronal activation to enhance axon regeneration in a mixed nerve. We evaluated sensory and motor axon regeneration in two different mouse models expressing the light-sensitive cation channel, channelrhodopsin (ChR2). We selectively activated either sensory or motor axons using light stimulation combined with transection and repair of the sciatic nerve. Regardless of genotype, the number of ChR2-positive neurons whose axons had regenerated successfully was greater following system-specific optical treatment, with no effect on the number of ChR2-negative neurons (whether motor or sensory neurons). We conclude that acute system-specific neuronal activation is sufficient to enhance both motor and sensory axon regeneration. This regeneration-enhancing effect is likely cell autonomous. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling.

Science.gov (United States)

Zhang, Zilai; Cao, Mou; Chang, Chia-Wei; Wang, Cindy; Shi, Xuanming; Zhan, Xiaoming; Birnbaum, Shari G; Bezprozvanny, Ilya; Huber, Kimberly M; Wu, Jiang I

2016-01-01

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Mirror neurons and motor intentionality.

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Rizzolatti, Giacomo; Sinigaglia, Corrado

2007-01-01

Our social life rests to a large extent on our ability to understand the intentions of others. What are the bases of this ability? A very influential view is that we understand the intentions of others because we are able to represent them as having mental states. Without this meta-representational (mind-reading) ability their behavior would be meaningless to us. Over the past few years this view has been challenged by neurophysiological findings and, in particular, by the discovery of mirror neurons. The functional properties of these neurons indicate that intentional understanding is based primarily on a mechanism that directly matches the sensory representation of the observed actions with one's own motor representation of those same actions. These findings reveal how deeply motor and intentional components of action are intertwined, suggesting that both can be fully comprehended only starting from a motor approach to intentionality.

Protective effect of parvalbumin on excitotoxic motor neuron death

DEFF Research Database (Denmark)

Van den Bosch, L.; Schwaller, B.; Vleminckx, V.

2002-01-01

Amyotrophic lateral sclerosis, ALS, AMPA receptor, calcium-binding proteins, calcium buffering, excitotoxity, kainic acid, motor neuron, parvalbumin......Amyotrophic lateral sclerosis, ALS, AMPA receptor, calcium-binding proteins, calcium buffering, excitotoxity, kainic acid, motor neuron, parvalbumin...

Organization of central synapses by adhesion molecules.

Science.gov (United States)

Tallafuss, Alexandra; Constable, John R L; Washbourne, Philip

2010-07-01

Synapses are the primary means for transmitting information from one neuron to the next. They are formed during the development of the nervous system, and the formation of appropriate synapses is crucial for the establishment of neuronal circuits that underlie behavior and cognition. Understanding how synapses form and are maintained will allow us to address developmental disorders such as autism, mental retardation and possibly also psychological disorders. A number of biochemical and proteomic studies have revealed a diverse and vast assortment of molecules that are present at the synapse. It is now important to untangle this large array of proteins and determine how it assembles into a functioning unit. Here we focus on recent reports describing how synaptic cell adhesion molecules interact with and organize the presynaptic and postsynaptic specializations of both excitatory and inhibitory central synapses. © The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons.

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Devinney, Michael J; Fields, Daryl P; Huxtable, Adrianne G; Peterson, Timothy J; Dale, Erica A; Mitchell, Gordon S

2015-05-27

Acute intermittent hypoxia (AIH) induces a form of spinal motor plasticity known as phrenic long-term facilitation (pLTF); pLTF is a prolonged increase in phrenic motor output after AIH has ended. In anesthetized rats, we demonstrate that pLTF requires activity of the novel PKC isoform, PKCθ, and that the relevant PKCθ is within phrenic motor neurons. Whereas spinal PKCθ inhibitors block pLTF, inhibitors targeting other PKC isoforms do not. PKCθ is highly expressed in phrenic motor neurons, and PKCθ knockdown with intrapleural siRNAs abolishes pLTF. Intrapleural siRNAs targeting PKCζ, an atypical PKC isoform expressed in phrenic motor neurons that underlies a distinct form of phrenic motor plasticity, does not affect pLTF. Thus, PKCθ plays a critical role in spinal AIH-induced respiratory motor plasticity, and the relevant PKCθ is localized within phrenic motor neurons. Intrapleural siRNA delivery has considerable potential as a therapeutic tool to selectively manipulate plasticity in vital respiratory motor neurons. Copyright © 2015 the authors 0270-6474/15/358107-11$15.00/0.

Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

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Brian J. Wainger

2014-04-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1, C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.

The spectrum of lower motor neuron syndromes : classification, natural course and treatment

NARCIS (Netherlands)

Berg-Vos, R.M. van den

2002-01-01

This thesis focusses on patients with lower motor neuron syndromes. This relatively rare group of syndromes is clinically not well described and the pathogenesis is largely unknown. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) or motor

Motor neuron, nerve, and neuromuscular junction disease.

Science.gov (United States)

Finsterer, Josef; Papić, Lea; Auer-Grumbach, Michaela

2011-10-01

The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.

Respiratory function after selective respiratory motor neuron death from intrapleural CTB–saporin injections

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Nichols, Nicole L.; Vinit, Stéphane; Bauernschmidt, Lorene; Mitchell, Gordon S.

2015-01-01

Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, paralysis and death by ventilatory failure. In rodent ALS models: 1) breathing capacity is preserved until late in disease progression despite major respiratory motor neuron death, suggesting unknown forms of compensatory respiratory plasticity; and 2) spinal microglia become activated in association with motor neuron cell death. Here, we report a novel experimental model to study the impact of respiratory motor neuron death on compensatory responses without many complications attendant to spontaneous motor neuron disease. In specific, we used intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB–SAP) to selectively kill motor neurons with access to the pleural space. Motor neuron survival, CD11b labeling (microglia), ventilatory capacity and phrenic motor output were assessed in rats 3–28 days after intrapleural injections of: 1) CTB–SAP (25 and 50 μg), or 2) unconjugated CTB and SAP (i.e. control; (CTB + SAP). CTB–SAP elicited dose-dependent phrenic and intercostal motor neuron death; 7 days post-25 μg CTB–SAP, motor neuron survival approximated that in end-stage ALS rats (phrenic: 36 ± 7%; intercostal: 56 ± 10% of controls; n = 9; p phrenic motor nucleus, indicating microglial activation; 2) decreased breathing during maximal chemoreceptor stimulation; and 3) diminished phrenic motor output in anesthetized rats (7 days post-25 μg, CTB–SAP: 0.3 ± 0.07 V; CTB + SAP: 1.5 ± 0.3; n = 9; p < 0.05). Intrapleural CTB–SAP represents a novel, inducible model of respiratory motor neuron death and provides an opportunity to study compensation for respiratory motor neuron loss. PMID:25476493

Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections.

Science.gov (United States)

Nichols, Nicole L; Vinit, Stéphane; Bauernschmidt, Lorene; Mitchell, Gordon S

2015-05-01

Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, paralysis and death by ventilatory failure. In rodent ALS models: 1) breathing capacity is preserved until late in disease progression despite major respiratory motor neuron death, suggesting unknown forms of compensatory respiratory plasticity; and 2) spinal microglia become activated in association with motor neuron cell death. Here, we report a novel experimental model to study the impact of respiratory motor neuron death on compensatory responses without many complications attendant to spontaneous motor neuron disease. In specific, we used intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) to selectively kill motor neurons with access to the pleural space. Motor neuron survival, CD11b labeling (microglia), ventilatory capacity and phrenic motor output were assessed in rats 3-28days after intrapleural injections of: 1) CTB-SAP (25 and 50μg), or 2) unconjugated CTB and SAP (i.e. control; (CTB+SAP). CTB-SAP elicited dose-dependent phrenic and intercostal motor neuron death; 7days post-25μg CTB-SAP, motor neuron survival approximated that in end-stage ALS rats (phrenic: 36±7%; intercostal: 56±10% of controls; n=9; pneuron death and provides an opportunity to study compensation for respiratory motor neuron loss. Copyright © 2014 Elsevier Inc. All rights reserved.

The Diversity of Cortical Inhibitory Synapses

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Yoshiyuki eKubota

2016-04-01

Full Text Available The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their IPSP size is not uniform. Thus cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit.

Localization of mineralocorticoid receptors at mammalian synapses.

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Eric M Prager

Full Text Available In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

Risk factors for motor neuron diseases : genes, environment and lifestyle

NARCIS (Netherlands)

Sutedja, N.A.

2010-01-01

The main focus of this thesis is to identify susceptibility factors in diseases affecting the motor neuron: both motor neuron disease (MND), in which primarily the cell body is affected, and multifocal motor neuropathy (MMN), in which primarily the axon is affected, are covered. Due to its

Neuronal mechanisms of motor learning and motor memory consolidation in healthy old adults

NARCIS (Netherlands)

Berghuis, K. M. M.; Veldman, M. P.; Solnik, S.; Koch, G.; Zijdewind, I.; Hortobagyi, T.

It is controversial whether or not old adults are capable of learning new motor skills and consolidate the performance gains into motor memory in the offline period. The underlying neuronal mechanisms are equally unclear. We determined the magnitude of motor learning and motor memory consolidation

Expression of diverse neuropeptide cotransmitters by identified motor neurons in Aplysia

International Nuclear Information System (INIS)

Church, P.J.; Lloyd, P.E.

1991-01-01

Neuropeptide synthesis was determined for individual identified ventral-cluster neurons in the buccal ganglia of Aplysia. Each of these cells was shown to be a motor neuron that innervates buccal muscles that generate biting and swallowing movements during feeding. Individual neurons were identified by a battery of physiological criteria and stained with intracellular injection of a vital dye, and the ganglia were incubated in 35S-methionine. Peptide synthesis was determined by measuring labeled peptides in extracts from individually dissected neuronal cell bodies analyzed by HPLC. Previously characterized peptides found to be synthesized included buccalin, FMRFamide, myomodulin, and the 2 small cardioactive peptides (SCPs). Each of these neuropeptides has been shown to modulate buccal muscle responses to motor neuron stimulation. Two other peptides were found to be synthesized in individual motor neurons. One peptide, which was consistently observed in neurons that also synthesized myomodulin, is likely to be the recently sequenced myomodulin B. The other peptide was observed in a subset of the neurons that synthesize FMRFamide. While identified motor neurons consistently synthesized the same peptide(s), neurons that innervate the same muscle often express different peptides. Neurons that synthesized the SCPs also contained SCP-like activity, as determined by snail heart bioassay. Our results indicate that every identified motor neuron synthesizes a subset of these methionine-containing peptides, and that several neurons consistently synthesize peptides that are likely to be processed from multiple precursors

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.

Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

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Marta Esteves da Silva

2015-11-01

Full Text Available Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to recruit kinesin (KIF1C or myosin (MyosinV/VI motors to Rab11-positive recycling endosomes, we controlled their trafficking and found that induced removal of recycling endosomes from spines decreases surface AMPAR expression and PSD-95 clusters at synapses. Our data suggest a mechanistic link between endosome positioning and postsynaptic structure and composition.

Neuronal mechanisms of motor learning and motor memory consolidation in healthy old adults.

Science.gov (United States)

Berghuis, K M M; Veldman, M P; Solnik, S; Koch, G; Zijdewind, I; Hortobágyi, T

2015-06-01

It is controversial whether or not old adults are capable of learning new motor skills and consolidate the performance gains into motor memory in the offline period. The underlying neuronal mechanisms are equally unclear. We determined the magnitude of motor learning and motor memory consolidation in healthy old adults and examined if specific metrics of neuronal excitability measured by magnetic brain stimulation mediate the practice and retention effects. Eleven healthy old adults practiced a wrist extension-flexion visuomotor skill for 20 min (MP, 71.3 years), while a second group only watched the templates without movements (attentional control, AC, n = 11, 70.5 years). There was 40 % motor learning in MP but none in AC (interaction, p learn a new motor skill and consolidate the learned skill into motor memory, processes that are most likely mediated by disinhibitory mechanisms. These results are relevant for the increasing number of old adults who need to learn and relearn movements during motor rehabilitation.

Reciprocal synapses between outer hair cells and their afferent terminals: evidence for a local neural network in the mammalian cochlea.

Science.gov (United States)

Thiers, Fabio A; Nadol, Joseph B; Liberman, M Charles

2008-12-01

Cochlear outer hair cells (OHCs) serve both as sensory receptors and biological motors. Their sensory function is poorly understood because their afferent innervation, the type-II spiral ganglion cell, has small unmyelinated axons and constitutes only 5% of the cochlear nerve. Reciprocal synapses between OHCs and their type-II terminals, consisting of paired afferent and efferent specialization, have been described in the primate cochlea. Here, we use serial and semi-serial-section transmission electron microscopy to quantify the nature and number of synaptic interactions in the OHC area of adult cats. Reciprocal synapses were found in all OHC rows and all cochlear frequency regions. They were more common among third-row OHCs and in the apical half of the cochlea, where 86% of synapses were reciprocal. The relative frequency of reciprocal synapses was unchanged following surgical transection of the olivocochlear bundle in one cat, confirming that reciprocal synapses were not formed by efferent fibers. In the normal ear, axo-dendritic synapses between olivocochlear terminals and type-II terminals and/or dendrites were as common as synapses between olivocochlear terminals and OHCs, especially in the first row, where, on average, almost 30 such synapses were seen in the region under a single OHC. The results suggest that a complex local neuronal circuitry in the OHC area, formed by the dendrites of type-II neurons and modulated by the olivocochlear system, may be a fundamental property of the mammalian cochlea, rather than a curiosity of the primate ear. This network may mediate local feedback control of, and bidirectional communication among, OHCs throughout the cochlear spiral.

IR wireless cluster synapses of HYDRA very large neural networks

Science.gov (United States)

Jannson, Tomasz; Forrester, Thomas

2008-04-01

RF/IR wireless (virtual) synapses are critical components of HYDRA (Hyper-Distributed Robotic Autonomy) neural networks, already discussed in two earlier papers. The HYDRA network has the potential to be very large, up to 10 11-neurons and 10 18-synapses, based on already established technologies (cellular RF telephony and IR-wireless LANs). It is organized into almost fully connected IR-wireless clusters. The HYDRA neurons and synapses are very flexible, simple, and low-cost. They can be modified into a broad variety of biologically-inspired brain-like computing capabilities. In this third paper, we focus on neural hardware in general, and on IR-wireless synapses in particular. Such synapses, based on LED/LD-connections, dominate the HYDRA neural cluster.

iPSC-derived Insights into Motor Neuron Disease and Inflammatory Neuropathies

NARCIS (Netherlands)

Härschnitz, O.

2017-01-01

The proper function of the motor circuit is essential for normal interaction as a human being with external cues. While the motor circuit consists of a variety of cell types, one of its core components is the motor neuron itself. Dysfunction of motor neurons is a hallmark of many neuromuscular

Sailing to and Docking at the Immune Synapse: Role of Tubulin Dynamics and Molecular Motors

Directory of Open Access Journals (Sweden)

Noa Beatriz Martín-Cófreces

2018-05-01

Full Text Available The different cytoskeleton systems and their connecting molecular motors move vesicles and intracellular organelles to shape cells. Polarized cells with specialized functions display an exquisite spatio-temporal regulation of both cytoskeletal and organelle arrangements that support their specific tasks. In particular, T cells rapidly change their shape and cellular function through the establishment of cell surface and intracellular polarity in response to a variety of cues. This review focuses on the contribution of the microtubule-based dynein/dynactin motor complex, the tubulin and actin cytoskeletons, and different organelles to the formation of the antigen-driven immune synapse.

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

Institute of Scientific and Technical Information of China (English)

Manoj Kumar Jaiswal

2017-01-01

Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenera-tive diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord.The clinical phenotype is characterized by loss of motor neurons (MNs), mus-cular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro"disease in dish"and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.

Science.gov (United States)

Jaiswal, Manoj Kumar

2017-05-01

Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro " disease in dish " and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

The challenges of dysphagia in treating motor neurone disease.

Science.gov (United States)

Vesey, Siobhan

2017-07-01

Motor neurone disease (MND) is a relatively rare degenerative disorder. Its impacts are manifested in progressive loss of motor function and often accompanied by wider non-motor changes. Swallowing and speech abilities are frequently severely impaired. Effective management of dysphagia (swallowing difficulty) symptoms and nutritional care requires a holistic multidisciplinary approach. Care must be patient focused, facilitate patient decision making, and support planning towards end of life care. This article discusses the challenges of providing effective nutritional care to people living with motor neurone disease who have dysphagia.

Motor neuron disease in blacks | Cosnett | South African Medical ...

African Journals Online (AJOL)

A series of 86 black, Indian and white patients with motor neuron disease were analysed retrospectively. Although the material does not allow statistically valid conclusions, there are sufficient cases among blacks to allow two prima facie observations in this population group: (i) motor neuron disease has an earlier age of ...

Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.

Science.gov (United States)

Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao

2015-11-20

Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord

DEFF Research Database (Denmark)

Kiehn, O; Kjaerulff, O; Tresch, M C

2000-01-01

Motor neurons are endowed with intrinsic and conditional membrane properties that may shape the final motor output. In the first half of this paper we present data on the contribution of I(h), a hyperpolarization-activated inward cation current, to phase-transition in motor neurons during rhythmic...... firing. Motor neurons were recorded intracellularly during locomotion induced with a mixture of N-methyl-D-aspartate (NMDA) and serotonin, after pharmacological blockade of I(h). I(h) was then replaced by using dynamic clamp, a computer program that allows artificial conductances to be inserted into real...... neurons. I(h) was simulated with biophysical parameters determined in voltage clamp experiments. The data showed that electronic replacement of the native I(h) caused a depolarization of the average membrane potential, a phase-advance of the locomotor drive potential, and increased motor neuron spiking...

Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

Directory of Open Access Journals (Sweden)

Carmen E Flores

2014-10-01

Full Text Available Inhibitory transmission through the neurotransmitter Ɣ-aminobutyric acid (GABA shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons.

Correlated conductance parameters in leech heart motor neurons contribute to motor pattern formation.

Science.gov (United States)

Lamb, Damon G; Calabrese, Ronald L

2013-01-01

Neurons can have widely differing intrinsic membrane properties, in particular the density of specific conductances, but how these contribute to characteristic neuronal activity or pattern formation is not well understood. To explore the relationship between conductances, and in particular how they influence the activity of motor neurons in the well characterized leech heartbeat system, we developed a new multi-compartmental Hodgkin-Huxley style leech heart motor neuron model. To do so, we evolved a population of model instances, which differed in the density of specific conductances, capable of achieving specific output activity targets given an associated input pattern. We then examined the sensitivity of measures of output activity to conductances and how the model instances responded to hyperpolarizing current injections. We found that the strengths of many conductances, including those with differing dynamics, had strong partial correlations and that these relationships appeared to be linked by their influence on heart motor neuron activity. Conductances that had positive correlations opposed one another and had the opposite effects on activity metrics when perturbed whereas conductances that had negative correlations could compensate for one another and had similar effects on activity metrics.

Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1.

Science.gov (United States)

Tachibana, Masaya; Shinohara, Mitsuru; Yamazaki, Yu; Liu, Chia-Chen; Rogers, Justin; Bu, Guojun; Kanekiyo, Takahisa

2016-03-01

Apolipoprotein E (apoE) plays a critical role in maintaining synaptic integrity by transporting cholesterol to neurons through the low-density lipoprotein receptor related protein-1 (LRP1). Bexarotene, a retinoid X receptor (RXR) agonist, has been reported to have potential beneficial effects on cognition by increasing brain apoE levels and lipidation. To investigate the effects of bexarotene on aging-related synapse loss and the contribution of neuronal LRP1 to the pathway, forebrain neuron-specific LRP1 knockout (nLrp1(-/-)) and littermate control mice were administered with bexarotene-formulated diet (100mg/kg/day) or control diet at the age of 20-24 months for 8 weeks. Upon bexarotene treatment, levels of brain apoE and ATP-binding cassette sub-family A member 1 (ABCA1) were significantly increased in both mice. While levels of PSD95, glutamate receptor 1 (GluR1), and N-methyl-d-aspartate receptor NR1 subunit (NR1), which are key postsynaptic proteins that regulate synaptic plasticity, were decreased with aging, they were restored by bexarotene treatment in the brains of control but not nLrp1(-/-) mice. These results indicate that the beneficial effects of bexarotene on synaptic integrity depend on the presence of neuronal LRP1. However, we also found that bexarotene treatment led to the activation of glial cells, weight loss and hepatomegaly, which are likely due to hepatic failure. Taken together, our results demonstrate that apoE-targeted treatment through the RXR pathway has a potential beneficial effect on synapses during aging; however, the therapeutic application of bexarotene requires extreme caution due to its toxic side effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiple neuropeptides in cholinergic motor neurons of Aplysia: evidence for modulation intrinsic to the motor circuit

International Nuclear Information System (INIS)

Cropper, E.C.; Lloyd, P.E.; Reed, W.; Tenenbaum, R.; Kupfermann, I.; Weiss, K.R.

1987-01-01

Changes in Aplysia biting responses during food arousal are partially mediated by the serotonergic metacerebral cells (MCCs). The MCCs potentiate contractions of a muscle utilized in biting, the accessory radula closer (ARCM), when contractions are elicited by stimulation of either of the two cholinergic motor neurons B15 or B16 that innervate the muscle. The authors have now shown that ARCM contractions may also be potentiated by peptide cotransmitters in the ARCM motor neurons. They found that motor neuron B15 contains small cardioactive peptides A and B (SCP/sub A/ and SCP/sub B/) i.e., whole B15 neurons were bioactive on the SCP-sensitive Helix heart, as were reverse-phase HPLC fractions of B15 neurons that eluted like synthetic SCP/sub A/ and SCP/sub B/. Furthermore, [ 35 S]methionine-labeled B15 peptides precisely coeluted with synthetic SCP/sub A/ and SCP/sub B/. SCP/sub B/-like immunoreactivity was associated with dense-core vesicles in the soma of B15 and in neuritic varicosities and terminals in the ARCM. B16 motor neurons did not contain SCP/sub A/ or SCP/sub B/ but contained an unidentified bioactive peptide. RP-HPLC of [ 35 S]methionine-labeled B16s resulted in one major peak of radioactivity that did not coelute with either SCP and which, when subject to Edman degradation, yielded [ 35 S]methionine in positions where there is no methionine in the SCPs. Exogenously applied B16 peptide potentiated ARCM contractions elicited by stimulation of B15 or B16 neurons. Thus, in this system there appear to be two types of modulation; one type arises from the MCCs and is extrinsic to the motor system, whereas the second type arises from the motor neurons themselves and hence is intrinsic

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

Science.gov (United States)

Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

2016-01-01

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

MicroRNA-128 governs neuronal excitability and motor behavior in mice

DEFF Research Database (Denmark)

Tan, Chan Lek; Plotkin, Joshua L.; Venø, Morten Trillingsgaard

2013-01-01

The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excita...

Spin switches for compact implementation of neuron and synapse

Energy Technology Data Exchange (ETDEWEB)

Quang Diep, Vinh, E-mail: vdiep@purdue.edu; Sutton, Brian; Datta, Supriyo [School of Electrical and Computer Engineering, Purdue University, West Lafayette, Indiana 47907 (United States); Behin-Aein, Behtash [GLOBALFOUNDRIES, Inc., Sunnyvale, California 94085 (United States)

2014-06-02

Nanomagnets driven by spin currents provide a natural implementation for a neuron and a synapse: currents allow convenient summation of multiple inputs, while the magnet provides the threshold function. The objective of this paper is to explore the possibility of a hardware neural network implementation using a spin switch (SS) as its basic building block. SS is a recently proposed device based on established technology with a transistor-like gain and input-output isolation. This allows neural networks to be constructed with purely passive interconnections without intervening clocks or amplifiers. The weights for the neural network are conveniently adjusted through analog voltages that can be stored in a non-volatile manner in an underlying CMOS layer using a floating gate low dropout voltage regulator. The operation of a multi-layer SS neural network designed for character recognition is demonstrated using a standard simulation model based on coupled Landau-Lifshitz-Gilbert equations, one for each magnet in the network.

Spin switches for compact implementation of neuron and synapse

International Nuclear Information System (INIS)

Quang Diep, Vinh; Sutton, Brian; Datta, Supriyo; Behin-Aein, Behtash

2014-01-01

Nanomagnets driven by spin currents provide a natural implementation for a neuron and a synapse: currents allow convenient summation of multiple inputs, while the magnet provides the threshold function. The objective of this paper is to explore the possibility of a hardware neural network implementation using a spin switch (SS) as its basic building block. SS is a recently proposed device based on established technology with a transistor-like gain and input-output isolation. This allows neural networks to be constructed with purely passive interconnections without intervening clocks or amplifiers. The weights for the neural network are conveniently adjusted through analog voltages that can be stored in a non-volatile manner in an underlying CMOS layer using a floating gate low dropout voltage regulator. The operation of a multi-layer SS neural network designed for character recognition is demonstrated using a standard simulation model based on coupled Landau-Lifshitz-Gilbert equations, one for each magnet in the network

Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice.

Science.gov (United States)

Kosuge, Yasuhiro; Miyagishi, Hiroko; Yoneoka, Yuki; Yoneda, Keiko; Nango, Hiroshi; Ishige, Kumiko; Ito, Yoshihisa

2017-07-04

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice. Copyright © 2017 Elsevier Ltd. All rights

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

Science.gov (United States)

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.

The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses

Science.gov (United States)

Garcia, Rolando A. G.; Vasudevan, Kuzhalini; Buonanno, Andres

2000-01-01

Neuregulins regulate the expression of ligand- and voltage-gated channels in neurons and skeletal muscle by the activation of their cognate tyrosine kinase receptors, ErbB 1–4. The subcellular distribution and mechanisms that regulate the localization of ErbB receptors are unknown. We have found that ErbB receptors are present in brain subcellular fractions enriched for postsynaptic densities (PSD). The ErbB-4 receptor is unique among the ErbB proteins because its C-terminal tail (T-V-V) conforms to a sequence that binds to a protein motif known as the PDZ domain. Using the yeast two-hybrid system, we found that the C-terminal region of ErbB-4 interacts with the three related membrane-associated guanylate kinases (MAGUKs) PSD-95/SAP90, PSD-93/chapsyn-110, and SAP 102, which harbor three PDZ domains, as well as with β2-syntrophin, which has a single PDZ domain. As with N-methyl-d-aspartate (NMDA) receptors, ErbB4 interacts with the first two PDZ domains of PSD-95. Using coimmunoprecipitation assays, we confirmed the direct interactions between ErbB-4 and PSD-95 in transfected heterologous cells, as well as in vivo, where both proteins are coimmunoprecipitated from brain lysates. Moreover, evidence for colocalization of these proteins was also observed by immunofluorescence in cultured hippocampal neurons. ErbB-4 colocalizes with PSD-95 and NMDA receptors at a subset of excitatory synapses apposed to synaptophysin-positive presynaptic terminals. The capacity of ErbB receptors to interact with PDZ-domain proteins at cell junctions is conserved from invertebrates to mammals. As discussed, the interactions found between receptor tyrosine kinases and MAGUKs at neuronal synapses may have important implications for activity-dependent plasticity. PMID:10725395

Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy.

Science.gov (United States)

Konagaya, M; Sakai, M; Matsuoka, Y; Konagaya, Y; Hashizume, Y

1998-11-01

The autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. He showed slowly progressive spasticity, pseudobulbar palsy and character change, and died 32 months after the onset of symptoms. Autopsy revealed severe atrophy of the frontal and temporal lobes, remarkable neuronal loss and gliosis in the precentral gyrus, left temporal lobe pole and amygdala, mild degeneration of the Ammon's horn, degeneration of the corticospinal tract, and very mild involvement of the lower motor neurons. The anterior horn cells only occasionally demonstrated Bunina body by cystatin-C staining, and skein-like inclusions by ubiquitin staining. This is a peculiar case with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease predominantly affecting the upper motor neuron.

How do glial cells contribute to motor control?

DEFF Research Database (Denmark)

Christensen, Rasmus Kordt; Petersen, Anders Victor; Perrier, Jean-Francois Marie

2013-01-01

that glia play an active role in several physiological functions. The discovery that a bidirectional communication takes place between astrocytes (the star shaped glial cell of the brain) and neurons, was a major breakthrough in the field of synaptic physiology. Astrocytes express receptors that get...... activated by neurotransmitters during synaptic transmission. In turn they release other transmitters - called gliotransmitters - that bind to neuronal receptors and modulate synaptic transmission. This feedback, which led to the concept of the tripartite synapse, has been reported with various transmitters...... including glutamate, ATP, GABA or serine. In the present review we will focus on astrocytes and review the evidence suggesting and demonstrating their role in motor control. Rhythmic motor behaviors such as locomotion, swimming or chewing are generated by networks of neurons termed central pattern...

Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

Science.gov (United States)

Genç, Barış; Lagrimas, Amiko Krisa Bunag; Kuru, Pınar; Hess, Robert; Tu, Michael William; Menichella, Daniela Maria; Miller, Richard J; Paller, Amy S; Özdinler, P Hande

2015-01-01

Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

The chemical component of the mixed GF-TTMn synapse in Drosophila melanogaster uses acetylcholine as its neurotransmitter.

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Allen, Marcus J; Murphey, R K

2007-07-01

The largest central synapse in adult Drosophila is a mixed electro-chemical synapse whose gap junctions require the product of the shaking-B (shak-B) gene. Shak-B(2) mutant flies lack gap junctions at this synapse, which is between the giant fibre (GF) and the tergotrochanteral motor neuron (TTMn), but it still exhibits a long latency response upon GF stimulation. We have targeted the expression of the light chain of tetanus toxin to the GF, to block chemical transmission, in shak-B(2) flies. The long latency response in the tergotrochanteral muscle (TTM) was abolished indicating that the chemical component of the synapse mediates this response. Attenuation of GAL4-mediated labelling by a cha-GAL80 transgene, reveals the GF to be cholinergic. We have used a temperature-sensitive allele of the choline acetyltransferase gene (cha(ts2)) to block cholinergic synapses in adult flies and this also abolished the long latency response in shak-B(2) flies. Taken together the data provide evidence that both components of this mixed synapse are functional and that the chemical neurotransmitter between the GF and the TTMn is acetylcholine. Our findings show that the two components of this synapse can be separated to allow further studies into the mechanisms by which mixed synapses are built and function.

On the Universality and Non-Universality of Spiking Neural P Systems With Rules on Synapses.

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Song, Tao; Xu, Jinbang; Pan, Linqiang

2015-12-01

Spiking neural P systems with rules on synapses are a new variant of spiking neural P systems. In the systems, the neuron contains only spikes, while the spiking/forgetting rules are moved on the synapses. It was obtained that such system with 30 neurons (using extended spiking rules) or with 39 neurons (using standard spiking rules) is Turing universal. In this work, this number is improved to 6. Specifically, we construct a Turing universal spiking neural P system with rules on synapses having 6 neurons, which can generate any set of Turing computable natural numbers. As well, it is obtained that spiking neural P system with rules on synapses having less than two neurons are not Turing universal: i) such systems having one neuron can characterize the family of finite sets of natural numbers; ii) the family of sets of numbers generated by the systems having two neurons is included in the family of semi-linear sets of natural numbers.

In search for a gold-standard procedure to count motor neurons in the spinal cord.

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Ferrucci, Michela; Lazzeri, Gloria; Flaibani, Marina; Biagioni, Francesca; Cantini, Federica; Madonna, Michele; Bucci, Domenico; Limanaqi, Fiona; Soldani, Paola; Fornai, Francesco

2018-03-14

Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol. A special emphasis is placed on discussing automated stereology. When automated stereology does not take into account site-specificity and does not distinguish between heterogeneous neuronal populations, it may confound data making such a procedure a sort of "guide for the perplex". Thus, if on the one hand automated stereology improves our ability to quantify neuronal populations, it may also hide false positives/negatives in neuronal counts. For instance, classic staining for antigens such as SMI-32, SMN and ChAT, which are routinely considered to be specific for motor neurons, may also occur in other neuronal types of the spinal cord. Even site specificity within Lamina IX may be misleading due to neuronal populations having a size and shape typical of motor neurons. This is the case of spinal border cells, which often surpass the border of Lamina VII and intermingle with motor neurons of Lamina IX. The present article discusses the need to join automated stereology with a dedicated knowledge of each specific neuroanatomical setting.

LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding

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Ji Won Um

2016-02-01

Full Text Available The four members of the LRRTM family (LRRTM1-4 are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

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Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

2013-01-01

SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

IGF-1: elixir for motor neuron diseases.

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Papanikolaou, Theodora; Ellerby, Lisa M

2009-08-13

Modulation of testosterone levels is a therapeutic approach for spinal and bulbar muscular atrophy (SBMA), a polyglutamine disorder that affects the motor neurons. The article by Palazzolo et al. in this issue of Neuron provides compelling evidence that the expression of insulin growth hormone is a potential therapeutic for SBMA.

Cell Biology of Astrocyte-Synapse Interactions.

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Allen, Nicola J; Eroglu, Cagla

2017-11-01

Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development. Copyright © 2017 Elsevier Inc. All rights reserved.

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

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Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

2013-11-20

A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury

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Westerdahl Ann-Charlotte

2010-06-01

Full Text Available Abstract Background Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity. Results Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability. Conclusions This analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper

Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury.

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Ryge, Jesper; Winther, Ole; Wienecke, Jacob; Sandelin, Albin; Westerdahl, Ann-Charlotte; Hultborn, Hans; Kiehn, Ole

2010-06-09

Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity. Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability. This analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper-excitability, the manipulation of which potentially could be

An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

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Xinglong Gu

2016-01-01

Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

Diversity of layer 5 projection neurons in the mouse motor cortex

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Oswald, Manfred J.; Tantirigama, Malinda L. S.; Sonntag, Ivo; Hughes, Stephanie M.; Empson, Ruth M.

2013-01-01

In the primary motor cortex (M1), layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labeled M1 corticospinal (CSp), corticothalamic (CTh), and commissural projecting corticostriatal (CStr) and corticocortical (CC) neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP) waveform, firing behavior, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behavior in corticofugal neurons. At 26°C CTh neurons fired bursts of APs more often than CSp neurons, but at 36°C both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function. PMID:24137110

Diversity of Layer 5 Projection Neurons in the Mouse Motor Cortex

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Manfred J Oswald

2013-10-01

Full Text Available In the primary motor cortex (M1, layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labelled M1 corticospinal (CSp, corticothalamic (CTh, and commissural projecting corticostriatal (CStr and corticocortical (CC neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP waveform, firing behaviour, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behaviour in corticofugal neurons. At 26 ºC CTh neurons fired bursts of APs more often than CSp neurons, but at 36 ºC both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function.

Target tissue influences on cholinergic development of parasympathetic motor neurons

International Nuclear Information System (INIS)

Tuttle, J.B.; Pilar, G.

1986-01-01

The normal function of neurons in the nervous system depends upon the orderly formation and maintenance of appropriate connections with other neurons and with non-neural target tissues. Having formed an appropriate synapse, the authors attempt to find how the interaction influences the subsequent program of neuronal differentiation and survival. The studies were made on neurons from the avian ciliary ganglion and their terminals in the iris. Concomitantly in time with the shift from an embryonic, fatiguable junction to the mature, more secure transmission, there is a large change in the capacity for ACh synthesis measured using radiolableled substrate. Only at this point in development does one detect and increase in the amount of tritium-ACh synthesized from tritium-choline in response to a pre-conditioning depolarization. The studies of development in vivo have provided a description of the steps taking place during maturation of a neuromuscular junction

Motor Axonal Regeneration After Partial and Complete Spinal Cord Transection

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Lu, Paul; Blesch, Armin; Graham, Lori; Wang, Yaozhi; Samara, Ramsey; Banos, Karla; Haringer, Verena; Havton, Leif; Weishaupt, Nina; Bennett, David; Fouad, Karim; Tuszynski, Mark H.

2012-01-01

We subjected rats to either partial mid-cervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor (BDNF) gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared to several control groups. Combinatorial treatment generated motor axon regeneration beyond both C5 hemisection and complete transection sites. Yet despite formation of synapses with neurons below the lesion, motor outcomes worsened after partial cervical lesions and spasticity worsened after complete transection. These findings highlight the complexity of spinal cord repair, and the need for additional control and shaping of axonal regeneration. PMID:22699902

A chemical-genetic strategy reveals distinct temporal requirements for SAD-1 kinase in neuronal polarization and synapse formation

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Shokat Kevan M

2008-09-01

Full Text Available Abstract Background Neurons assemble into a functional network through a sequence of developmental processes including neuronal polarization and synapse formation. In Caenorhabditis elegans, the serine/threonine SAD-1 kinase is essential for proper neuronal polarity and synaptic organization. To determine if SAD-1 activity regulates the establishment or maintenance of these neuronal structures, we examined its temporal requirements using a chemical-genetic method that allows for selective and reversible inactivation of its kinase activity in vivo. Results We generated a PP1 analog-sensitive variant of SAD-1. Through temporal inhibition of SAD-1 kinase activity we show that its activity is required for the establishment of both neuronal polarity and synaptic organization. However, while SAD-1 activity is needed strictly when neurons are polarizing, the temporal requirement for SAD-1 is less stringent in synaptic organization, which can also be re-established during maintenance. Conclusion This study reports the first temporal analysis of a neural kinase activity using the chemical-genetic system. It reveals that neuronal polarity and synaptic organization have distinct temporal requirements for SAD-1.

Assessment of the upper motor neuron in amyotrophic lateral sclerosis.

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Huynh, William; Simon, Neil G; Grosskreutz, Julian; Turner, Martin R; Vucic, Steve; Kiernan, Matthew C

2016-07-01

Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

In Vivo Neuromechanics: Decoding Causal Motor Neuron Behavior with Resulting Musculoskeletal Function.

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Sartori, Massimo; Yavuz, Utku Ş; Farina, Dario

2017-10-18

Human motor function emerges from the interaction between the neuromuscular and the musculoskeletal systems. Despite the knowledge of the mechanisms underlying neural and mechanical functions, there is no relevant understanding of the neuro-mechanical interplay in the neuro-musculo-skeletal system. This currently represents the major challenge to the understanding of human movement. We address this challenge by proposing a paradigm for investigating spinal motor neuron contribution to skeletal joint mechanical function in the intact human in vivo. We employ multi-muscle spatial sampling and deconvolution of high-density fiber electrical activity to decode accurate α-motor neuron discharges across five lumbosacral segments in the human spinal cord. We use complete α-motor neuron discharge series to drive forward subject-specific models of the musculoskeletal system in open-loop with no corrective feedback. We perform validation tests where mechanical moments are estimated with no knowledge of reference data over unseen conditions. This enables accurate blinded estimation of ankle function purely from motor neuron information. Remarkably, this enables observing causal associations between spinal motor neuron activity and joint moment control. We provide a new class of neural data-driven musculoskeletal modeling formulations for bridging between movement neural and mechanical levels in vivo with implications for understanding motor physiology, pathology, and recovery.

Advances in synapse formation: forging connections in the worm.

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Cherra, Salvatore J; Jin, Yishi

2015-01-01

Synapse formation is the quintessential process by which neurons form specific connections with their targets to enable the development of functional circuits. Over the past few decades, intense research efforts have identified thousands of proteins that localize to the pre- and postsynaptic compartments. Genetic dissection has provided important insights into the nexus of the molecular and cellular network, and has greatly advanced our knowledge about how synapses form and function physiologically. Moreover, recent studies have highlighted the complex regulation of synapse formation with the identification of novel mechanisms involving cell interactions from non-neuronal sources. In this review, we cover the conserved pathways required for synaptogenesis and place specific focus on new themes of synapse modulation arising from studies in Caenorhabditis elegans. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article. © 2014 Wiley Periodicals, Inc.

Magnetic resonance imaging applied to motor neuron disease

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Markarian, Maria F.; Villarroal, Gonzalo M.; Giavitto, Enrique; Nagel, Jorge

2005-01-01

Objective: Differentiate Motor Neuron Disease by MRI. Material and Methods: 10 patients were studied, 7 patients had a diagnosis of definite ALS by the El Escorial criteria, 2 patients had lower motor neuron signs (LMN) and hyperreflexia and one patient had LMN signs without pain. MRI was performed: slices brain: Sagittal T1-weighted, sagittal and axial FSE T2, axial and coronal FLAIR, diffusion, singlevoxel spectroscopy in protuberances. Functional MRI with motor test; slices in cervical spine: Sagittal T1-weighted, sagittal and axial FSE T2, sagittal FSIR. Results: The 7 patients with definite ALS by El Escorial criteria and 2 patients with LMN signs and hyperreflexia: hyperintensity signal in FSE T2 and FLAIR extending from the motor cortex down to the corona radiate, posterior limb of internal capsules, cerebral peduncles and protuberance base; FSE T2: hypointensity sign in motor cortex; elevation in diffusivity and hyperintensity signal in ADC in posterior limb of internal capsule; reduction of NAA, high levels of Glutamine-Glutamate and of Colina. One of these 9 patients showed disc hernia in C4-5, and other patient in C3-C4, C4-C5 without cord lesion. The patient with LMN signs without pain showed normal brain and disc hernia C5-C6, hypertrophy yellow ligament, anterior-posterior diminution of medullar canal, hyperintensity signal in spine cord in the same level in sagittal FSIR. fMRI: increase signal in contralateral, ipsilateral motor area, and areas involved in initiation and planning movement. Conclusion: MRI allow differentiation between ALS and myelopathy cervical spondylitis and others motor neuron disease. (author) [es

Shaping Synapses by the Neural Extracellular Matrix

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Maura Ferrer-Ferrer

2018-05-01

Full Text Available Accumulating data support the importance of interactions between pre- and postsynaptic neuronal elements with astroglial processes and extracellular matrix (ECM for formation and plasticity of chemical synapses, and thus validate the concept of a tetrapartite synapse. Here we outline the major mechanisms driving: (i synaptogenesis by secreted extracellular scaffolding molecules, like thrombospondins (TSPs, neuronal pentraxins (NPs and cerebellins, which respectively promote presynaptic, postsynaptic differentiation or both; (ii maturation of synapses via reelin and integrin ligands-mediated signaling; and (iii regulation of synaptic plasticity by ECM-dependent control of induction and consolidation of new synaptic configurations. Particularly, we focused on potential importance of activity-dependent concerted activation of multiple extracellular proteases, such as ADAMTS4/5/15, MMP9 and neurotrypsin, for permissive and instructive events in synaptic remodeling through localized degradation of perisynaptic ECM and generation of proteolytic fragments as inducers of synaptic plasticity.

Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

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Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

2013-01-01

Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

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Christian M. Simon

2017-12-01

Full Text Available The hallmark of spinal muscular atrophy (SMA, an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.

The space where aging acts: focus on the GABAergic synapse.

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Rozycka, Aleksandra; Liguz-Lecznar, Monika

2017-08-01

As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.

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Nichols, Nicole L; Craig, Taylor A; Tanner, Miles A

2017-08-16

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1 G93A ), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1 G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28days following bilateral intrapleural injections of: 1) CTB-SAP (25μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162±18%, n=8 vs. 63±3%; n=8; pSAP: 64±10%, n=10 vs. 60±13; n=8; p>0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases.

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Günther, René; Richter, Nicole; Sauerbier, Anna; Chaudhuri, Kallol Ray; Martinez-Martin, Pablo; Storch, Alexander; Hermann, Andreas

2016-01-01

The recently postulated "disease spreading hypothesis" has gained much attention, especially for Parkinson's disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated "disease spreading hypothesis." The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

miRNA-431 Prevents Amyloid-β-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1.

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Ross, Sean P; Baker, Kelly E; Fisher, Amanda; Hoff, Lee; Pak, Elena S; Murashov, Alexander K

2018-01-01

Synapse loss is well regarded as the underlying cause for the progressive decline of memory function over the course of Alzheimer's disease (AD) development. Recent observations suggest that the accumulation of the Wnt antagonist Dickkopf-1 (Dkk1) in the AD brain plays a critical role in triggering synaptic degeneration. Mechanistically, Dkk1 cooperates with Kremen1 (Krm1), its transmembrane receptor, to block the Wnt/β-catenin signaling pathway. Here, we show that silencing Krm1 with miR-431 prevents amyloid-β-mediated synapse loss in cortico-hippocampal cultures isolated from triple transgenic 3xTg-AD mice. Exposure to AβDDL (an amyloid-β derived diffusive ligand) or Dkk1 reduced the number of pre- and post-synaptic puncta in primary neuronal cultures, while treatment with miR-431 prevented synapse loss. In addition, treatment with miR-431 also prevented neurite degeneration. Our findings demonstrate that miR-431 protects synapses and neurites from Aβ-toxicity in an AD cell culture model and may be a promising therapeutic target.

Changes in rat hippocampal CA1 synapses following imipramine treatment

DEFF Research Database (Denmark)

Chen, Fenghua; Madsen, Torsten M; Wegener, Gregers

2008-01-01

Neuronal plasticity in hippocampus is hypothesized to play an important role in both the pathophysiology of depressive disorders and the treatment. In this study, we investigated the consequences of imipramine treatment on neuroplasticity (including neurogenesis, synaptogenesis, and remodelling...... and number of neurons of hippocampal subregions following imipramine treatment were found. However, the number and percentage of CA1 asymmetric spine synapses increased significantly and, conversely, the percentage of asymmetric shaft synapses significantly decreased in the imipramine treated group. Our...

Neuron activity in rat hippocampus and motor cortex during discrimination reversal.

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Disterhoft, J F; Segal, M

1978-01-01

Chronic unit activity and gross movement were recorded from rats during two discrimination reversals in a classical appetitive conditioning situation. The anticipatory movement decreased in response to the former CS+ tone and increased to the previous CS- tone after each reversal. Hippocampus and motor cortex were differently related to these two kinds of behavioral change. Response rates of hippocampal neurons were more closely related to the increased movement response to the former CS- which now signaled food. Motor cortex neuron responses were more closely correlated with the decrease in movement responses to the former CS+ which became neutral after the reversal. It appeared that hippocampal neurons could have been involved in one cognitive aspect of the situation, motor cortex neurons in another. The data were related to current functional concepts of these brain regions.

Transplantation of Xenopus laevis tissues to determine the ability of motor neurons to acquire a novel target.

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Karen L Elliott

Full Text Available The evolutionary origin of novelties is a central problem in biology. At a cellular level this requires, for example, molecularly resolving how brainstem motor neurons change their innervation target from muscle fibers (branchial motor neurons to neural crest-derived ganglia (visceral motor neurons or ear-derived hair cells (inner ear and lateral line efferent neurons. Transplantation of various tissues into the path of motor neuron axons could determine the ability of any motor neuron to innervate a novel target. Several tissues that receive direct, indirect, or no motor innervation were transplanted into the path of different motor neuron populations in Xenopus laevis embryos. Ears, somites, hearts, and lungs were transplanted to the orbit, replacing the eye. Jaw and eye muscle were transplanted to the trunk, replacing a somite. Applications of lipophilic dyes and immunohistochemistry to reveal motor neuron axon terminals were used. The ear, but not somite-derived muscle, heart, or liver, received motor neuron axons via the oculomotor or trochlear nerves. Somite-derived muscle tissue was innervated, likely by the hypoglossal nerve, when replacing the ear. In contrast to our previous report on ear innervation by spinal motor neurons, none of the tissues (eye or jaw muscle was innervated when transplanted to the trunk. Taken together, these results suggest that there is some plasticity inherent to motor innervation, but not every motor neuron can become an efferent to any target that normally receives motor input. The only tissue among our samples that can be innervated by all motor neurons tested is the ear. We suggest some possible, testable molecular suggestions for this apparent uniqueness.

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

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Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

2017-06-01

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

The human motor neuron pools receive a dominant slow‐varying common synaptic input

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Negro, Francesco; Yavuz, Utku Şükrü

2016-01-01

Key points Motor neurons in a pool receive both common and independent synaptic inputs, although the proportion and role of their common synaptic input is debated.Classic correlation techniques between motor unit spike trains do not measure the absolute proportion of common input and have limitations as a result of the non‐linearity of motor neurons.We propose a method that for the first time allows an accurate quantification of the absolute proportion of low frequency common synaptic input (60%) of common input, irrespective of their different functional and control properties.These results increase our knowledge about the role of common and independent input to motor neurons in force control. Abstract Motor neurons receive both common and independent synaptic inputs. This observation is classically based on the presence of a significant correlation between pairs of motor unit spike trains. The functional significance of different relative proportions of common input across muscles, individuals and conditions is still debated. One of the limitations in our understanding of correlated input to motor neurons is that it has not been possible so far to quantify the absolute proportion of common input with respect to the total synaptic input received by the motor neurons. Indeed, correlation measures of pairs of output spike trains only allow for relative comparisons. In the present study, we report for the first time an approach for measuring the proportion of common input in the low frequency bandwidth (60%) proportion of common low frequency oscillations with respect to their total synaptic input. These results suggest that the central nervous system provides a large amount of common input to motor neuron pools, in a similar way to that for muscles with different functional and control properties. PMID:27151459

Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans

International Nuclear Information System (INIS)

Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong

2015-01-01

Graphical abstract: - Highlights: • We investigated in vivo neurotoxicity of CdTe QDs on RMEs motor neurons in C. elegans. • CdTe QDs in the range of μg/L caused neurotoxicity on RMEs motor neurons. • Bioavailability of CdTe QDs may be the primary inducer for CdTe QDs neurotoxicity. • Both oxidative stress and cell identity regulate the CdTe QDs neurotoxicity. • CdTe QDs were translocated and deposited into RMEs motor neurons. - Abstract: We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1–1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd 2+ . Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals

New players tip the scales in the balance between excitatory and inhibitory synapses

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El-Husseini Alaa

2005-03-01

Full Text Available Abstract Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

Mechanisms of input and output synaptic specificity: finding partners, building synapses, and fine-tuning communication.

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Rawson, Randi L; Martin, E Anne; Williams, Megan E

2017-08-01

For most neurons to function properly, they need to develop synaptic specificity. This requires finding specific partner neurons, building the correct types of synapses, and fine-tuning these synapses in response to neural activity. Synaptic specificity is common at both a neuron's input and output synapses, whereby unique synapses are built depending on the partnering neuron. Neuroscientists have long appreciated the remarkable specificity of neural circuits but identifying molecular mechanisms mediating synaptic specificity has only recently accelerated. Here, we focus on recent progress in understanding input and output synaptic specificity in the mammalian brain. We review newly identified circuit examples for both and the latest research identifying molecular mediators including Kirrel3, FGFs, and DGLα. Lastly, we expect the pace of research on input and output specificity to continue to accelerate with the advent of new technologies in genomics, microscopy, and proteomics. Copyright © 2017 Elsevier Ltd. All rights reserved.

EMG analysis in 78 cases with motor neuron disease

Institute of Scientific and Technical Information of China (English)

Zhang Qiubin

2000-01-01

This paper analysed the FMGs of 78 cases with the motor neuron disease(MND). The EMG of all patients showed following characteristics that the average duration of wave prolonged, the average voltage increased and it was found that fibrillation and fasciculatton potentials appeared spontaneously. The fibrillation potential of ENG waa related to course of disease. In the patients whose course of disease was short, the fibri llation potential increased obviously, while in the cases of chronic MND, It usually decreased. The motor nerve conduction velocity of most pa tients (41%) reduced, however, the sensory nerve conduction velocity was normal but two. We reviewed some references about EMG of the motor neuron disease and discussed their characteristics and mechanism

Synaptic heterogeneity and stimulus-induced modulation of depression in central synapses.

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Hunter, J D; Milton, J G

2001-08-01

Short-term plasticity is a pervasive feature of synapses. Synapses exhibit many forms of plasticity operating over a range of time scales. We develop an optimization method that allows rapid characterization of synapses with multiple time scales of facilitation and depression. Investigation of paired neurons that are postsynaptic to the same identified interneuron in the buccal ganglion of Aplysia reveals that the responses of the two neurons differ in the magnitude of synaptic depression. Also, for single neurons, prolonged stimulation of the presynaptic neuron causes stimulus-induced increases in the early phase of synaptic depression. These observations can be described by a model that incorporates two availability factors, e.g., depletable vesicle pools or desensitizing receptor populations, with different time courses of recovery, and a single facilitation component. This model accurately predicts the responses to novel stimuli. The source of synaptic heterogeneity is identified with variations in the relative sizes of the two availability factors, and the stimulus-induced decrement in the early synaptic response is explained by a slowing of the recovery rate of one of the availability factors. The synaptic heterogeneity and stimulus-induced modifications in synaptic depression observed here emphasize that synaptic efficacy depends on both the individual properties of synapses and their past history.

eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

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Yasvoina, Marina V.

Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

Direct conversion of human pluripotent stem cells into cranial motor neurons using a piggyBac vector

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Riccardo De Santis

2018-05-01

Full Text Available Human pluripotent stem cells (PSCs are widely used for in vitro disease modeling. One of the challenges in the field is represented by the ability of converting human PSCs into specific disease-relevant cell types. The nervous system is composed of a wide variety of neuronal types with selective vulnerability in neurodegenerative diseases. This is particularly relevant for motor neuron diseases, in which different motor neurons populations show a different susceptibility to degeneration. Here we developed a fast and efficient method to convert human induced Pluripotent Stem Cells into cranial motor neurons of the branchiomotor and visceral motor subtype. These populations represent the motor neuron subgroup that is primarily affected by a severe form of amyotrophic lateral sclerosis with bulbar onset and worst prognosis. This goal was achieved by stable integration of an inducible vector, based on the piggyBac transposon, allowing controlled activation of Ngn2, Isl1 and Phox2a (NIP. The NIP module effectively produced electrophysiologically active cranial motor neurons. Our method can be easily extended to PSCs carrying disease-associated mutations, thus providing a useful tool to shed light on the cellular and molecular bases of selective motor neuron vulnerability in pathological conditions. Keywords: Spinal motor neuron, Cranial motor neuron, Induced pluripotent stem cells, Amyotrophic lateral sclerosis, Phox2a, piggyBac

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

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Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

2017-07-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

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Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

2016-01-01

Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons

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Dupuis, Luc; Gonzalez de Aguilar, Jose-Luis; Echaniz-Laguna, Andoni; Eschbach, Judith; Rene, Frédérique; Oudart, Hugues; Halter, Benoit; Huze, Caroline; Schaeffer, Laurent; Bouillaud, Frédéric; Loeffler, Jean-Philippe

2009-01-01

Background Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS. Methodology/Principal Findings We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model. Conclusions/Significance These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases. PMID:19404401

The actin-binding protein capulet genetically interacts with the microtubule motor kinesin to maintain neuronal dendrite homeostasis.

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Paul M B Medina

Full Text Available BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease.

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

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Streeter, K.A.; Baker-Herman, T.L.

2014-01-01

Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30 min) block axon conduction in bulbospinal axons from medullary respiratory neurons that innervate one phrenic motor pool; during procaine injections, contralateral phrenic neural activity was maintained. Once axon conduction resumed, a prolonged increase in phrenic burst amplitude was observed in the ipsilateral phrenic nerve, demonstrating inactivity-induced phrenic motor facilitation (iPMF). Inhibition of tumor necrosis factor alpha (TNFα) and atypical PKC (aPKC) activity in spinal segments containing the phrenic motor nucleus impaired ipsilateral iPMF, suggesting a key role for spinal TNFα and aPKC in iPMF following unilateral axon conduction block. A small phrenic burst amplitude facilitation was also observed contralateral to axon conduction block, indicating crossed spinal phrenic motor facilitation (csPMF). csPMF was independent of spinal TNFα and aPKC. Ipsilateral iPMF and csPMF following unilateral withdrawal of phrenic synaptic inputs were associated with proportional increases in phrenic responses to chemoreceptor stimulation (hypercapnia), suggesting iPMF and csPMF increase phrenic dynamic range. These data suggest that local, spinal mechanisms sense and respond to reduced synaptic inputs to phrenic motor neurons. We hypothesize that iPMF and csPMF may represent compensatory mechanisms that assure adequate motor output is maintained in a physiological system in which prolonged inactivity ends life. PMID:24681155

Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans

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Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong, E-mail: dayongw@seu.edu.cn

2015-02-11

Graphical abstract: - Highlights: • We investigated in vivo neurotoxicity of CdTe QDs on RMEs motor neurons in C. elegans. • CdTe QDs in the range of μg/L caused neurotoxicity on RMEs motor neurons. • Bioavailability of CdTe QDs may be the primary inducer for CdTe QDs neurotoxicity. • Both oxidative stress and cell identity regulate the CdTe QDs neurotoxicity. • CdTe QDs were translocated and deposited into RMEs motor neurons. - Abstract: We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1–1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd{sup 2+}. Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals.

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

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Bernard-Marissal, Nathalie; Médard, Jean-Jacques; Azzedine, Hamid; Chrast, Roman

2015-04-01

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

Science.gov (United States)

Statland, Jeffrey M; Barohn, Richard J; McVey, April L; Katz, Jonathan S; Dimachkie, Mazen M

2015-11-01

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

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Ewan West

2015-06-01

Full Text Available Alzheimer’s disease (AD is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ and the loss of synapses. Aggregation of the cellular prion protein (PrPC by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2 and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage.

Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression.

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Kerk, Sze Yen; Kratsios, Paschalis; Hart, Michael; Mourao, Romulo; Hobert, Oliver

2017-01-04

A common organizational feature of nervous systems is the existence of groups of neurons that share common traits but can be divided into individual subtypes based on anatomical or molecular features. We elucidate the mechanistic basis of neuronal diversification processes in the context of C.elegans ventral cord motor neurons that share common traits that are directly activated by the terminal selector UNC-3. Diversification of motor neurons into different classes, each characterized by unique patterns of effector gene expression, is controlled by distinct combinations of phylogenetically conserved, class-specific transcriptional repressors. These repressors are continuously required in postmitotic neurons to prevent UNC-3, which is active in all neuron classes, from activating class-specific effector genes in specific motor neuron subsets via discrete cis-regulatory elements. The strategy of antagonizing the activity of broadly acting terminal selectors of neuron identity in a subtype-specific fashion may constitute a general principle of neuron subtype diversification. Copyright © 2017 Elsevier Inc. All rights reserved.

Sleep-Active Neurons: Conserved Motors of Sleep

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Bringmann, Henrik

2018-01-01

Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Institute of Scientific and Technical Information of China (English)

Zhi-Bo Wang; Xiaoqing Zhang; Xue-Jun Li

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease.Here,we developed a closely representative cell model of SMA by knocking down the disease-determining gene,survival motor neuron (SMN),in human embryonic stem cells (hESCs).Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons.Notably,the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated.Furthermore,these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-A7 (lacking exon 7)knockdown,and were specific to spinal motor neurons.Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes,including specific axonal defects and motor neuron loss.Finally,knockdown of SMNFL led to excessive mitochondrial oxidative stress in human motor neuron progenitors.The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine,a potent antioxidant,which prevented disease-related apoptosis and subsequent motor neuron death.Thus,we report here the successful establishment of an hESC-based SMA model,which exhibits disease gene isoform specificity,cell type specificity,and phenotype reversibility.Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

Motor neurone disease presenting with raised serum Troponin T.

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Mamo, Jonathan P

2015-05-01

Myocardial damage indicated by a rise in cardiac Troponin may not necessarily be due to a cardiac event. Many diseases such as sepsis, pulmonary embolism, heart and renal failure can also be associated with an elevated cardiac Troponin level. This brief report discusses the rare event of a patient with motor neurone disease, where the possible diagnosis of acute myocardial infarction arose due to an elevated cardiac Troponin. A 69-year-old gentleman presented with a history of a central chest ache of mild intensity, lasting a total of 2 h prior to complete resolution. Multiple cardiac Troponin assays were elevated, and echocardiography did not show any acute changes of myocardial damage. His electrocardiogram was also normal. This patient's raised cardiac Troponin was therefore explained on the basis of his active motor neurone disease. This rare case outlines the importance of considering motor neurone disease as a cause of elevated cardiac Troponin in the absence of clinical evidence of an acute coronary event. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Alterations in the properties of neonatal thalamocortical synapses with time in in vitro slices.

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Liliana L Luz

Full Text Available New synapses are constantly being generated and lost in the living brain with only a subset of these being stabilized to form an enduring component of neuronal circuitry. The properties of synaptic transmission have primarily been established in a variety of in vitro neuronal preparations. It is not clear, however, if newly-formed and persistent synapses contribute to the results of these studies consistently throughout the lifespan of these preparations. In neonatal somatosensory, barrel, cortex we have previously hypothesized that a population of thalamocortical synapses displaying unusually slow kinetics represent newly-formed, default-transient synapses. This clear phenotype would provide an ideal tool to investigate if such newly formed synapses consistently contribute to synaptic transmission throughout a normal experimental protocol. We show that the proportion of synapses recorded in vitro displaying slow kinetics decreases with time after brain slice preparation. However, slow synapses persist in vitro in the presence of either minocycline, an inhibitor of microglia-mediated synapse elimination, or the TrkB agonist 7,8-dihydroxyflavone a promoter of synapse formation. These findings show that the observed properties of synaptic transmission may systematically change with time in vitro in a standard brain slice preparation.

associated neuron disease carCInoma Motor with

African Journals Online (AJOL)

1983-02-19

Feb 19, 1983 ... Department of Anatomical Pathology, School of Pathology,. South Mrican Institute ... drooling from the mouth, a spastic tongue, a positive jaw jerk, pout and glabellar tap .... The possibility that the coexistence of motor neuron ...

NeuroD2 regulates the development of hippocampal mossy fiber synapses

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Wilke Scott A

2012-02-01

Full Text Available Abstract Background The assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF synapse. Results Using NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice. Conclusion These experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation.

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Streeter, K A; Baker-Herman, T L

2014-06-01

Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30min) block axon conduction in bulbospinal axons from medullary respiratory neurons that innervate one phrenic motor pool; during procaine injections, contralateral phrenic neural activity was maintained. Once axon conduction resumed, a prolonged increase in phrenic burst amplitude was observed in the ipsilateral phrenic nerve, demonstrating inactivity-induced phrenic motor facilitation (iPMF). Inhibition of tumor necrosis factor alpha (TNFα) and atypical PKC (aPKC) activity in spinal segments containing the phrenic motor nucleus impaired ipsilateral iPMF, suggesting a key role for spinal TNFα and aPKC in iPMF following unilateral axon conduction block. A small phrenic burst amplitude facilitation was also observed contralateral to axon conduction block, indicating crossed spinal phrenic motor facilitation (csPMF). csPMF was independent of spinal TNFα and aPKC. Ipsilateral iPMF and csPMF following unilateral withdrawal of phrenic synaptic inputs were associated with proportional increases in phrenic responses to chemoreceptor stimulation (hypercapnia), suggesting iPMF and csPMF increase phrenic dynamic range. These data suggest that local, spinal mechanisms sense and respond to reduced synaptic inputs to phrenic motor neurons. We hypothesize that iPMF and csPMF may represent compensatory mechanisms that assure adequate motor output is maintained in a physiological system in which prolonged inactivity ends life. Copyright © 2014 Elsevier Inc. All rights reserved.

Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease.

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Christou, Y A; Moore, H D; Shaw, P J; Monk, P N

2007-10-01

Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.

Combined effect of chemical and electrical synapses in Hindmarsh-Rose neural networks on synchronization and the rate of information.

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Baptista, M S; Moukam Kakmeni, F M; Grebogi, C

2010-09-01

In this work we studied the combined action of chemical and electrical synapses in small networks of Hindmarsh-Rose (HR) neurons on the synchronous behavior and on the rate of information produced (per time unit) by the networks. We show that if the chemical synapse is excitatory, the larger the chemical synapse strength used the smaller the electrical synapse strength needed to achieve complete synchronization, and for moderate synaptic strengths one should expect to find desynchronous behavior. Otherwise, if the chemical synapse is inhibitory, the larger the chemical synapse strength used the larger the electrical synapse strength needed to achieve complete synchronization, and for moderate synaptic strengths one should expect to find synchronous behaviors. Finally, we show how to calculate semianalytically an upper bound for the rate of information produced per time unit (Kolmogorov-Sinai entropy) in larger networks. As an application, we show that this upper bound is linearly proportional to the number of neurons in a network whose neurons are highly connected.

Frontal lobe atrophy in motor neuron diseases.

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Kiernan, J A; Hudson, A J

1994-08-01

Neuronal degeneration in the precentral gyrus alone cannot account for the occurrence of spastic paresis in motor neuron diseases. To look for more extensive cortical atrophy we measured MRIs of the upper parts of the frontal and parietal lobes in 11 sporadic cases of classical amyotrophic lateral sclerosis (ALS), eight patients with primary lateral sclerosis (PLS) and an age- and sex-matched group of 49 neurologically normal people. None of the patients had overt dementia or other mental diseases. In PLS there is progressive spastic paresis but in contrast to ALS there is no lower motor neuron degeneration. The surface area of the precentral gyri and the amount of underlying white matter in PLS were consistently approximately 75% of the normal size. By contrast, there was some shrinkage of the precentral gyri in some of the ALS patients but the mean measurements for the group did not differ significantly from the controls. Anterior to the precentral sulci, the cortical surface area in PLS was approximately 85% of that of the controls, with correspondingly reduced white matter. In ALS the cortical surface areas of the anterior frontal lobes did not differ from those of the controls, but the amount of underlying white matter was reduced almost as much in ALS as it was in PLS. The measured changes in the frontal lobes suggest that in PLS there is simultaneous atrophy of the primary, premotor and supplementary motor areas of the cortex, with consequent degeneration of corticospinal and corticoreticular axons descending through the underlying white matter. These changes could account for the progressive upper motor neuron syndrome. In ALS, with no significant frontal cortical atrophy, the shrinkage of the white matter may be due to degeneration of axons projecting to the frontal cortex from elsewhere. Deprivation of afferents could explain the diminution of motor functions of the frontal lobes in ALS and also the changes in word fluency, judgement and attention that

Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

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Ximena Paez-Colasante

Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

运动神经元病%Motor Neuron Disease

Institute of Scientific and Technical Information of China (English)

蒋雨平

2014-01-01

Motor neuron disease (MND) represents a group of sporadic or genetic neurodegenerative diseases which principally affect the motor neurons and result in progressive paralysis and death. The epidemiology, genetics, clinical manifestation, diagnostic criteria of MND were reviewed.%运动神经元病是一组散发或遗传的神经变性病。主要累及运动神经元，病程进展而死亡。文中就其临床表现和诊断标准、流行病学和遗传学进行综述。

More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases.

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Boyer, Justin G; Ferrier, Andrew; Kothary, Rashmi

2013-12-18

Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases.

A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

NARCIS (Netherlands)

Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

2015-01-01

Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

Zebrafish embryos exposed to alcohol undergo abnormal development of motor neurons and muscle fibers.

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Sylvain, Nicole J; Brewster, Daniel L; Ali, Declan W

2010-01-01

Children exposed to alcohol in utero have significantly delayed gross and fine motor skills, as well as deficiencies in reflex development. The reasons that underlie the motor deficits caused by ethanol (EtOH) exposure remain to be fully elucidated. The present study was undertaken to investigate the effects of embryonic alcohol exposure (1.5%, 2% and 2.5% EtOH) on motor neuron and muscle fiber morphology in 3 days post fertilization (dpf) larval zebrafish. EtOH treated fish exhibited morphological deformities and fewer bouts of swimming in response to touch, compared with untreated fish. Immunolabelling with anti-acetylated tubulin indicated that fish exposed to 2.5% EtOH had significantly higher rates of motor neuron axon defects. Immunolabelling of primary and secondary motor neurons, using znp-1 and zn-8, revealed that fish exposed to 2% and 2.5% EtOH exhibited significantly higher rates of primary and secondary motor neuron axon defects compared to controls. Examination of red and white muscle fibers revealed that fish exposed to EtOH had significantly smaller fibers compared with controls. These findings indicate that motor neuron and muscle fiber morphology is affected by early alcohol exposure in zebrafish embryos, and that this may be related to deficits in locomotion. Copyright 2010 Elsevier Inc. All rights reserved.

IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice.

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Tsai, Li-Kai; Chen, Yi-Chun; Cheng, Wei-Cheng; Ting, Chen-Hung; Dodge, James C; Hwu, Wuh-Liang; Cheng, Seng H; Passini, Marco A

2012-01-01

The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2 months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8 months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA. Copyright © 2011 Elsevier Inc. All rights reserved.

Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

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Schmauss Claudia

2007-01-01

Full Text Available Abstract Background In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy. Results Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon. Conclusion Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of

BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

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Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

2003-01-01

The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

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Gonçalves, Inês do Carmo G; Rehorst, Wiebke A; Kye, Min Jeong

2016-01-01

Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.

Dynamic mobility of functional GABAA receptors at inhibitory synapses.

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Thomas, Philip; Mortensen, Martin; Hosie, Alastair M; Smart, Trevor G

2005-07-01

Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor alpha1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

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Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

2017-11-01

Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons.

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Kratsios, Paschalis; Kerk, Sze Yen; Catela, Catarina; Liang, Joseph; Vidal, Berta; Bayer, Emily A; Feng, Weidong; De La Cruz, Estanisla Daniel; Croci, Laura; Consalez, G Giacomo; Mizumoto, Kota; Hobert, Oliver

2017-07-05

A core principle of nervous system organization is the diversification of neuron classes into subclasses that share large sets of features but differ in select traits. We describe here a molecular mechanism necessary for motor neurons to acquire subclass-specific traits in the nematode Caenorhabditis elegans . Cholinergic motor neuron classes of the ventral nerve cord can be subdivided into subclasses along the anterior-posterior (A-P) axis based on synaptic connectivity patterns and molecular features. The conserved COE-type terminal selector UNC-3 not only controls the expression of traits shared by all members of a neuron class, but is also required for subclass-specific traits expressed along the A-P axis. UNC-3, which is not regionally restricted, requires region-specific cofactors in the form of Hox proteins to co-activate subclass-specific effector genes in post-mitotic motor neurons. This intersectional gene regulatory principle for neuronal subclass diversification may be conserved from nematodes to mice.

Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

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Delva, Aline; Thakore, Nimish; Pioro, Erik P; Poesen, Koen; Saunders-Pullman, Rachel; Meijer, Inge A; Rucker, Janet C; Kissel, John T; Van Damme, Philip

2017-12-01

Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017. © 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

Targeting the Full Length of the Motor End Plate Regions in the Mouse Forelimb Increases the Uptake of Fluoro-Gold into Corresponding Spinal Cord Motor Neurons

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Andrew Paul Tosolini

2013-05-01

Full Text Available Lower motor neuron dysfunction is one of the most debilitating motor conditions. In this regard, transgenic mouse models of various lower motor neuron dysfunctions provide insight into the mechanisms underlying these pathologies and can also aid the development of new therapies. Viral-mediated gene therapy can take advantage of the muscle-motor neuron topographical relationship to shuttle therapeutic genes into specific populations of motor neurons in these mouse models. In this context, motor end plates (MEPs are highly specialised regions on the skeletal musculature that offer direct access to the pre-synaptic nerve terminals, henceforth to the spinal cord motor neurons. The aim of this study was two-folded. First it was to characterise the exact position of the MEP regions for several muscles of the mouse forelimb using acetylcholinesterase histochemistry. This MEP-muscle map was then used to guide a series of intramuscular injections of Fluoro-Gold (FG in order to characterise the distribution of the innervating motor neurons. This analysis revealed that the MEPs are typically organised in an orthogonal fashion across the muscle fibres and extending throughout the full width of each muscle. Furthermore, targeting the full length of the MEP regions gave rise to a seemingly greater number of labelled motor neurons that are organised into columns spanning through more spinal cord segments than previously reported. The present analysis suggests that targeting the full width of the muscles’ MEP regions with FG increases the somatic availability of the tracer. This process ensures a greater uptake of the tracer by the pre-synaptic nerve terminals, hence maximising the labelling in spinal cord motor neurons. This investigation should have positive implications for future studies involving the somatic delivery of therapeutic genes into motor neurons for the treatment of various motor dysfunctions.

TRANSGENIC GDNF POSITIVELY INFLUENCES PROLIFERATION, DIFFERENTIATION, MATURATION AND SURVIVAL OF MOTOR NEURONS PRODUCED FROM MOUSE EMBRYONIC STEM CELLS.

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Daniel Édgar Cortés

2016-09-01

Full Text Available Embryonic stem cells (ESC are pluripotent and thus can differentiate into every cell type present in the body. Directed differentiation into motor neurons has been described for pluripotent cells. Although neurotrophic factors promote neuronal survival, their role in neuronal commitment is elusive. Here, we developed double-transgenic lines of mouse ESC that constitutively produce Glial cell-derived neurotrophic factor (GDNF and also contain a GFP reporter, driven by HB9, which is expressed only by postmitotic motor neurons. After lentiviral transduction, ESC lines integrated and expressed the human GDNF gene without altering pluripotency markers before differentiation. Further, GDNF-ESC showed significantly higher spontaneous release of this neurotrophin to the medium, when compared to controls. To study motor neuron induction, control and GDNF cell lines were grown as embryoid bodies and stimulated with retinoic acid and Sonic Hedgehog. In GDNF-overexpressing cells, a significant increase of proliferative Olig2+ precursors, which are specified as spinal motor neurons, was found. Accordingly, GDNF increases the yield of cells with the pan motor neuronal markers HB9, monitored by GFP expression, and Isl1. At terminal differentiation, almost all differentiated neurons express phenotypic markers of motor neurons in GDNF cultures, with lower proportions in control cells. To test if the effects of GDNF were present at early differentiation stages, exogenous recombinant human GDNF was added to control ESC, also resulting in enhanced motor neuron differentiation. This effect was abolished by the co-addition of neutralizing anti-GDNF antibodies, strongly suggesting that differentiating ESC are responsive to GDNF. Using the HB9::GFP reporter, motor neurons were selected for electrophysiological recordings. Motor neurons differentiated from GDNF-ESC, compared to control motor neurons, showed greater electrophysiological maturation, characterized by

Stabilization of memory States by stochastic facilitating synapses.

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Miller, Paul

2013-12-06

Bistability within a small neural circuit can arise through an appropriate strength of excitatory recurrent feedback. The stability of a state of neural activity, measured by the mean dwelling time before a noise-induced transition to another state, depends on the neural firing-rate curves, the net strength of excitatory feedback, the statistics of spike times, and increases exponentially with the number of equivalent neurons in the circuit. Here, we show that such stability is greatly enhanced by synaptic facilitation and reduced by synaptic depression. We take into account the alteration in times of synaptic vesicle release, by calculating distributions of inter-release intervals of a synapse, which differ from the distribution of its incoming interspike intervals when the synapse is dynamic. In particular, release intervals produced by a Poisson spike train have a coefficient of variation greater than one when synapses are probabilistic and facilitating, whereas the coefficient of variation is less than one when synapses are depressing. However, in spite of the increased variability in postsynaptic input produced by facilitating synapses, their dominant effect is reduced synaptic efficacy at low input rates compared to high rates, which increases the curvature of neural input-output functions, leading to wider regions of bistability in parameter space and enhanced lifetimes of memory states. Our results are based on analytic methods with approximate formulae and bolstered by simulations of both Poisson processes and of circuits of noisy spiking model neurons.

Sleep: The hebbian reinforcement of the local inhibitory synapses.

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Touzet, Claude

2015-09-01

Sleep is ubiquitous among the animal realm, and represents about 30% of our lives. Despite numerous efforts, the reason behind our need for sleep is still unknown. The Theory of neuronal Cognition (TnC) proposes that sleep is the period of time during which the local inhibitory synapses (in particular the cortical ones) are replenished. Indeed, as long as the active brain stays awake, hebbian learning guarantees that efficient inhibitory synapses lose their efficiency – just because they are efficient at avoiding the activation of the targeted neurons. Since hebbian learning is the only known mechanism of synapse modification, it follows that to replenish the inhibitory synapses' efficiency, source and targeted neurons must be activated together. This is achieved by a local depolarization that may travel (wave). The period of time during which such slow waves are experienced has been named the "slow-wave sleep" (SWS). It is cut into several pieces by shorter periods of paradoxical sleep (REM) which activity resembles that of the awake state. Indeed, SWS – because it only allows local neural activation – decreases the excitatory long distance connections strength. To avoid losing the associations built during the awake state, these long distance activations are played again during the REM sleep. REM and SWS sleeps act together to guarantee that when the subject awakes again, his inhibitory synaptic efficiency is restored and his (excitatory) long distance associations are still there. Copyright © 2015 Elsevier Ltd. All rights reserved.

Local-circuit phenotypes of layer 5 neurons in motor-frontal cortex of YFP-H mice

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Jianing Yu

2008-12-01

Full Text Available Layer 5 pyramidal neurons comprise an important but heterogeneous group of cortical projection neurons. In motor-frontal cortex, these neurons are centrally involved in the cortical control of movement. Recent studies indicate that local excitatory networks in mouse motor-frontal cortex are dominated by descending pathways from layer 2/3 to 5. However, those pathways were identified in experiments involving unlabeled neurons in wild type mice. Here, to explore the possibility of class-specific connectivity in this descending pathway, we mapped the local sources of excitatory synaptic input to a genetically labeled population of cortical neurons: YFP-positive layer 5 neurons of YFP-H mice. We found, first, that in motor cortex, YFP-positive neurons were distributed in a double blade, consistent with the idea of layer 5B having greater thickness in frontal neocortex. Second, whereas unlabeled neurons in upper layer 5 received their strongest inputs from layer 2, YFP-positive neurons in the upper blade received prominent layer 3 inputs. Third, YFP-positive neurons exhibited distinct electrophysiological properties, including low spike frequency adaptation, as reported previously. Our results with this genetically labeled neuronal population indicate the presence of distinct local-circuit phenotypes among layer 5 pyramidal neurons in mouse motor-frontal cortex, and present a paradigm for investigating local circuit organization in other genetically labeled populations of cortical neurons.

Glutamate synapses in human cognitive disorders.

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Volk, Lenora; Chiu, Shu-Ling; Sharma, Kamal; Huganir, Richard L

2015-07-08

Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin.

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Pivetta, Chiara; Esposito, Maria Soledad; Sigrist, Markus; Arber, Silvia

2014-01-30

Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement. Copyright © 2014 Elsevier Inc. All rights reserved.

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

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Kia, Azadeh; McAvoy, Kevin; Krishnamurthy, Karthik; Trotti, Davide

2018-01-01

Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS. PMID:29380416

Effects of cerebrolysin on motor-neuron-like NSC-34 cells

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Keilhoff, Gerburg, E-mail: Gerburg.keilhoff@med.ovgu.de [Institute of Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg (Germany); Lucas, Benjamin; Pinkernelle, Josephine; Steiner, Michael [Institute of Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg (Germany); Fansa, Hisham [Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Klinikum Bielefeld, Teutoburger Str. 50, D-33604 Bielefeld (Germany)

2014-10-01

Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL on motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and

Effects of cerebrolysin on motor-neuron-like NSC-34 cells

International Nuclear Information System (INIS)

Keilhoff, Gerburg; Lucas, Benjamin; Pinkernelle, Josephine; Steiner, Michael; Fansa, Hisham

2014-01-01

Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL on motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and

Cell Adhesion, the Backbone of the Synapse: “Vertebrate” and “Invertebrate” Perspectives

OpenAIRE

Giagtzoglou, Nikolaos; Ly, Cindy V.; Bellen, Hugo J.

2009-01-01

Synapses are asymmetric intercellular junctions that mediate neuronal communication. The number, type, and connectivity patterns of synapses determine the formation, maintenance, and function of neural circuitries. The complexity and specificity of synaptogenesis relies upon modulation of adhesive properties, which regulate contact initiation, synapse formation, maturation, and functional plasticity. Disruption of adhesion may result in structural and functional imbalance that may lead to neu...

Adult rat motor neurons do not re-establish electrical coupling during axonal regeneration and muscle reinnervation.

Directory of Open Access Journals (Sweden)

Morgana Favero

Full Text Available Gap junctions (GJs between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii slow synchronization of locomotor-like oscillatory activity. Soon after birth this coupling disappears. Since in the adult rat regeneration of motor fibers after peripheral nerve injury leads to a recapitulation of synaptic refinement at the target muscles, we tested whether GJs between motor neurons are transiently re-expressed. We found that in conditions of maximal responsiveness of lumbar motor neurons (such as no depression by anesthetics, decerebrate release of activity of subsets of motor neurons, use of temporal and spatial summation by antidromic and orthodromic stimulations, testing of large ensembles of motor neurons no firing is observed in ventral root axons in response to antidromic spike invasion of nearby counterparts. We conclude that junctional coupling between motor neurons is not required for the refinement of neuromuscular innervation in the adult.

Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function

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Carola Dewitz

2018-02-01

Full Text Available Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, and afadin signaling. Our findings reveal that nuclear organization of motor neurons is dependent on inside-out positioning, orchestrated by N-cadherin, catenin, and afadin activities, controlling cell body layering on the medio-lateral axis. In addition to this lamination-like program, motor neurons undergo a secondary, independent phase of organization. This process results in segregation of motor neurons along the dorso-ventral axis of the spinal cord, does not require N-cadherin or afadin activity, and can proceed even when medio-lateral positioning is perturbed.

Neurons in primary motor cortex engaged during action observation.

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Dushanova, Juliana; Donoghue, John

2010-01-01

Neurons in higher cortical areas appear to become active during action observation, either by mirroring observed actions (termed mirror neurons) or by eliciting mental rehearsal of observed motor acts. We report the existence of neurons in the primary motor cortex (M1), an area that is generally considered to initiate and guide movement performance, responding to viewed actions. Multielectrode recordings in monkeys performing or observing a well-learned step-tracking task showed that approximately half of the M1 neurons that were active when monkeys performed the task were also active when they observed the action being performed by a human. These 'view' neurons were spatially intermingled with 'do' neurons, which are active only during movement performance. Simultaneously recorded 'view' neurons comprised two groups: approximately 38% retained the same preferred direction (PD) and timing during performance and viewing, and the remainder (62%) changed their PDs and time lag during viewing as compared with performance. Nevertheless, population activity during viewing was sufficient to predict the direction and trajectory of viewed movements as action unfolded, although less accurately than during performance. 'View' neurons became less active and contained poorer representations of action when only subcomponents of the task were being viewed. M1 'view' neurons thus appear to reflect aspects of a learned movement when observed in others, and form part of a broadly engaged set of cortical areas routinely responding to learned behaviors. These findings suggest that viewing a learned action elicits replay of aspects of M1 activity needed to perform the observed action, and could additionally reflect processing related to understanding, learning or mentally rehearsing action.

Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits.

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Friedman, Lauren G; Riemslagh, Fréderike W; Sullivan, Josefa M; Mesias, Roxana; Williams, Frances M; Huntley, George W; Benson, Deanna L

2015-01-01

Neocortical interactions with the dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson's disease, and Huntington's disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of the molecular mechanisms that control generation of prefrontal cortex-striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin-8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in the medial prefrontal cortex and in striatal medium spiny neurons forming the direct or indirect pathways. Developmental analysis of quantitative real-time polymerase chain reaction and western blot data show that Cdh8 expression peaks in the prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron microscopy shows that Cdh8 is concentrated at excitatory synapses in the dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together, our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. © 2014 Wiley Periodicals, Inc.

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

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Chung, Won-Suk; Clarke, Laura E.; Wang, Gordon X.; Stafford, Benjamin K.; Sher, Alexander; Chakraborty, Chandrani; Joung, Julia; Foo, Lynette C.; Thompson, Andrew; Chen, Chinfei; Smith, Stephen J.; Barres, Ben A.

2013-12-01

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

Science.gov (United States)

Nash, L A; Burns, J K; Chardon, J Warman; Kothary, R; Parks, R J

2016-01-01

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

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Tomassy, Giulio Srubek; De Leonibus, Elvira; Jabaudon, Denis; Lodato, Simona; Alfano, Christian; Mele, Andrea; Macklis, Jeffrey D.; Studer, Michèle

2010-01-01

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. PMID:20133588

Morphological and electrophysiological changes in intratelencephalic-type pyramidal neurons in the motor cortex of a rat model of levodopa-induced dyskinesia.

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Ueno, Tatsuya; Yamada, Junko; Nishijima, Haruo; Arai, Akira; Migita, Keisuke; Baba, Masayuki; Ueno, Shinya; Tomiyama, Masahiko

2014-04-01

Levodopa-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy for Parkinson's disease, and becomes increasingly problematic in the advanced stage of the disease. Although the cause of LID still remains unclear, there is accumulating evidence from animal experiments that it results from maladaptive plasticity, resulting in supersensitive excitatory transmission at corticostriatal synapses. Recent work using transcranial magnetic stimulation suggests that the motor cortex displays the same supersensitivity in Parkinson's disease patients with LID. To date, the cellular mechanisms underlying the abnormal cortical plasticity have not been examined. The morphology of the dendritic spines has a strong relationship to synaptic plasticity. Therefore, we explored the spine morphology of pyramidal neurons in the motor cortex in a rat model of LID. We used control rats, 6-hydroxydopamine-lesioned rats (a model of Parkinson's disease), 6-hydroxydopamine-lesioned rats chronically treated with levodopa (a model of LID), and control rats chronically treated with levodopa. Because the direct pathway of the basal ganglia plays a central role in the development of LID, we quantified the density and size of dendritic spines in intratelencephalic (IT)-type pyramidal neurons in M1 cortex that project to the striatal medium spiny neurons in the direct pathway. The spine density was not different among the four groups. In contrast, spine size became enlarged in the Parkinson's disease and LID rat models. The enlargement was significantly greater in the LID model than in the Parkinson's disease model. This enlargement of the spines suggests that IT-type pyramidal neurons acquire supersensitivity to excitatory stimuli. To confirm this possibility, we monitored miniature excitatory postsynaptic currents (mEPSCs) in the IT-type pyramidal neurons in M1 cortex using whole-cell patch clamp. The amplitude of the mEPSCs was significantly increased in the LID

Cell Biological Mechanisms of Activity-Dependent Synapse to Nucleus Translocation of CRTC1 in Neurons

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Toh Hean eCh'ng

2015-09-01

Full Text Available Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1 in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of synaptic glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.

Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice

KAUST Repository

Jeong, Suh Young; Crooks, Daniel R.; Wilson-Ollivierre, Hayden; Ghosh, Manik C.; Sougrat, Rachid; Lee, Jaekwon; Cooperman, Sharon; Mitchell, James B.; Beaumont, Carole; Rouault, Tracey A.

2011-01-01

Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice

KAUST Repository

Jeong, Suh Young

2011-10-07

Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

Impact of weak excitatory synapses on chaotic transients in a diffusively coupled Morris-Lecar neuronal network

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Lafranceschina, Jacopo, E-mail: jlafranceschina@alaska.edu; Wackerbauer, Renate, E-mail: rawackerbauer@alaska.edu [Department of Physics, University of Alaska, Fairbanks, Alaska 99775-5920 (United States)

2015-01-15

Spatiotemporal chaos collapses to either a rest state or a propagating pulse solution in a ring network of diffusively coupled, excitable Morris-Lecar neurons. Weak excitatory synapses can increase the Lyapunov exponent, expedite the collapse, and promote the collapse to the rest state rather than the pulse state. A single traveling pulse solution may no longer be asymptotic for certain combinations of network topology and (weak) coupling strengths, and initiate spatiotemporal chaos. Multiple pulses can cause chaos initiation due to diffusive and synaptic pulse-pulse interaction. In the presence of chaos initiation, intermittent spatiotemporal chaos exists until typically a collapse to the rest state.

Impact of weak excitatory synapses on chaotic transients in a diffusively coupled Morris-Lecar neuronal network

International Nuclear Information System (INIS)

Lafranceschina, Jacopo; Wackerbauer, Renate

2015-01-01

Spatiotemporal chaos collapses to either a rest state or a propagating pulse solution in a ring network of diffusively coupled, excitable Morris-Lecar neurons. Weak excitatory synapses can increase the Lyapunov exponent, expedite the collapse, and promote the collapse to the rest state rather than the pulse state. A single traveling pulse solution may no longer be asymptotic for certain combinations of network topology and (weak) coupling strengths, and initiate spatiotemporal chaos. Multiple pulses can cause chaos initiation due to diffusive and synaptic pulse-pulse interaction. In the presence of chaos initiation, intermittent spatiotemporal chaos exists until typically a collapse to the rest state

Super Resolution Imaging of Genetically Labeled Synapses in Drosophila Brain Tissue.

Science.gov (United States)

Spühler, Isabelle A; Conley, Gaurasundar M; Scheffold, Frank; Sprecher, Simon G

2016-01-01

Understanding synaptic connectivity and plasticity within brain circuits and their relationship to learning and behavior is a fundamental quest in neuroscience. Visualizing the fine details of synapses using optical microscopy remains however a major technical challenge. Super resolution microscopy opens the possibility to reveal molecular features of synapses beyond the diffraction limit. With direct stochastic optical reconstruction microscopy, dSTORM, we image synaptic proteins in the brain tissue of the fruit fly, Drosophila melanogaster. Super resolution imaging of brain tissue harbors difficulties due to light scattering and the density of signals. In order to reduce out of focus signal, we take advantage of the genetic tools available in the Drosophila and have fluorescently tagged synaptic proteins expressed in only a small number of neurons. These neurons form synapses within the calyx of the mushroom body, a distinct brain region involved in associative memory formation. Our results show that super resolution microscopy, in combination with genetically labeled synaptic proteins, is a powerful tool to investigate synapses in a quantitative fashion providing an entry point for studies on synaptic plasticity during learning and memory formation.

Intracortical Microstimulation (ICMS) Activates Motor Cortex Layer 5 Pyramidal Neurons Mainly Transsynaptically.

Science.gov (United States)

Hussin, Ahmed T; Boychuk, Jeffery A; Brown, Andrew R; Pittman, Quentin J; Teskey, G Campbell

2015-01-01

Intracortical microstimulation (ICMS) is a technique used for a number of purposes including the derivation of cortical movement representations (motor maps). Its application can activate the output layer 5 of motor cortex and can result in the elicitation of body movements depending upon the stimulus parameters used. The extent to which pyramidal tract projection neurons of the motor cortex are activated transsynaptically or directly by ICMS remains an open question. Given this uncertainty in the mode of activation, we used a preparation that combined patch clamp whole-cell recordings from single layer 5 pyramidal neurons and extracellular ICMS in slices of motor cortex as well as a standard in vivo mapping technique to ask how ICMS activated motor cortex pyramidal neurons. We measured changes in synaptic spike threshold and spiking rate to ICMS in vitro and movement threshold in vivo in the presence or absence of specific pharmacological blockers of glutamatergic (AMPA, NMDA and Kainate) receptors and GABAA receptors. With major excitatory and inhibitory synaptic transmission blocked (with DNQX, APV and bicuculline methiodide), we observed a significant increase in the ICMS current intensity required to elicit a movement in vivo as well as to the first spike and an 85% reduction in spiking responses in vitro. Subsets of neurons were still responsive after the synaptic block, especially at higher current intensities, suggesting a modest direct activation. Taken together our data indicate a mainly synaptic mode of activation to ICMS in layer 5 of rat motor cortex. Copyright © 2015 Elsevier Inc. All rights reserved.

Differentiation of neural crest stem cells from nasal mucosa into motor neuron-like cells.

Science.gov (United States)

Bagher, Zohreh; Kamrava, Seyed Kamran; Alizadeh, Rafieh; Farhadi, Mohammad; Absalan, Moloud; Falah, Masoumeh; Faghihi, Faezeh; Zare-Sadeghi, Arash; Komeili, Ali

2018-05-25

Cell transplantation is a potential therapeutic approach for repairing neuropathological and neurodegenerative disorders of central nervous system by replacing the degenerated cells with new ones. Among a variety of stem cell candidates to provide these new cells, olfactory ectomesenchymal stem cells (OE-MSCs) have attracted a great attention due to their neural crest origin, easy harvest, high proliferation, and autologous transplantation. Since there is no report on differentiation potential of these cells into motor neuron-like cells, we evaluated this potential using Real-time PCR, flowcytometry and immunocytochemistry after the treatment with differentiation cocktail containing retinoic acid and Sonic Hedgehog. Immunocytochemistry staining of the isolated OE-MSCs demonstrated their capability to express nestin and vimentin, as the two markers of primitive neuroectoderm. The motor neuron differentiation of OE-MSCs resulted in changing their morphology into bipolar cells with high expression of motor neuron markers of ChAT, Hb-9 and Islet-1 at the level of mRNA and protein. Consequently, we believe that the OE-MSCs have great potential to differentiate into motor neuron-like cells and can be an ideal stem cell source for the treatment of motor neuron-related disorders of central nervous system. Copyright © 2018 Elsevier B.V. All rights reserved.

Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning

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Seeds, Nicholas W.; Williams, Brian L.; Bickford, Paula C.

1995-12-01

The cerebellar cortex is implicated in the learning of complex motor skills. This learning may require synaptic remodeling of Purkinje cell inputs. An extracellular serine protease, tissue plasminogen activator (tPA), is involved in remodeling various nonneural tissues and is associated with developing and regenerating neurons. In situ hybridization showed that expression of tPA messenger RNA was increased in the Purkinje neurons of rats within an hour of their being trained for a complex motor task. Antibody to tPA also showed the induction of tPA protein associated with cerebellar Purkinje cells. Thus, the induction of tPA during motor learning may play a role in activity-dependent synaptic plasticity.

Astrocyte lipid metabolism is critical for synapse development and function in vivo.

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van Deijk, Anne-Lieke F; Camargo, Nutabi; Timmerman, Jaap; Heistek, Tim; Brouwers, Jos F; Mogavero, Floriana; Mansvelder, Huibert D; Smit, August B; Verheijen, Mark H G

2017-04-01

The brain is considered to be autonomous in lipid synthesis with astrocytes producing lipids far more efficiently than neurons. Accordingly, it is generally assumed that astrocyte-derived lipids are taken up by neurons to support synapse formation and function. Initial confirmation of this assumption has been obtained in cell cultures, but whether astrocyte-derived lipids support synapses in vivo is not known. Here, we address this issue and determined the role of astrocyte lipid metabolism in hippocampal synapse formation and function in vivo. Hippocampal protein expression for the sterol regulatory element-binding protein (SREBP) and its target gene fatty acid synthase (Fasn) was found in astrocytes but not in neurons. Diminishing SREBP activity in astrocytes using mice in which the SREBP cleavage-activating protein (SCAP) was deleted from GFAP-expressing cells resulted in decreased cholesterol and phospholipid secretion by astrocytes. Interestingly, SCAP mutant mice showed more immature synapses, lower presynaptic protein SNAP-25 levels as well as reduced numbers of synaptic vesicles, indicating impaired development of the presynaptic terminal. Accordingly, hippocampal short-term and long-term synaptic plasticity were defective in mutant mice. These findings establish a critical role for astrocyte lipid metabolism in presynaptic terminal development and function in vivo. GLIA 2017;65:670-682. © 2017 Wiley Periodicals, Inc.

Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function.

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Dewitz, Carola; Pimpinella, Sofia; Hackel, Patrick; Akalin, Altuna; Jessell, Thomas M; Zampieri, Niccolò

2018-02-13

Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, and afadin signaling. Our findings reveal that nuclear organization of motor neurons is dependent on inside-out positioning, orchestrated by N-cadherin, catenin, and afadin activities, controlling cell body layering on the medio-lateral axis. In addition to this lamination-like program, motor neurons undergo a secondary, independent phase of organization. This process results in segregation of motor neurons along the dorso-ventral axis of the spinal cord, does not require N-cadherin or afadin activity, and can proceed even when medio-lateral positioning is perturbed. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.

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Ana Boulanger

Full Text Available Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment and received by the motor neuron (presynaptic compartment resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.

Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.

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Boulanger, Ana; Farge, Morgane; Ramanoudjame, Christophe; Wharton, Kristi; Dura, Jean-Maurice

2012-01-01

Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor) triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment) and received by the motor neuron (presynaptic compartment) resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.

Kalirin, a key player in synapse formation, is implicated in human diseases.

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Mandela, Prashant; Ma, Xin-Ming

2012-01-01

Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington's Disease, Alzheimer's Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function.

Highly Efficient Differentiation and Enrichment of Spinal Motor Neurons Derived from Human and Monkey Embryonic Stem Cells

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Wada, Tamaki; Honda, Makoto; Minami, Itsunari; Tooi, Norie; Amagai, Yuji; Nakatsuji, Norio; Aiba, Kazuhiro

2009-01-01

Background There are no cures or efficacious treatments for severe motor neuron diseases. It is extremely difficult to obtain naïve spinal motor neurons (sMNs) from human tissues for research due to both technical and ethical reasons. Human embryonic stem cells (hESCs) are alternative sources. Several methods for MN differentiation have been reported. However, efficient production of naïve sMNs and culture cost were not taken into consideration in most of the methods. Methods/Principal Findings We aimed to establish protocols for efficient production and enrichment of sMNs derived from pluripotent stem cells. Nestin+ neural stem cell (NSC) clusters were induced by Noggin or a small molecule inhibitor of BMP signaling. After dissociation of NSC clusters, neurospheres were formed in a floating culture containing FGF2. The number of NSCs in neurospheres could be expanded more than 30-fold via several passages. More than 33% of HB9+ sMN progenitor cells were observed after differentiation of dissociated neurospheres by all-trans retinoic acid (ATRA) and a Shh agonist for another week on monolayer culture. HB9+ sMN progenitor cells were enriched by gradient centrifugation up to 80% purity. These HB9+ cells differentiated into electrophysiologically functional cells and formed synapses with myotubes during a few weeks after ATRA/SAG treatment. Conclusions and Significance The series of procedures we established here, namely neural induction, NSC expansion, sMN differentiation and sMN purification, can provide large quantities of naïve sMNs derived from human and monkey pluripotent stem cells. Using small molecule reagents, reduction of culture cost could be achieved. PMID:19701462

Synaptic Circuit Organization of Motor Corticothalamic Neurons

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Yamawaki, Naoki

2015-01-01

Corticothalamic (CT) neurons in layer 6 constitute a large but enigmatic class of cortical projection neurons. How they are integrated into intracortical and thalamo-cortico-thalamic circuits is incompletely understood, especially outside of sensory cortex. Here, we investigated CT circuits in mouse forelimb motor cortex (M1) using multiple circuit-analysis methods. Stimulating and recording from CT, intratelencephalic (IT), and pyramidal tract (PT) projection neurons, we found strong CT↔ CT and CT↔ IT connections; however, CT→IT connections were limited to IT neurons in layer 6, not 5B. There was strikingly little CT↔ PT excitatory connectivity. Disynaptic inhibition systematically accompanied excitation in these pathways, scaling with the amplitude of excitation according to both presynaptic (class-specific) and postsynaptic (cell-by-cell) factors. In particular, CT neurons evoked proportionally more inhibition relative to excitation (I/E ratio) than IT neurons. Furthermore, the amplitude of inhibition was tuned to match the amount of excitation at the level of individual neurons; in the extreme, neurons receiving no excitation received no inhibition either. Extending these studies to dissect the connectivity between cortex and thalamus, we found that M1-CT neurons and thalamocortical neurons in the ventrolateral (VL) nucleus were remarkably unconnected in either direction. Instead, VL axons in the cortex excited both IT and PT neurons, and CT axons in the thalamus excited other thalamic neurons, including those in the posterior nucleus, which additionally received PT excitation. These findings, which contrast in several ways with previous observations in sensory areas, illuminate the basic circuit organization of CT neurons within M1 and between M1 and thalamus. PMID:25653383

Differentiation of neuronal stem cells into motor neurons using electrospun poly-L-lactic acid/gelatin scaffold.

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Binan, Loïc; Tendey, Charlène; De Crescenzo, Gregory; El Ayoubi, Rouwayda; Ajji, Abdellah; Jolicoeur, Mario

2014-01-01

Neural stem cells (NSCs) provide promising therapeutic potential for cell replacement therapy in spinal cord injury (SCI). However, high increases of cell viability and poor control of cell differentiation remain major obstacles. In this study, we have developed a non-woven material made of co-electrospun fibers of poly L-lactic acid and gelatin with a degradation rate and mechanical properties similar to peripheral nerve tissue and investigated their effect on cell survival and differentiation into motor neuronal lineages through the controlled release of retinoic acid (RA) and purmorphamine. Engineered Neural Stem-Like Cells (NSLCs) seeded on these fibers, with and without the instructive cues, differentiated into β-III-tubulin, HB-9, Islet-1, and choactase-positive motor neurons by immunostaining, in response to the release of the biomolecules. In addition, the bioactive material not only enhanced the differentiation into motor neuronal lineages but also promoted neurite outgrowth. This study elucidated that a combination of electrospun fiber scaffolds, neural stem cells, and controlled delivery of instructive cues could lead to the development of a better strategy for peripheral nerve injury repair. Copyright © 2013 Elsevier Ltd. All rights reserved.

CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.

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Ricciardi, Sara; Ungaro, Federica; Hambrock, Melanie; Rademacher, Nils; Stefanelli, Gilda; Brambilla, Dario; Sessa, Alessandro; Magagnotti, Cinzia; Bachi, Angela; Giarda, Elisa; Verpelli, Chiara; Kilstrup-Nielsen, Charlotte; Sala, Carlo; Kalscheuer, Vera M; Broccoli, Vania

2012-09-01

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.

Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

Science.gov (United States)

2015-08-24

Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

Reappraisal of VAChT-Cre: Preference in slow motor neurons innervating type I or IIa muscle fibers.

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Misawa, Hidemi; Inomata, Daijiro; Kikuchi, Miseri; Maruyama, Sae; Moriwaki, Yasuhiro; Okuda, Takashi; Nukina, Nobuyuki; Yamanaka, Tomoyuki

2016-11-01

VAChT-Cre.Fast and VAChT-Cre.Slow mice selectively express Cre recombinase in approximately one half of postnatal somatic motor neurons. The mouse lines have been used in various studies with selective genetic modifications in adult motor neurons. In the present study, we crossed VAChT-Cre lines with a reporter line, CAG-Syp/tdTomato, in which synaptophysin-tdTomato fusion proteins are efficiently sorted to axon terminals, making it possible to label both cell bodies and axon terminals of motor neurons. In the mice, Syp/tdTomato fluorescence preferentially co-localized with osteopontin, a recently discovered motor neuron marker for slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) types. The fluorescence did not preferentially co-localize with matrix metalloproteinase-9, a marker for fast-twitch fatigable (FF) motor neurons. In the neuromuscular junctions, Syp/tdTomato fluorescence was detected mainly in motor nerve terminals that innervate type I or IIa muscle fibers. These results suggest that the VAChT-Cre lines are Cre-drivers that have selectivity in S and FR motor neurons. In order to avoid confusion, we have changed the mouse line names from VAChT-Cre.Fast and VAChT-Cre.Slow to VAChT-Cre.Early and VAChT-Cre.Late, respectively. The mouse lines will be useful tools to study slow-type motor neurons, in relation to physiology and pathology. © 2016 Wiley Periodicals, Inc.

Spinal muscular atrophy: Selective motor neuron loss and global defect in the assembly of ribonucleoproteins.

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Beattie, Christine E; Kolb, Stephen J

2018-08-15

Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair. Thus, SMA is an exemplar, selective motor neuron disorder that is caused by defects in fundamental RNA processing events. A detailed molecular understanding of how motor neurons fail, and why other neurons do not, in SMA will yield important principals about motor neuron maintenance and neuronal specificity in neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis.

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Riancho, J; Gonzalo, I; Ruiz-Soto, M; Berciano, J

2016-02-04

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

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Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

2016-03-01

The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

Genetic overlap between apparently sporadic motor neuron diseases

NARCIS (Netherlands)

van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A.; van der Pol, W.-Ludo; Hennekam, Eric A. M.; Dooijes, Dennis; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne; Veldink, Jan H.; van den Berg, Leonard H.

2012-01-01

Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and

Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice.

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Suh Young Jeong

Full Text Available Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2, which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

Neurobeachin regulates neurotransmitter receptor trafficking to synapses

NARCIS (Netherlands)

Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

2013-01-01

The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

Action observation and mirror neuron network: a tool for motor stroke rehabilitation.

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Sale, P; Franceschini, M

2012-06-01

Mirror neurons are a specific class of neurons that are activated and discharge both during observation of the same or similar motor act performed by another individual and during the execution of a motor act. Different studies based on non invasive neuroelectrophysiological assessment or functional brain imaging techniques have demonstrated the presence of the mirror neuron and their mechanism in humans. Various authors have demonstrated that in the human these networks are activated when individuals learn motor actions via execution (as in traditional motor learning), imitation, observation (as in observational learning) and motor imagery. Activation of these brain areas (inferior parietal lobe and the ventral premotor cortex, as well as the caudal part of the inferior frontal gyrus [IFG]) following observation or motor imagery may thereby facilitate subsequent movement execution by directly matching the observed or imagined action to the internal simulation of that action. It is therefore believed that this multi-sensory action-observation system enables individuals to (re) learn impaired motor functions through the activation of these internal action-related representations. In humans, the mirror mechanism is also located in various brain segment: in Broca's area, which is involved in language processing and speech production and not only in centres that mediate voluntary movement, but also in cortical areas that mediate visceromotor emotion-related behaviours. On basis of this finding, during the last 10 years various studies were carry out regarding the clinical use of action observation for motor rehabilitation of sub-acute and chronic stroke patients.

The Effects of Motor Neurone Disease on Language: Further Evidence

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Bak, Thomas H.; Hodges, John R.

2004-01-01

It might sound surprising that Motor Neurone Disease (MND), regarded still by many as the very example of a neurodegenerative disease affecting selectively the motor system and sparing the sensory functions as well as cognition, can have a significant influence on language. In this article we hope to demonstrate that language dysfunction is not…

Local synaptic signaling enhances the stochastic transport of motor-driven cargo in neurons

KAUST Repository

Newby, Jay

2010-08-23

The tug-of-war model of motor-driven cargo transport is formulated as an intermittent trapping process. An immobile trap, representing the cellular machinery that sequesters a motor-driven cargo for eventual use, is located somewhere within a microtubule track. A particle representing a motor-driven cargo that moves randomly with a forward bias is introduced at the beginning of the track. The particle switches randomly between a fast moving phase and a slow moving phase. When in the slow moving phase, the particle can be captured by the trap. To account for the possibility that the particle avoids the trap, an absorbing boundary is placed at the end of the track. Two local signaling mechanisms-intended to improve the chances of capturing the target-are considered by allowing the trap to affect the tug-of-war parameters within a small region around itself. The first is based on a localized adenosine triphosphate (ATP) concentration gradient surrounding a synapse, and the second is based on a concentration of tau-a microtubule-associated protein involved in Alzheimer\\'s disease-coating the microtubule near the synapse. It is shown that both mechanisms can lead to dramatic improvements in the capture probability, with a minimal increase in the mean capture time. The analysis also shows that tau can cause a cargo to undergo random oscillations, which could explain some experimental observations. © 2010 IOP Publishing Ltd.

Mixed electrical-chemical synapses in adult rat hippocampus are primarily glutamatergic and coupled by connexin-36

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Farid eHamzei-Sichani

2012-05-01

Full Text Available Dendrodendritic electrical signaling via gap junctions is now an accepted feature of neuronal communication in the mammalian brain, whereas axodendritic and axosomatic gap junctions have rarely been described. We present ultrastructural, immunocytochemical, and dye-coupling evidence for mixed (electrical/chemical synapses in adult rat hippocampus on both principal cells and interneurons. Thin-section electron microscopic images of small gap junction-like appositions were found at mossy fiber (MF terminals on thorny excrescences of CA3 pyramidal neurons (CA3pyr, apparently forming glutamatergic mixed synapses. Lucifer Yellow injected into four weakly-fixed CA3pyr was detected in MF axons that contacted the injected CA3pyr, supporting gap junction-mediated coupling between those two types of principal cells. Freeze-fracture replica immunogold-labeling revealed diverse sizes and morphologies of connexin36-containing gap junctions throughout hippocampus. Of 20 immunogold-labeled gap junctions, seven were large (328-1140 connexons, three of which were consistent with electrical synapses between interneurons; but nine were at axon terminal synapses, three of which were immediately adjacent to distinctive glutamate receptor-containing postsynaptic densities, forming mixed glutamatergic synapses. Four others were adjacent to small clusters of immunogold-labeled 10-nm E-face intramembrane particles, apparently representing extrasynaptic glutamate receptor particles. Gap junctions also were on spines in stratum lucidum, stratum oriens, dentate gyrus, and hilus, on both interneurons and unidentified neurons. In addition, one putative GABAergic mixed synapse was found in thin section images of a CA3pyr, but none found by immunogold-labeling were at GABAergic mixed synapses, suggesting their rarity. Cx36-containing gap junctions throughout hippocampus suggest the possibility of reciprocal modulation of electrical and chemical signals in diverse hippocampal

Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

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Meng-Lu Liu

2016-01-01

Full Text Available Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS. Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

Alteration of protein folding and degradation in motor neuron diseases : Implications and protective functions of small heat shock proteins

NARCIS (Netherlands)

Carra, Serena; Crippa, Valeria; Rusmini, Paola; Boncoraglio, Alessandra; Minoia, Melania; Giorgetti, Elisa; Kampinga, Harm H.; Poletti, Angelo

Motor neuron diseases (MNDs) are neurodegenerative disorders that specifically affect the survival and function of upper and/or lower motor neurons. Since motor neurons are responsible for the control of voluntary muscular movement, MNDs are characterized by muscle spasticity, weakness and atrophy.

GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

Science.gov (United States)

Nagahara, Yuki; Shimazawa, Masamitsu; Ohuchi, Kazuki; Ito, Junko; Takahashi, Hitoshi; Tsuruma, Kazuhiro; Kakita, Akiyoshi; Hara, Hideaki

2017-08-01

Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Advance care planning in motor neuron disease: A qualitative study of caregiver perspectives.

Science.gov (United States)

Murray, Leigh; Butow, Phyllis N; White, Kate; Kiernan, Matthew C; D'Abrew, Natalie; Herz, Helen

2016-05-01

Motor neuron disease is a fatal disease, characterised by progressive loss of motor function, often associated with cognitive deterioration and, in some, the development of frontotemporal dementia. Life-sustaining technologies are available (e.g. non-invasive ventilation and enteral nutrition) but may compromise quality of life for some patients. Timely commencement of 'Advance Care Planning' enables patients to participate in future care choices; however, this approach has rarely been explored in motor neuron disease. We aimed to investigate caregiver perspectives on the acceptability and impact of advance care planning, documented in a letter format, for patients with motor neuron disease and caregivers. This is a qualitative cross-sectional study. Data were analysed by a narrative synthesis approach. Structured interviews were held with 18 former caregivers of deceased patients with motor neuron disease. A total of 10 patients had created a disease-specific advanced directive, 'Letter of Future Care', and 8 had not. A total of four global themes emerged: Readiness for death, Empowerment, Connections and Clarifying decisions and choices. Many felt the letter of future care was or would be beneficial, engendering autonomy and respect for patients, easing difficult decision-making and enhancing communication within families. However, individuals' 'readiness' to accept encroaching death would influence uptake. Appropriate timing to commence advance care planning may depend on case-based clinical and personal characteristics. Advance care planning can assist patients to achieve a sense of control and 'peace of mind' and facilitates important family discussion. However, the timing and style of its introduction needs to be approached sensitively. Tools and strategies for increasing the efficacy of advance care planning for motor neuron disease should be evaluated and implemented. © The Author(s) 2016.

Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

Science.gov (United States)

Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

2018-02-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K + concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells

NARCIS (Netherlands)

Maldonado, Paloma P; Angulo, María Cecilia

The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

Directory of Open Access Journals (Sweden)

Lisa eMapelli

2015-05-01

Full Text Available The way long-term potentiation (LTP and depression (LTD are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network , in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei and correspondingly regulate the function of their three main neurons: granule cells (GrCs, Purkinje cells (PCs and deep cerebellar nuclear (DCN cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

Science.gov (United States)

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Super resolution imaging of genetically labelled synapses in Drosophila brain tissue

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Isabelle Ayumi Spühler

2016-05-01

Full Text Available Understanding synaptic connectivity and plasticity within brain circuits and their relationship to learning and behavior is a fundamental quest in neuroscience. Visualizing the fine details of synapses using optical microscopy remains however a major technical challenge. Super resolution microscopy opens the possibility to reveal molecular features of synapses beyond the diffraction limit. With direct stochastic optical reconstruction microscopy, dSTORM, we image synaptic proteins in the brain tissue of the fruit fly, Drosophila melanogaster. Super resolution imaging of brain tissue harbors difficulties due to light scattering and the density of signals. In order to reduce out of focus signal, we take advantage of the genetic tools available in the Drosophila and have fluorescently tagged synaptic proteins expressed in only a small number of neurons. These neurons form synapses within the calyx of the mushroom body, a distinct brain region involved in associative memory formation. Our results show that super resolution microscopy, in combination with genetically labelled synaptic proteins, is a powerful tool to investigate synapses in a quantitative fashion providing an entry point for studies on synaptic plasticity during learning and memory formation

Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.

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Adel Zeidan

Full Text Available Neuroligins (Nlgns are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8-12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.

Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.

Science.gov (United States)

De Gregorio, Cristian; Delgado, Ricardo; Ibacache, Andrés; Sierralta, Jimena; Couve, Andrés

2017-10-15

Hereditary spastic paraplegias (HSPs) are characterized by spasticity and weakness of the lower limbs, resulting from length-dependent axonopathy of the corticospinal tracts. In humans, the HSP-related atlastin genes ATL1 - ATL3 catalyze homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila , we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the atlastin -null Drosophila mutant ( atl 2 ) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes. Our findings suggest that trafficking defects produced by Atlastin dysfunction in motor neurons result in redistribution of presynaptic components and aberrant mobilization of synaptic vesicles, stressing the importance of ER-shaping proteins and the susceptibility of motor neurons to their mutations or depletion. © 2017. Published by The Company of Biologists Ltd.

Maximization of learning speed in the motor cortex due to neuronal redundancy.

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Ken Takiyama

2012-01-01

Full Text Available Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves; there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal redundancy. This analytical result does not depend on whether the distribution of the preferred direction is uniform or a skewed bimodal, both of which have been reported in neurophysiological studies. Neuronal redundancy maximizes learning speed, even if the neural network model includes recurrent connections, a nonlinear activation function, or nonlinear muscle units. Furthermore, our results do not rely on the shape of the generalization function. The results of this study suggest that one of the functional roles of neuronal redundancy is to maximize learning speed.

Phrenic motor neuron TrkB expression is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation.

Science.gov (United States)

Dale, Erica A; Fields, Daryl P; Devinney, Michael J; Mitchell, Gordon S

2017-01-01

Phrenic long-term facilitation (pLTF) is a form of hypoxia-induced spinal respiratory motor plasticity that requires new synthesis of brain derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB). Since the cellular location of relevant TrkB receptors is not known, we utilized intrapleural siRNA injections to selectively knock down TrkB receptor protein within phrenic motor neurons. TrkB receptors within phrenic motor neurons are necessary for BDNF-dependent acute intermittent hypoxia-induced pLTF, demonstrating that phrenic motor neurons are a critical site of respiratory motor plasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord.

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Sharyn L Rossi

2010-07-01

Full Text Available Motor neuron loss is characteristic of cervical spinal cord injury (SCI and contributes to functional deficit.In order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP derived from human embryonic stem cells (hESCs. In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI.These findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery.

Nuclear organization in the spinal cord depends on motor neuron lamination orchestrated by catenin and afadin function

OpenAIRE

Dewitz, C.; Pimpinella, S.; Hackel, P.; Akalin, A.; Jessell, T.M.; Zampieri, N.

2018-01-01

Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, a...

Imaging Flow Cytometry Analysis to Identify Differences of Survival Motor Neuron Protein Expression in Patients With Spinal Muscular Atrophy.

Science.gov (United States)

Arakawa, Reiko; Arakawa, Masayuki; Kaneko, Kaori; Otsuki, Noriko; Aoki, Ryoko; Saito, Kayoko

2016-08-01

Spinal muscular atrophy is a neurodegenerative disorder caused by the deficient expression of survival motor neuron protein in motor neurons. A major goal of disease-modifying therapy is to increase survival motor neuron expression. Changes in survival motor neuron protein expression can be monitored via peripheral blood cells in patients; therefore we tested the sensitivity and utility of imaging flow cytometry for this purpose. After the immortalization of peripheral blood lymphocytes from a human healthy control subject and two patients with spinal muscular atrophy type 1 with two and three copies of SMN2 gene, respectively, we used imaging flow cytometry analysis to identify significant differences in survival motor neuron expression. A bright detail intensity analysis was used to investigate differences in the cellular localization of survival motor neuron protein. Survival motor neuron expression was significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. Moreover, survival motor neuron expression correlated with the clinical severity of spinal muscular atrophy according to SMN2 copy number. The cellular accumulation of survival motor neuron protein was also significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. The benefits of imaging flow cytometry for peripheral blood analysis include its capacities for analyzing heterogeneous cell populations; visualizing cell morphology; and evaluating the accumulation, localization, and expression of a target protein. Imaging flow cytometry analysis should be implemented in future studies to optimize its application as a tool for spinal muscular atrophy clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Learning-induced Dependence of Neuronal Activity in Primary Motor Cortex on Motor Task Condition.

Science.gov (United States)

Cai, X; Shimansky, Y; He, Jiping

2005-01-01

A brain-computer interface (BCI) system such as a cortically controlled robotic arm must have a capacity of adjusting its function to a specific environmental condition. We studied this capacity in non-human primates based on chronic multi-electrode recording from the primary motor cortex of a monkey during the animal's performance of a center-out 3D reaching task and adaptation to external force perturbations. The main condition-related feature of motor cortical activity observed before the onset of force perturbation was a phasic raise of activity immediately before the perturbation onset. This feature was observed during a series of perturbation trials, but were absent under no perturbations. After adaptation has been completed, it usually was taking the subject only one trial to recognize a change in the condition to switch the neuronal activity accordingly. These condition-dependent features of neuronal activity can be used by a BCI for recognizing a change in the environmental condition and making corresponding adjustments, which requires that the BCI-based control system possess such advanced properties of the neural motor control system as capacity to learn and adapt.

Otanps synapse linear relation multiplier circuit

International Nuclear Information System (INIS)

Chible, H.

2008-01-01

In this paper, a four quadrant VLSI analog multiplier will be proposed, in order to be used in the implementation of the neurons and synapses modules of the artificial neural networks. The main characteristics of this multiplier are the small silicon area and the low power consumption and the high value of the weight input voltage. (author)

A latent low-dimensional common input drives a pool of motor neurons: a probabilistic latent state-space model.

Science.gov (United States)

Feeney, Daniel F; Meyer, François G; Noone, Nicholas; Enoka, Roger M

2017-10-01

Motor neurons appear to be activated with a common input signal that modulates the discharge activity of all neurons in the motor nucleus. It has proven difficult for neurophysiologists to quantify the variability in a common input signal, but characterization of such a signal may improve our understanding of how the activation signal varies across motor tasks. Contemporary methods of quantifying the common input to motor neurons rely on compiling discrete action potentials into continuous time series, assuming the motor pool acts as a linear filter, and requiring signals to be of sufficient duration for frequency analysis. We introduce a space-state model in which the discharge activity of motor neurons is modeled as inhomogeneous Poisson processes and propose a method to quantify an abstract latent trajectory that represents the common input received by motor neurons. The approach also approximates the variation in synaptic noise in the common input signal. The model is validated with four data sets: a simulation of 120 motor units, a pair of integrate-and-fire neurons with a Renshaw cell providing inhibitory feedback, the discharge activity of 10 integrate-and-fire neurons, and the discharge times of concurrently active motor units during an isometric voluntary contraction. The simulations revealed that a latent state-space model is able to quantify the trajectory and variability of the common input signal across all four conditions. When compared with the cumulative spike train method of characterizing common input, the state-space approach was more sensitive to the details of the common input current and was less influenced by the duration of the signal. The state-space approach appears to be capable of detecting rather modest changes in common input signals across conditions. NEW & NOTEWORTHY We propose a state-space model that explicitly delineates a common input signal sent to motor neurons and the physiological noise inherent in synaptic signal

Pursuit of Neurotransmitter Functions: Being Attracted with Fascination of the Synapse.

Science.gov (United States)

Konishi, Shiro

2017-01-01

In the beginning of the 1970s, only two chemical substances, acetylcholine and γ-aminobutyric acid (GABA), had been definitely established as neurotransmitters. Under such circumstances, I started my scientific career in Professor Masanori Otsuka's lab searching for the transmitter of primary sensory neurons. Until 1976, lines of evidence had accumulated indicating that the undecapeptide substance P could be released as a transmitter from primary afferent fibers into spinal synapses, although the substance P-mediated synaptic response had yet to be identified. Peripheral synapses could serve as a good model and thus, it was demonstrated in the prevertebral sympathetic ganglia by1985 that substance P released from axon collaterals of primary sensory neurons acts as the transmitter mediating non-cholinergic slow excitatory postsynaptic potential (EPSP). At that time, we also found that autonomic synapses were useful to uncover the transmitter role of the opioid peptide enkephalins, whose functions had been unknown since their discovery in 1975. Accordingly, enkephalins were found to serve a transmitter role in mediating presynaptic inhibition of cholinergic fast and non-cholinergic slow transmission in the prevertebral sympathetic ganglia. In 1990s, we attempted to devise a combined technique of brain slices and patch-clamp recordings. We applied it to study the regulatory mechanisms that operate around cerebellar GABAergic inhibitory synapses, because most of the studies then had centered on excitatory synapses and because inhibitory synapses are crucially involved in brain functions and disorders. Consequently, we discovered novel forms of heterosynaptic interactions, dual actions of a single transmitter, and receptor crosstalk, the details of which are described in this review.

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

Science.gov (United States)

Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

2016-02-04

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development.

Science.gov (United States)

Tomàs, Josep; Garcia, Neus; Lanuza, Maria A; Santafé, Manel M; Tomàs, Marta; Nadal, Laura; Hurtado, Erica; Simó, Anna; Cilleros, Víctor

2017-01-01

During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ) are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR), adenosine autoreceptors (AR) and trophic factor receptors (TFR, for neurotrophins and trophic cytokines) during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development

Directory of Open Access Journals (Sweden)

Josep Tomàs

2017-05-01

Full Text Available During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR, adenosine autoreceptors (AR and trophic factor receptors (TFR, for neurotrophins and trophic cytokines during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

Characterization of Some Morphological Parameters of Orbicularis Oculi Motor Neurons in the Monkey

OpenAIRE

McNeal, DW; Ge, J; Herrick, JL; Stilwell-Morecraft, KS; Morecraft, RJ

2007-01-01

The primate facial nucleus is a prominent brainstem structure that is composed of cell bodies giving rise to axons forming the facial nerve. It is musculotopically organized, but we know little about the morphological features of its motor neurons. Using the Lucifer yellow intracellular filling method, we examined 17 morphological parameters of motor neurons innervating the monkey orbicularis oculi (OO) muscle, which plays an important role in eye lid closure and voluntary and emotional facia...

Emergent Synapse Organizers: LAR-RPTPs and Their Companions.

Science.gov (United States)

Han, K A; Jeon, S; Um, J W; Ko, J

2016-01-01

Leukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) have emerged as key players that organize various aspects of neuronal development, including axon guidance, neurite extension, and synapse formation and function. Recent research has highlighted the roles of LAR-RPTPs at neuronal synapses in mediating distinct synaptic adhesion pathways through interactions with a host of extracellular ligands and in governing a variety of intracellular signaling cascades through binding to various scaffolds and signaling proteins. In this chapter, we review and update current research progress on the extracellular ligands of LAR-RPTPs, regulation of their extracellular interactions by alternative splicing and heparan sulfates, and their intracellular signaling machineries. In particular, we review structural insights on complexes of LAR-RPTPs with their various ligands. These studies lend support to general molecular mechanisms underlying LAR-RPTP-mediated synaptic adhesion and signaling pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

OpenAIRE

Streeter, K.A.; Baker-Herman, T.L.

2014-01-01

Phrenic motor neurons receive rhythmic synaptic inputs throughout life. Since even brief disruption in phrenic neural activity is detrimental to life, on-going neural activity may play a key role in shaping phrenic motor output. To test the hypothesis that spinal mechanisms sense and respond to reduced phrenic activity, anesthetized, ventilated rats received micro-injections of procaine in the C2 ventrolateral funiculus (VLF) to transiently (~30 min) block axon conduction in bulbospinal axons...

Evaluation of Motor Neuron-Like Cell Differentiation of hEnSCs on Biodegradable PLGA Nanofiber Scaffolds.

Science.gov (United States)

Ebrahimi-Barough, Somayeh; Norouzi Javidan, Abbas; Saberi, Hoshangh; Joghataei, Mohammad Tghi; Rahbarghazi, Reza; Mirzaei, Esmaeil; Faghihi, Faezeh; Shirian, Sadegh; Ai, Armin; Ai, Jafar

2015-12-01

Human endometrium is a high-dynamic tissue that contains human endometrial stem cells (hEnSCs) which can be differentiated into a number of cell lineages. The differentiation of hEnSCs into many cell lineages such as osteoblast, adipocyte, and neural cells has been investigated previously. However, the differentiation of these stem cells into motor neuron-like cells has not been investigated yet. Different biochemical and topographical cues can affect the differentiation of stem cells into a specific cell. The aim of this study was to investigate the capability of hEnSCs to be differentiated into motor neuron-like cells under biochemical and topographical cues. The biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) electrospun nanofibrous scaffold was used as a topographical cue. Human EnSCs were cultured on the PLGA scaffold and tissue culture polystyrene (TCP), then differentiation of hEnSCs into motor neuron-like cells under induction media including retinoic acid (RA) and sonic hedgehog (Shh) were evaluated for 15 days. The proliferation rate of cells was assayed by using MTT assay. The morphology of cells was studied by scanning electron microscopy imaging, and the expression of motor neuron-specific markers by real-time PCR and immunocytochemistry. Results showed that survival and differentiation of hEnSCs into motor neuron-like cells on the PLGA scaffold were better than those on the TCP group. Taken together, the results suggest that differentiated hEnSCs on PLGA can provide a suitable, three-dimensional situation for neuronal survival and outgrowth for regeneration of the central nervous system, and these cells may be a potential candidate in cellular therapy for motor neuron diseases.

Rhythmic activity of feline dorsal and ventral spinocerebellar tract neurons during fictive motor actions

DEFF Research Database (Denmark)

Fedirchuk, Brent; Stecina, Katinka; Kristensen, Kasper Kyhl

2013-01-01

(without phasic afferent feedback). In this study, we compared the activity of DSCT and VSCT neurons during fictive rhythmic motor behaviors. We used decerebrate cat preparations in which fictive motor tasks can be evoked while the animal is paralyzed and there is no rhythmic sensory input from hindlimb......Neurons of the dorsal spinocerebellar tracts (DSCT) have been described to be rhythmically active during walking on a treadmill in decerebrate cats, but this activity ceased following deafferentation of the hindlimb. This observation supported the hypothesis that DSCT neurons primarily relay...

Survival of adult neurons lacking cholesterol synthesis in vivo.

Science.gov (United States)

Fünfschilling, Ursula; Saher, Gesine; Xiao, Le; Möbius, Wiebke; Nave, Klaus-Armin

2007-01-02

Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system.

Survival of adult neurons lacking cholesterol synthesis in vivo

Directory of Open Access Journals (Sweden)

Möbius Wiebke

2007-01-01

Full Text Available Abstract Background Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Results Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1, which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. Conclusion We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system.

Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse

Energy Technology Data Exchange (ETDEWEB)

Sun, Li; Wu, Zhou; Baba, Masashi [Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582 (Japan); Peters, Christoph [Institute fuer Molekulare Medizin und Zellforshung, Albert-Ludwings-Universitaet Freiburg, D-79104 Freiburg (Germany); Uchiyama, Yasuo [Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo (Japan); Nakanishi, Hiroshi, E-mail: nakan@dent.kyushu-u.ac.jp [Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582 (Japan)

2010-08-27

Research highlights: {yields} Cathepsin B (CB), a lysosomal cysteine protease, is expressed in neuron and glia. {yields} CB increased in hypogrossal nucleus neurons after nerve injury in adult mice. {yields} CB-deficiency significantly increased the mean survival ratio of injured neurons. {yields} Thus, CB plays a critical role in axotomy-induced neuronal death in adult mice. -- Abstract: There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, the understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in axotomy

Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse

International Nuclear Information System (INIS)

Sun, Li; Wu, Zhou; Baba, Masashi; Peters, Christoph; Uchiyama, Yasuo; Nakanishi, Hiroshi

2010-01-01

Research highlights: → Cathepsin B (CB), a lysosomal cysteine protease, is expressed in neuron and glia. → CB increased in hypogrossal nucleus neurons after nerve injury in adult mice. → CB-deficiency significantly increased the mean survival ratio of injured neurons. → Thus, CB plays a critical role in axotomy-induced neuronal death in adult mice. -- Abstract: There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, the understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in axotomy-induced mortor neuron

Target-Dependent Structural Changes Accompanying Long-Term Synaptic Facilitation in Aplysia Neurons

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Glanzman, David L.; Kandel, Eric R.; Schacher, Samuel

1990-08-01

The mechanisms underlying structural changes that accompany learning and memory have been difficult to investigate in the intact nervous system. In order to make these changes more accessible for experimental analysis, dissociated cell culture and low-light-level video microscopy were used to examine Aplysia sensory neurons in the presence or absence of their target cells. Repeated applications of serotonin, a facilitating transmitter important in behavioral dishabituation and sensitization, produced growth of the sensory neurons that paralleled the long-term enhancement of synaptic strength. This growth required the presence of the postsynaptic motor neuron. Thus, both the structural changes and the synaptic facilitation of Aplysia sensorimotor synapses accompanying long-term behavioral sensitization can be produced in vitro by applying a single facilitating transmitter repeatedly. These structural changes depend on an interaction of the presynaptic neuron with an appropriate postsynaptic target.

Impacts of hybrid synapses on the noise-delayed decay in scale-free neural networks

International Nuclear Information System (INIS)

Yilmaz, Ergin

2014-01-01

Highlights: • We investigate the NDD phenomenon in a hybrid scale-free network. • Electrical synapses are more impressive on the emergence of NDD. • Electrical synapses are more efficient in suppressing of the NDD. • Average degree has two opposite effects on the appearance time of the first spike. - Abstract: We study the phenomenon of noise-delayed decay in a scale-free neural network consisting of excitable FitzHugh–Nagumo neurons. In contrast to earlier works, where only electrical synapses are considered among neurons, we primarily examine the effects of hybrid synapses on the noise-delayed decay in this study. We show that the electrical synaptic coupling is more impressive than the chemical coupling in determining the appearance time of the first-spike and more efficient on the mitigation of the delay time in the detection of a suprathreshold input signal. We obtain that hybrid networks including inhibitory chemical synapses have higher signal detection capabilities than those of including excitatory ones. We also find that average degree exhibits two different effects, which are strengthening and weakening the noise-delayed decay effect depending on the noise intensity

Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation

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Li, Xiling; Goel, Pragya; Chen, Catherine; Angajala, Varun; Chen, Xun

2018-01-01

Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments. PMID:29620520

Motor neuron disease: the impact of decreased speech intelligibility ...

African Journals Online (AJOL)

Background: The onset of motor neuron disease (MND), a neurodegenerative disease, results in physical and communication disabilities that impinge on an individual's ability to remain functionally independent. Multiple aspects of the marital relationship are affected by the continuously changing roles and responsibilities.

A central pattern generator producing alternative outputs: phase relations of leech heart motor neurons with respect to premotor synaptic input.

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Norris, Brian J; Weaver, Adam L; Wenning, Angela; García, Paul S; Calabrese, Ronald L

2007-11-01

The central pattern generator (CPG) for heartbeat in leeches consists of seven identified pairs of segmental heart interneurons and one unidentified pair. Four of the identified pairs and the unidentified pair of interneurons make inhibitory synaptic connections with segmental heart motor neurons. The CPG produces a side-to-side asymmetric pattern of intersegmental coordination among ipsilateral premotor interneurons corresponding to a similarly asymmetric fictive motor pattern in heart motor neurons, and asymmetric constriction pattern of the two tubular hearts: synchronous and peristaltic. Using extracellular techniques, we recorded, in 61 isolated nerve cords, the activity of motor neurons in conjunction with the phase reference premotor heart interneuron, HN(4), and another premotor interneuron that allowed us to assess the coordination mode. These data were then coupled with a previous description of the temporal pattern of premotor interneuron activity in the two coordination modes to synthesize a global phase diagram for the known elements of the CPG and the entire motor neuron ensemble. These average data reveal the stereotypical side-to-side asymmetric patterns of intersegmental coordination among the motor neurons and show how this pattern meshes with the activity pattern of premotor interneurons. Analysis of animal-to-animal variability in this coordination indicates that the intersegmental phase progression of motor neuron activity in the midbody in the peristaltic coordination mode is the most stereotypical feature of the fictive motor pattern. Bilateral recordings from motor neurons corroborate the main features of the asymmetric motor pattern.

Altered neuronal activities in the motor cortex with impaired motor performance in adult rats observed after infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients.

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Sankaranarayani, R; Nalini, A; Rao Laxmi, T; Raju, T R

2010-01-05

Although definite evidences are available to state that, neuronal activity is a prime determinant of animal behavior, the specific relationship between local field potentials of the motor cortex after intervention with CSF from human patients and animal behavior have remained opaque. The present study has investigated whether cerebrospinal fluid from sporadic amyotrophic lateral sclerosis (sALS) patients could disrupt neuronal activity of the motor cortex, which could be associated with disturbances in the motor performance of adult rats. CSF from ALS patients (ALS-CSF) was infused into the lateral ventricle of Wistar rats. After 24h, the impact of ALS-CSF on the local field potentials (LFPs) of the motor cortex and on the motor behavior of animals were examined. The results indicate that ALS-CSF produced a bivariate distribution on the relative power values of the LFPs of the motor cortex 24h following infusion. However, the behavioral results did not show bimodality, instead showed consistent decrease in motor performance: on rotarod and grip strength meter. The neuronal activity of the motor cortex negatively correlated with the duration of ALS symptoms at the time of lumbar puncture. Although the effect of ALS-CSF was more pronounced at 24h following infusion, the changes observed in LFPs and motor performance appeared to revert to baseline values at later time points of testing. In the current study, we have shown that, ALS-CSF has the potential to perturb neuronal activity of the rat motor cortex which was associated with poor performance on motor function tests.

Brain-wide neuronal dynamics during motor adaptation in zebrafish.

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Ahrens, Misha B; Li, Jennifer M; Orger, Michael B; Robson, Drew N; Schier, Alexander F; Engert, Florian; Portugues, Ruben

2012-05-09

A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.

Hereditary spastic paraplegia: More than an upper motor neuron disease.

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Parodi, L; Fenu, S; Stevanin, G; Durr, A

2017-05-01

Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Birth of projection neurons in adult avian brain may be related to perceptual or motor learning

International Nuclear Information System (INIS)

Alvarez-Buylla, A.; Kirn, J.R.; Nottebohm, F.

1990-01-01

Projection neurons that form part of the motor pathway for song control continue to be produced and to replace older projection neurons in adult canaries and zebra finches. This is shown by combining [3H]thymidine, a cell birth marker, and fluorogold, a retrogradely transported tracer of neuronal connectivity. Species and seasonal comparisons suggest that this process is related to the acquisition of perceptual or motor memories. The ability of an adult brain to produce and replace projection neurons should influence our thinking on brain repair

Interplay of upper and lower motor neuron degeneration in amyotrophic lateral sclerosis.

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de Carvalho, Mamede; Poliakov, Artiom; Tavares, Cristiano; Swash, Michael

2017-11-01

We studied motor unit recruitment to test a new method to identify motor unit firing rate (FR) variability. We studied 68 ALS patients, with and without upper neuron signs (UMN) in lower limbs, 24 patients with primary lateral sclerosis (PLS), 13 patients with spinal cord lesion and 39 normal subjects. All recordings were made from tibialis anterior muscles of normal strength. Subjects performed a very slight contraction in order to activate 2 motor units in each recording. 5-7 motor unit pairs were recorded in each subject. Mean consecutive differences (MCD) were calculated for each pair of potentials. The mean MCD for each muscle was estimated as the mean from the total number of pairs recorded. Ap valuemotor unit in a pair of units was markedly reduced in PLS, and in subjects with spinal cord lesions. These results support a lower threshold and reduced FR fluctuation in spinal motor neurons of spastic patients. This method can be developed for detection of UMN lesions. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Associative Memory Extinction Is Accompanied by Decayed Plasticity at Motor Cortical Neurons and Persistent Plasticity at Sensory Cortical Neurons.

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Guo, Rui; Ge, Rongjing; Zhao, Shidi; Liu, Yulong; Zhao, Xin; Huang, Li; Guan, Sodong; Lu, Wei; Cui, Shan; Wang, Shirlene; Wang, Jin-Hui

2017-01-01

Associative memory is essential for cognition, in which associative memory cells and their plasticity presumably play important roles. The mechanism underlying associative memory extinction vs. maintenance remains unclear, which we have studied in a mouse model of cross-modal associative learning. Paired whisker and olfaction stimulations lead to a full establishment of odorant-induced whisker motion in training day 10, which almost disappears if paired stimulations are not given in a week, and then recovers after paired stimulation for an additional day. In mice that show associative memory, extinction and recovery, we have analyzed the dynamical plasticity of glutamatergic neurons in layers II-III of the barrel cortex and layers IV-V of the motor cortex. Compared with control mice, the rate of evoked spikes as well as the amplitude and frequency of excitatory postsynaptic currents increase, whereas the amplitude and frequency of inhibitory postsynaptic currents (IPSC) decrease at training day 10 in associative memory mice. Without paired training for a week, these plastic changes are persistent in the barrel cortex and decayed in the motor cortex. If paired training is given for an additional day to revoke associative memory, neuronal plasticity recovers in the motor cortex. Our study indicates persistent neuronal plasticity in the barrel cortex for cross-modal memory maintenance as well as the dynamical change of neuronal plasticity in the motor cortex for memory retrieval and extinction. In other words, the sensory cortices are essential for long-term memory while the behavior-related cortices with the inability of memory retrieval are correlated to memory extinction.

Associative Memory Extinction Is Accompanied by Decayed Plasticity at Motor Cortical Neurons and Persistent Plasticity at Sensory Cortical Neurons

Directory of Open Access Journals (Sweden)

Rui Guo

2017-06-01

Full Text Available Associative memory is essential for cognition, in which associative memory cells and their plasticity presumably play important roles. The mechanism underlying associative memory extinction vs. maintenance remains unclear, which we have studied in a mouse model of cross-modal associative learning. Paired whisker and olfaction stimulations lead to a full establishment of odorant-induced whisker motion in training day 10, which almost disappears if paired stimulations are not given in a week, and then recovers after paired stimulation for an additional day. In mice that show associative memory, extinction and recovery, we have analyzed the dynamical plasticity of glutamatergic neurons in layers II–III of the barrel cortex and layers IV–V of the motor cortex. Compared with control mice, the rate of evoked spikes as well as the amplitude and frequency of excitatory postsynaptic currents increase, whereas the amplitude and frequency of inhibitory postsynaptic currents (IPSC decrease at training day 10 in associative memory mice. Without paired training for a week, these plastic changes are persistent in the barrel cortex and decayed in the motor cortex. If paired training is given for an additional day to revoke associative memory, neuronal plasticity recovers in the motor cortex. Our study indicates persistent neuronal plasticity in the barrel cortex for cross-modal memory maintenance as well as the dynamical change of neuronal plasticity in the motor cortex for memory retrieval and extinction. In other words, the sensory cortices are essential for long-term memory while the behavior-related cortices with the inability of memory retrieval are correlated to memory extinction.

The organization of plasticity in the cerebellar cortex: from synapses to control.

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D'Angelo, Egidio

2014-01-01

The cerebellum is thought to play a critical role in procedural learning, but the relationship between this function and the underlying cellular and synaptic mechanisms remains largely speculative. At present, at least nine forms of long-term synaptic and nonsynaptic plasticity (some of which are bidirectional) have been reported in the cerebellar cortex and deep cerebellar nuclei. These include long-term potentiation (LTP) and long-term depression at the mossy fiber-granule cell synapse, at the synapses formed by parallel fibers, climbing fibers, and molecular layer interneurons on Purkinje cells, and at the synapses formed by mossy fibers and Purkinje cells on deep cerebellar nuclear cells, as well as LTP of intrinsic excitability in granule cells, Purkinje cells, and deep cerebellar nuclear cells. It is suggested that the complex properties of cerebellar learning would emerge from the distribution of plasticity in the network and from its dynamic remodeling during the different phases of learning. Intrinsic and extrinsic factors may hold the key to explain how the different forms of plasticity cooperate to select specific transmission channels and to regulate the signal-to-noise ratio through the cerebellar cortex. These factors include regulation of neuronal excitation by local inhibitory networks, engagement of specific molecular mechanisms by spike bursts and theta-frequency oscillations, and gating by external neuromodulators. Therefore, a new and more complex view of cerebellar plasticity is emerging with respect to that predicted by the original "Motor Learning Theory," opening issues that will require experimental and computational testing. © 2014 Elsevier B.V. All rights reserved.

Objective markers for upper motor neuron involvement in amyotrophic lateral sclerosis

International Nuclear Information System (INIS)

Iwata, Nobue K.

2007-01-01

A reliable objective marker of upper motor neuron (UMN) involvement is critical for early diagnosis and monitoring disease course in patients with amyotrophic lateral sclerosis (ALS). Lower motor neuron (LMN) involvement can be identified by electromyography, whereas UMN dysfunction has been currently distinguished solely by neurological examination. In the search for diagnostic tests to evaluate UMN involvement in ALS, numerous reports on new markers using neurophysiological and imaging techniques are accumulating. Transcranial magnetic stimulation evaluates the neurophysiological integrity of UMN. Although the diagnostic reliability and sensitivity of various parameters of central motor conduction measurement differ, central motor conduction time measurement using brainstem stimulation is potentially useful for determining UMN dysfunction by distinguishing lesions above the pyramidal decussation. MR-based techniques also have the potential to be used as diagnostic markers and are continuously improving as a modality to pursue early diagnosis and monitoring of the disease progression. Conventional MRI reveals hyperintensity along the corticospinal tract, hypointensity in the motor cortex, and atrophy of the precentral gyrus. There is a lack of agreement regarding sensitivity and specificity in detecting UMN abnormalities. Recent advances in magnetizing transfer imaging (MTI) provide more sensitive and accurate detection of corticospinal tract abnormality than conventional MRI. Reduction in N-acetyl-aspartate by proton magnetic spectroscopy in the motor cortex or the brainstem of the patients with ALS is reported with different techniques. Its diagnostic value in clinical assessment is uncertain and remains to be established. Diffusion tensor imaging (DTI) reveals the structural integrity of neuronal fibers, and has great diagnostic promise for ALS. It shows reduced diffusion anisotropy in the corticospinal tract with good correlation with physiological index

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

Science.gov (United States)

Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

2016-05-17

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Synapse-centric mapping of cortical models to the SpiNNaker neuromorphic architecture

Directory of Open Access Journals (Sweden)

James Courtney Knight

2016-09-01

Full Text Available While the adult human brain has approximately 8.8x10^10 neurons, this number is dwarfed by its 1x10^15 synapses. From the point of view of neuromorphic engineering and neural simulation in general this makes the simulation of these synapses a particularly complex problem. SpiNNaker is a digital, neuromorphic architecture designed for simulating large-scale spiking neural networks at speeds close to biological real-time. Current solutions for simulating spiking neural networks on SpiNNaker are heavily inspired by work on distributed high-performance computing. However, while SpiNNaker shares many characteristics with such distributed systems, its component nodes have much more limited resources and, as the system lacks global synchronization, the computation performed on each node must complete within a fixed time step. We first analyze the performance of the current SpiNNaker neural simulation software and identify several problems that occur when it is used to simulate networks of the type often used to model the cortex which contain large numbers of sparsely connected synapses. We then present a new, more flexible approach for mapping the simulation of such networks to SpiNNaker which solves many of these problems. Finally we analyze the performance of our new approach using both benchmarks, designed to represent cortical connectivity, and larger, functional cortical models. In a benchmark network where neurons receive input from 8000 STDP synapses, our new approach allows more neurons to be simulated on each SpiNNaker core than has been previously possible. We also demonstrate that the largest plastic neural network previously simulated on neuromorphic hardware can be run in real time using our new approach: double the speed that was previously achieved. Additionally this network contains two types of plastic synapse which previously had to be trained separately but, using our new approach, can be trained simultaneously.

Generation of functional inhibitory synapses incorporating defined combinations of GABA(A or glycine receptor subunits

Directory of Open Access Journals (Sweden)

Christine Laura Dixon

2015-12-01

Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.

Formation and function of synapses with respect to Schwann cells at the end of motor nerve terminal branches on mature amphibian (Bufo marinus) muscle.

Science.gov (United States)

Macleod, G T; Dickens, P A; Bennett, M R

2001-04-01

A study has been made of the formation and regression of synapses with respect to Schwann cells at the ends of motor nerve terminal branches in mature toad (Bufo marinus) muscle. Synapse formation and regression, as inferred from the appearance and loss of N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide (FM1-43)-stained vesicle clusters, occurred at the ends of terminal branches over a 16 hr period. Multiple microelectrodes placed in an array about FM1-43 blobs at the ends of terminal branches detected the electrical signs of neurotransmitter being released onto receptors. Injection of a calcium indicator (Oregon Green 488 BAPTA-1) into the motor nerve with subsequent imaging of the calcium transients, in response to stimulation, often showed a reduced calcium influx in the ends of terminal branches. Injection of a fluorescent dye into motor nerves revealed the full extent of their terminal branches and growing processes. Injection of the terminal Schwann cells (TSCs) often revealed pseudopodial TSC processes up to 10-microm-long. Imaging of these TSC processes over minutes or hours showed that they were highly labile and capable of extending several micrometers in a few minutes. Injection of motor nerve terminals with a different dye to that injected into their TSCs revealed that terminal processes sometimes followed the TSC processes over a few hours. It is suggested that the ends of motor nerve terminals in vivo are in a constant state of remodeling through the formation and regression of processes, that TSC processes guide the remodeling, and that it can occur over a relatively short period of time.

Cadmium action in synapses in the brain

International Nuclear Information System (INIS)

Minami, Akira; Takeda, Atsushi; Nishibaba, Daisuke; Tekefuta, Sachiyo; Oku, Naoto

2001-01-01

Chronic exposure to cadmium causes central nervous system disorders, e.g., olfactory dysfunction. To clarify cadmium toxicity in synaptic neurotransmission in the brain, the movement and action of cadmium in the synapses was examined using in vivo microdialysis. One and 24 h after injection of 109 CdCl 2 into the amygdala of rats, 109 Cd release into the extracellular space was facilitated by stimulation with high K + , suggesting that cadmium taken up in amygdalar neurons is released into the synaptic clefts in a calcium- and impulse-dependent manner. To examine the action of cadmium in the synapses, the amygdala was perfused with artificial cerebrospinal fluid containing 10-30 μM CdCl 2 . The release of excitatory neurotransmitters, i.e., glutamate and aspartate, into the extracellular space was decreased during perfusion with cadmium, while the release of inhibitory neurotransmitters, i.e., glycine and γ-amino butyric acid (GABA), into the extracellular space was increased during the period. These results suggest that cadmium released from the amygdalar neuron terminals affects the degree and balance of excitation-inhibition in synaptic neurotransmission. (author)

Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS

NARCIS (Netherlands)

Filézac de L'Etang, Audrey; Maharjan, Niran; Cordeiro Braña, Marisa; Ruegsegger, Céline; Rehmann, Ruth; Goswami, Anand; Roos, Andreas; Troost, Dirk; Schneider, Bernard L.; Weis, Joachim; Saxena, Smita

2015-01-01

Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic

Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress.

Science.gov (United States)

Maras, P M; Molet, J; Chen, Y; Rice, C; Ji, S G; Solodkin, A; Baram, T Z

2014-07-01

The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress.

Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress

Science.gov (United States)

Maras, P M; Molet, J; Chen, Y; Rice, C; Ji, S G; Solodkin, A; Baram, T Z

2014-01-01

The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress. PMID:24589888

Prostaglandin E2 facilitates neurite outgrowth in a motor neuron-like cell line, NSC-34

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Hiroshi Nango

2017-10-01

Full Text Available Prostaglandin E2 (PGE2 exerts various biological effects by binding to E-prostanoid receptors (EP1-4. Although recent studies have shown that PGE2 induces cell differentiation in some neuronal cells such as mouse DRG neurons and sensory neuron-like ND7/23 cells, it is unclear whether PGE2 plays a role in differentiation of motor neurons. In the present study, we investigated the mechanism of PGE2-induced differentiation of motor neurons using NSC-34, a mouse motor neuron-like cell line. Exposure of undifferentiated NSC-34 cells to PGE2 and butaprost, an EP2-selective agonist, resulted in a reduction of MTT reduction activity without increase the number of propidium iodide-positive cells and in an increase in the number of neurite-bearing cells. Sulprostone, an EP1/3 agonist, also significantly lowered MTT reduction activity by 20%; however, no increase in the number of neurite-bearing cells was observed within the concentration range tested. PGE2-induced neurite outgrowth was attenuated significantly in the presence of PF-0441848, an EP2-selective antagonist. Treatment of these cells with dibutyryl-cAMP increased the number of neurite-bearing cells with no effect on cell proliferation. These results suggest that PGE2 promotes neurite outgrowth and suppresses cell proliferation by activating the EP2 subtype, and that the cAMP-signaling pathway is involved in PGE2-induced differentiation of NSC-34 cells. Keywords: Prostaglandin E2, E-prostanoid receptors, Motor neuron, Neurite outgrowth, cAMP

Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages.

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Laird, Angela S; Mackovski, Nikolce; Rinkwitz, Silke; Becker, Thomas S; Giacomotto, Jean

2016-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1 silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function and premature death. Interestingly, smn1 knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1 silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Highly efficient retrograde gene transfer into motor neurons by a lentiviral vector pseudotyped with fusion glycoprotein.

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Miyabi Hirano

Full Text Available The development of gene therapy techniques to introduce transgenes that promote neuronal survival and protection provides effective therapeutic approaches for neurological and neurodegenerative diseases. Intramuscular injection of adenoviral and adeno-associated viral vectors, as well as lentiviral vectors pseudotyped with rabies virus glycoprotein (RV-G, permits gene delivery into motor neurons in animal models for motor neuron diseases. Recently, we developed a vector with highly efficient retrograde gene transfer (HiRet by pseudotyping a human immunodeficiency virus type 1 (HIV-1-based vector with fusion glycoprotein B type (FuG-B or a variant of FuG-B (FuG-B2, in which the cytoplasmic domain of RV-G was replaced by the corresponding part of vesicular stomatitis virus glycoprotein (VSV-G. We have also developed another vector showing neuron-specific retrograde gene transfer (NeuRet with fusion glycoprotein C type, in which the short C-terminal segment of the extracellular domain and transmembrane/cytoplasmic domains of RV-G was substituted with the corresponding regions of VSV-G. These two vectors afford the high efficiency of retrograde gene transfer into different neuronal populations in the brain. Here we investigated the efficiency of the HiRet (with FuG-B2 and NeuRet vectors for retrograde gene transfer into motor neurons in the spinal cord and hindbrain in mice after intramuscular injection and compared it with the efficiency of the RV-G pseudotype of the HIV-1-based vector. The main highlight of our results is that the HiRet vector shows the most efficient retrograde gene transfer into both spinal cord and hindbrain motor neurons, offering its promising use as a gene therapeutic approach for the treatment of motor neuron diseases.

Synaptic Plasticity and Spike Synchronisation in Neuronal Networks

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Borges, Rafael R.; Borges, Fernando S.; Lameu, Ewandson L.; Protachevicz, Paulo R.; Iarosz, Kelly C.; Caldas, Iberê L.; Viana, Ricardo L.; Macau, Elbert E. N.; Baptista, Murilo S.; Grebogi, Celso; Batista, Antonio M.

2017-12-01

Brain plasticity, also known as neuroplasticity, is a fundamental mechanism of neuronal adaptation in response to changes in the environment or due to brain injury. In this review, we show our results about the effects of synaptic plasticity on neuronal networks composed by Hodgkin-Huxley neurons. We show that the final topology of the evolved network depends crucially on the ratio between the strengths of the inhibitory and excitatory synapses. Excitation of the same order of inhibition revels an evolved network that presents the rich-club phenomenon, well known to exist in the brain. For initial networks with considerably larger inhibitory strengths, we observe the emergence of a complex evolved topology, where neurons sparsely connected to other neurons, also a typical topology of the brain. The presence of noise enhances the strength of both types of synapses, but if the initial network has synapses of both natures with similar strengths. Finally, we show how the synchronous behaviour of the evolved network will reflect its evolved topology.

Modeling the phenotype of spinal muscular atrophy by the direct conversion of human fibroblasts to motor neurons.

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Zhang, Qi-Jie; Li, Jin-Jing; Lin, Xiang; Lu, Ying-Qian; Guo, Xin-Xin; Dong, En-Lin; Zhao, Miao; He, Jin; Wang, Ning; Chen, Wan-Jin

2017-02-14

Spinal muscular atrophy (SMA) is a lethal autosomal recessive neurological disease characterized by selective degeneration of motor neurons in the spinal cord. In recent years, the development of cellular reprogramming technology has provided an alternative and effective method for obtaining patient-specific neurons in vitro. In the present study, we applied this technology to the field of SMA to acquire patient-specific induced motor neurons that were directly converted from fibroblasts via the forced expression of 8 defined transcription factors. The infected fibroblasts began to grow in a dipolar manner, and the nuclei gradually enlarged. Typical Tuj1-positive neurons were generated at day 23. After day 35, induced neurons with multiple neurites were observed, and these neurons also expressed the hallmarks of Tuj1, HB9, ISL1 and CHAT. The conversion efficiencies were approximately 5.8% and 5.5% in the SMA and control groups, respectively. Additionally, the SMA-induced neurons exhibited a significantly reduced neurite outgrowth rate compared with the control neurons. After day 60, the SMA-induced neurons also exhibited a liability of neuronal degeneration and remarkable fracturing of the neurites was observed. By directly reprogramming fibroblasts, we established a feeder-free conversion system to acquire SMA patient-specific induced motor neurons that partially modeled the phenotype of SMA in vitro.

Reciprocal inhibition between motor neurons of the tibialis anterior and triceps surae in humans.

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Yavuz, Utku Ş; Negro, Francesco; Diedrichs, Robin; Farina, Dario

2018-05-01

Motor neurons innervating antagonist muscles receive reciprocal inhibitory afferent inputs to facilitate the joint movement in the two directions. The present study investigates the mutual transmission of reciprocal inhibitory afferent inputs between the tibialis anterior (TA) and triceps surae (soleus and medial gastrocnemius) motor units. We assessed this mutual mechanism in large populations of motor units for building a statistical distribution of the inhibition amplitudes during standardized input to the motor neuron pools to minimize the effect of modulatory pathways. Single motor unit activities were identified using high-density surface electromyography (HDsEMG) recorded from the TA, soleus (Sol), and medial gastrocnemius (GM) muscles during isometric dorsi- and plantarflexion. Reciprocal inhibition on the antagonist muscle was elicited by electrical stimulation of the tibial (TN) or common peroneal nerves (CPN). The probability density distributions of reflex strength for each muscle were estimated to examine the strength of mutual transmission of reciprocal inhibitory input. The results showed that the strength of reciprocal inhibition in the TA motor units was fourfold greater than for the GM and the Sol motor units. This suggests an asymmetric transmission of reciprocal inhibition between ankle extensor and flexor muscles. This asymmetry cannot be explained by differences in motor unit type composition between the investigated muscles since we sampled low-threshold motor units in all cases. Therefore, the differences observed for the strength of inhibition are presumably due to a differential reciprocal spindle afferent input and the relative contribution of nonreciprocal inhibitory pathways. NEW & NOTEWORTHY We investigated the mutual transmission of reciprocal inhibition in large samples of motor units using a standardized input (electrical stimulation) to the motor neurons. The results demonstrated that the disynaptic reciprocal inhibition exerted

Low-doses of cisplatin injure hippocampal synapses: a mechanism for 'chemo' brain?

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Andres, Adrienne L; Gong, Xing; Di, Kaijun; Bota, Daniela A

2014-05-01

Chemotherapy-related cognitive deficits are a major neurological problem, but the underlying mechanisms are unclear. The death of neural stem/precursor cell (NSC) by cisplatin has been reported as a potential cause, but this requires high doses of chemotherapeutic agents. Cisplatin is frequently used in modern oncology, and it achieves high concentrations in the patient's brain. Here we report that exposure to low concentrations of cisplatin (0.1μM) causes the loss of dendritic spines and synapses within 30min. Longer exposures injured dendritic branches and reduced dendritic complexity. At this low concentration, cisplatin did not affect NSC viability nor provoke apoptosis. However, higher cisplatin levels (1μM) led to the rapid loss of synapses and dendritic disintegration, and neuronal-but not NSC-apoptosis. In-vivo treatment with cisplatin at clinically relevant doses also caused a reduction of dendritic branches and decreased spine density in CA1 and CA3 hippocampal neurons. An acute increase in cell death was measured in the CA1 and CA3 neurons, as well as in the NSC population located in the subgranular zone of the dentate gyrus in the cisplatin treated animals. The density of dendritic spines is related to the degree of neuronal connectivity and function, and pathological changes in spine number or structure have significant consequences for brain function. Therefore, this synapse and dendritic damage might contribute to the cognitive impairment observed after cisplatin treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury

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Ryge, J.; Winther, Ole; Wienecke, J.

2010-01-01

Background: Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of ...

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

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Lipski, Witold J; Wozny, Thomas A; Alhourani, Ahmad; Kondylis, Efstathios D; Turner, Robert S; Crammond, Donald J; Richardson, Robert Mark

2017-09-01

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate. NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also

Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses

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Tanaka Mika

2013-01-01

Full Text Available Abstract Background Neuronal activity alters calcium ion (Ca2+ dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, “IP3 sponge”, attenuates astrocytic Ca2+ signaling. Results Attenuated Ca2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic ‘protection’ of the synapses facilitated glutamate ‘spillover’, which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions Our findings suggest that IP3-mediated astrocytic Ca2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus.

Dysarthria of Motor Neuron Disease: Clinician Judgments of Severity.

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Seikel, J. Anthony; And Others

1990-01-01

This study investigated the relationship between the temporal-acoustic parameters of the speech of 15 adults with motor neuron disease. Differences in predictions of the progression of the disease and clinician judgments of dysarthria severity were found to relate to the linguistic systems of both speaker and judge. (Author/JDD)

Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

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Laurent Ladepeche

Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

Neuronal synchrony: peculiarity and generality.

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Nowotny, Thomas; Huerta, Ramon; Rabinovich, Mikhail I

2008-09-01

Synchronization in neuronal systems is a new and intriguing application of dynamical systems theory. Why are neuronal systems different as a subject for synchronization? (1) Neurons in themselves are multidimensional nonlinear systems that are able to exhibit a wide variety of different activity patterns. Their "dynamical repertoire" includes regular or chaotic spiking, regular or chaotic bursting, multistability, and complex transient regimes. (2) Usually, neuronal oscillations are the result of the cooperative activity of many synaptically connected neurons (a neuronal circuit). Thus, it is necessary to consider synchronization between different neuronal circuits as well. (3) The synapses that implement the coupling between neurons are also dynamical elements and their intrinsic dynamics influences the process of synchronization or entrainment significantly. In this review we will focus on four new problems: (i) the synchronization in minimal neuronal networks with plastic synapses (synchronization with activity dependent coupling), (ii) synchronization of bursts that are generated by a group of nonsymmetrically coupled inhibitory neurons (heteroclinic synchronization), (iii) the coordination of activities of two coupled neuronal networks (partial synchronization of small composite structures), and (iv) coarse grained synchronization in larger systems (synchronization on a mesoscopic scale). (c) 2008 American Institute of Physics.

(--Epigallocatechin gallate attenuates NADPH-d/nNOS expression in motor neurons of rats following peripheral nerve injury

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Tseng Chi-Yu

2011-06-01

Full Text Available Abstract Background Oxidative stress and large amounts of nitric oxide (NO have been implicated in the pathophysiology of neuronal injury and neurodegenerative disease. Recent studies have shown that (--epigallocatechin gallate (EGCG, one of the green tea polyphenols, has potent antioxidant effects against free radical-mediated lipid peroxidation in ischemia-induced neuronal damage. The purpose of this study was to examine whether EGCG would attenuate neuronal expression of NADPH-d/nNOS in the motor neurons of the lower brainstem following peripheral nerve crush. Thus, young adult rats were treated with EGCG (10, 25, or 50 mg/kg, i.p. 30 min prior to crushing their hypoglossal and vagus nerves for 30 seconds (left side, at the cervical level. The treatment (pre-crush doses of EGCG was continued from day 1 to day 6, and the animals were sacrificed on days 3, 7, 14 and 28. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d histochemistry and neuronal nitric oxide synthase (nNOS immunohistochemistry were used to assess neuronal NADPH-d/nNOS expression in the hypoglossal nucleus and dorsal motor nucleus of the vagus. Results In rats treated with high dosages of EGCG (25 or 50 mg/kg, NADPH-d/nNOS reactivity and cell death of the motor neurons were significantly decreased. Conclusions The present evidence indicated that EGCG can reduce NADPH-d/nNOS reactivity and thus may enhance motor neuron survival time following peripheral nerve injury.

Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons.

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Cuesto, Germán; Enriquez-Barreto, Lilian; Caramés, Cristina; Cantarero, Marta; Gasull, Xavier; Sandi, Carmen; Ferrús, Alberto; Acebes, Ángel; Morales, Miguel

2011-02-23

The possibility of changing the number of synapses may be an important asset in the treatment of neurological diseases. In this context, the synaptogenic role of the phosphoinositide-3-kinase (PI3K) signaling cascade has been previously demonstrated in Drosophila. This study shows that treatment with a PI3K-activating transduction peptide is able to promote synaptogenesis and spinogenesis in primary cultures of rat hippocampal neurons, as well as in CA1 hippocampal neurons in vivo. In culture, the peptide increases synapse density independently of cell density, culture age, dendritic complexity, or synapse type. The induced synapses also increase neurotransmitter release from cultured neurons. The synaptogenic signaling pathway includes PI3K-Akt. Furthermore, the treatment is effective on adult neurons, where it induces spinogenesis and enhances the cognitive behavior of treated animals in a fear-conditioning assay. These findings demonstrate that functional synaptogenesis can be induced in mature mammalian brains through PI3K activation.

Unsupervised learning in neural networks with short range synapses

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Brunnet, L. G.; Agnes, E. J.; Mizusaki, B. E. P.; Erichsen, R., Jr.

2013-01-01

Different areas of the brain are involved in specific aspects of the information being processed both in learning and in memory formation. For example, the hippocampus is important in the consolidation of information from short-term memory to long-term memory, while emotional memory seems to be dealt by the amygdala. On the microscopic scale the underlying structures in these areas differ in the kind of neurons involved, in their connectivity, or in their clustering degree but, at this level, learning and memory are attributed to neuronal synapses mediated by longterm potentiation and long-term depression. In this work we explore the properties of a short range synaptic connection network, a nearest neighbor lattice composed mostly by excitatory neurons and a fraction of inhibitory ones. The mechanism of synaptic modification responsible for the emergence of memory is Spike-Timing-Dependent Plasticity (STDP), a Hebbian-like rule, where potentiation/depression is acquired when causal/non-causal spikes happen in a synapse involving two neurons. The system is intended to store and recognize memories associated to spatial external inputs presented as simple geometrical forms. The synaptic modifications are continuously applied to excitatory connections, including a homeostasis rule and STDP. In this work we explore the different scenarios under which a network with short range connections can accomplish the task of storing and recognizing simple connected patterns.

High Content Analysis of Hippocampal Neuron-Astrocyte Co-cultures Shows a Positive Effect of Fortasyn Connect on Neuronal Survival and Postsynaptic Maturation.

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van Deijk, Anne-Lieke F; Broersen, Laus M; Verkuyl, J Martin; Smit, August B; Verheijen, Mark H G

2017-01-01

Neuronal and synaptic membranes are composed of a phospholipid bilayer. Supplementation with dietary precursors for phospholipid synthesis -docosahexaenoic acid (DHA), uridine and choline- has been shown to increase neurite outgrowth and synaptogenesis both in vivo and in vitro . A role for multi-nutrient intervention with specific precursors and cofactors has recently emerged in early Alzheimer's disease, which is characterized by decreased synapse numbers in the hippocampus. Moreover, the medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect (FC), improves memory performance in early Alzheimer's disease patients, possibly via maintaining brain connectivity. This suggests an effect of FC on synapses, but the underlying cellular mechanism is not fully understood. Therefore, we investigated the effect of FC (consisting of DHA, eicosapentaenoic acid (EPA), uridine, choline, phospholipids, folic acid, vitamins B12, B6, C and E, and selenium), on synaptogenesis by supplementing it to primary neuron-astrocyte co-cultures, a cellular model that mimics metabolic dependencies in the brain. We measured neuronal developmental processes using high content screening in an automated manner, including neuronal survival, neurite morphology, as well as the formation and maturation of synapses. Here, we show that FC supplementation resulted in increased numbers of neurons without affecting astrocyte number. Furthermore, FC increased postsynaptic PSD95 levels in both immature and mature synapses. These findings suggest that supplementation with FC to neuron-astrocyte co-cultures increased both neuronal survival and the maturation of postsynaptic terminals, which might aid the functional interpretation of FC-based intervention strategies in neurological diseases characterized by neuronal loss and impaired synaptic functioning.

High Content Analysis of Hippocampal Neuron-Astrocyte Co-cultures Shows a Positive Effect of Fortasyn Connect on Neuronal Survival and Postsynaptic Maturation

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Anne-Lieke F. van Deijk

2017-08-01

Full Text Available Neuronal and synaptic membranes are composed of a phospholipid bilayer. Supplementation with dietary precursors for phospholipid synthesis –docosahexaenoic acid (DHA, uridine and choline– has been shown to increase neurite outgrowth and synaptogenesis both in vivo and in vitro. A role for multi-nutrient intervention with specific precursors and cofactors has recently emerged in early Alzheimer's disease, which is characterized by decreased synapse numbers in the hippocampus. Moreover, the medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect (FC, improves memory performance in early Alzheimer's disease patients, possibly via maintaining brain connectivity. This suggests an effect of FC on synapses, but the underlying cellular mechanism is not fully understood. Therefore, we investigated the effect of FC (consisting of DHA, eicosapentaenoic acid (EPA, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C and E, and selenium, on synaptogenesis by supplementing it to primary neuron-astrocyte co-cultures, a cellular model that mimics metabolic dependencies in the brain. We measured neuronal developmental processes using high content screening in an automated manner, including neuronal survival, neurite morphology, as well as the formation and maturation of synapses. Here, we show that FC supplementation resulted in increased numbers of neurons without affecting astrocyte number. Furthermore, FC increased postsynaptic PSD95 levels in both immature and mature synapses. These findings suggest that supplementation with FC to neuron-astrocyte co-cultures increased both neuronal survival and the maturation of postsynaptic terminals, which might aid the functional interpretation of FC-based intervention strategies in neurological diseases characterized by neuronal loss and impaired synaptic functioning.

Towards building hybrid biological/in silico neural networks for motor neuroprosthetic control

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Mehmet eKocaturk

2015-08-01

Full Text Available In this article, we introduce the Bioinspired Neuroprosthetic Design Environment (BNDE as a practical platform for the development of novel brain machine interface (BMI controllers which are based on spiking model neurons. We built the BNDE around a hard real-time system so that it is capable of creating simulated synapses from extracellularly recorded neurons to model neurons. In order to evaluate the practicality of the BNDE for neuroprosthetic control experiments, a novel, adaptive BMI controller was developed and tested using real-time closed-loop simulations. The present controller consists of two in silico medium spiny neurons which receive simulated synaptic inputs from recorded motor cortical neurons. In the closed-loop simulations, the recordings from the cortical neurons were imitated using an external, hardware-based neural signal synthesizer. By implementing a reward-modulated spike timing-dependent plasticity rule, the controller achieved perfect target reach accuracy for a two target reaching task in one dimensional space. The BNDE combines the flexibility of software-based spiking neural network (SNN simulations with powerful online data visualization tools and is a low-cost, PC-based and all-in-one solution for developing neurally-inspired BMI controllers. We believe the BNDE is the first implementation which is capable of creating hybrid biological/in silico neural networks for motor neuroprosthetic control and utilizes multiple CPU cores for computationally intensive real-time SNN simulations.

Suicide in patients with motor neuron disease

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Bak, Søren; Stenager, E N; Stenager, Egon

1994-01-01

The aim of the present study was to assess, through an epidemiological study, whether suicide risk is increased in patients with motor neuron disease (MND). The study involved 116 patients with MND. In the study period 92 patients died, 47 males and 45 females. No patients committed suicide....... The number of expected suicides was 0.27 for males and 0.12 for females, a total of 0.38. The difference between observed and expected suicides was not statistically significant for males and females....

dHb9 expressing larval motor neurons persist through metamorphosis to innervate adult-specific muscle targets and function in Drosophila eclosion.

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Banerjee, Soumya; Toral, Marcus; Siefert, Matthew; Conway, David; Dorr, Meredith; Fernandes, Joyce

2016-12-01

The Drosophila larval nervous system is radically restructured during metamorphosis to produce adult specific neural circuits and behaviors. Genesis of new neurons, death of larval neurons and remodeling of those neurons that persistent collectively act to shape the adult nervous system. Here, we examine the fate of a subset of larval motor neurons during this restructuring process. We used a dHb9 reporter, in combination with the FLP/FRT system to individually identify abdominal motor neurons in the larval to adult transition using a combination of relative cell body location, axonal position, and muscle targets. We found that segment specific cell death of some dHb9 expressing motor neurons occurs throughout the metamorphosis period and continues into the post-eclosion period. Many dHb9 > GFP expressing neurons however persist in the two anterior hemisegments, A1 and A2, which have segment specific muscles required for eclosion while a smaller proportion also persist in A2-A5. Consistent with a functional requirement for these neurons, ablating them during the pupal period produces defects in adult eclosion. In adults, subsequent to the execution of eclosion behaviors, the NMJs of some of these neurons were found to be dismantled and their muscle targets degenerate. Our studies demonstrate a critical continuity of some larval motor neurons into adults and reveal that multiple aspects of motor neuron remodeling and plasticity that are essential for adult motor behaviors. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1387-1416, 2016. © 2016 Wiley Periodicals, Inc.