The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells.

The mammalian brain is a complex organ comprising neurons, glia, and more than 1 × 1014 synapses. Neurons are a heterogeneous group of electrically active cells, which form the framework of the complex circuitry of the brain. However, glial cells, which are primarily divided into astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte precursor cells (OPCs), constitute approximately half of all neural cells in the mammalian central nervous system (CNS) and mainly provide nutrition and tropic support to neurons in the brain. In the last two decades, the concept of "tripartite synapses" has drawn great attention, which emphasizes that astrocytes are an integral part of the synapse and regulate neuronal activity in a feedback manner after receiving neuronal signals. Since then, synaptic modulation by glial cells has been extensively studied and substantially revised. In this review, we summarize the latest significant findings on how glial cells, in particular, microglia and OL lineage cells, impact and remodel the structure and function of synapses in the brain. Our review highlights the cellular and molecular aspects of neuron-glia crosstalk and provides additional information on how aberrant synaptic communication between neurons and glia may contribute to neural pathologies.

Synaptic pathology in Huntington's disease: Beyond the corticostriatal pathway.

Huntington's disease (HD) is a heritable, fatal neurodegenerative disorder caused by a mutation in the Huntingtin gene. It is characterized by chorea, as well as cognitive and psychiatric symptoms. Histopathologically, there is a massive loss of striatal projection neurons and less but significant loss in other areas throughout the cortico-basal ganglia-thalamocortical (CBGTC) loop. The mutant huntingtin protein has been implicated in numerous functions, including an important role in synaptic transmission. Most studies on anatomical and physiological alterations in HD have focused on striatum and cerebral cortex. However, based on recent CBGTC projectome evidence, the need to study other pathways has become increasingly clear. In this review, we examine the current status of our knowledge of morphological and electrophysiological alterations of those pathways in animal models of HD. Based on recent studies, there is accumulating evidence that synaptic disconnection, particularly along excitatory pathways, is pervasive and almost universal in HD, thus supporting a critical role of the huntingtin protein in synaptic transmission.

Space Microgravity Alters Neural Stem Cell Division: Implications for Brain Cancer Research on Earth and in Space.

Considering the imminence of long-term space travel, it is necessary to investigate the impact of space microgravity (SPC-µG) in order to determine if this environment has consequences on the astronauts' health, in particular, neural and cognitive functions. Neural stem cells (NSCs) are the basis for the regeneration of the central nervous system (CNS) cell populations and learning how weightlessness impacts NSCs in health and disease provides a critical tool for the potential mitigation of specific mechanisms leading to neurological disorders. In previous studies, we found that exposure to SPC-µG resulted in enhanced proliferation, a shortened cell cycle, and a larger cell diameter of NSCs compared to control cells. Here, we report the frequent occurrence of abnormal cell division (ACD) including incomplete cell division (ICD), where cytokinesis is not successfully completed, and multi-daughter cell division (MDCD) of NSCs following SPC-µG as well as secretome exposure compared to ground control (1G) NSCs. These findings provide new insights into the potential health implications of space travel and have far-reaching implications for understanding the mechanisms leading to the deleterious effects of long-term space travel as well as potential carcinogenic susceptibility. Knowledge of these mechanisms could help to develop preventive or corrective measures for successful long-term SPC-µG exposure.

Calcium dysregulation and compensation in cortical pyramidal neurons of the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that predominantly affects striatal medium-sized spiny neurons and cortical pyramidal neurons (CPNs). It has been proposed that perturbations in Ca2+ homeostasis could play a role in CPN alterations. To test this hypothesis, we used the R6/2 mouse model of juvenile HD at different stages of disease progression; presymptomatic, early symptomatic, and late symptomatic. We combined whole-cell patch-clamp recordings of layer 2/3 CPNs with two-photon laser scanning microscopy to image somatic and dendritic Ca2+ transients associated with evoked action potentials (APs). We found that the amplitude of AP-induced Ca2+ transients recorded at the somata of CPNs was significantly reduced in presymptomatic and late symptomatic R6/2 mice compared with wild-type (WT) littermates. However, reduced amplitudes were compensated by increases in decay times, so that Ca2+ transient areas were similar between genotypes. AP-induced Ca2+ transients in CPN proximal dendrites were variable and differences did not reach statistical significance, except for reduced areas in the late symptomatic group. In late symptomatic mice, a specific store-operated Ca2+ channel antagonist, EVP4593, reduced somatic Ca2+ transient amplitude similarly in WT and R6/2 CPNs. In contrast, dantrolene, a ryanodine receptor (RyR) antagonist, and nifedipine, an L-type Ca2+ channel blocker, significantly reduced both somatic Ca2+ transient amplitude and area in R6/2 but not WT CPNs. These findings demonstrate that perturbations of Ca2+ homeostasis and compensation occur in CPNs before and after the onset of overt symptoms, and suggest RyRs and L-type Ca2+ channels as potential targets for therapeutic intervention.NEW & NOTEWORTHY We used two-photon microscopy to examine calcium influx induced by action potentials in cortical pyramidal neurons from a mouse model of Huntington's disease (HD), the R6/2. The amplitude of somatic calcium transients was reduced in R6/2 mice compared with controls. This reduction was compensated by increased decay times, which could lead to reduced calcium buffering capacity. L-type calcium channel and ryanodine receptor blockers reduced calcium transient area in HD neurons, suggesting new therapeutic avenues.

Early impairment of thalamocortical circuit activity and coherence in a mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. There is no known cure for HD, but its progressive nature allows for early therapeutic intervention. Currently, much of the research has focused on the striatum, however, there is evidence suggesting that disruption of thalamocortical circuits could underlie some of the early symptoms of HD. Loss of both cortical pyramidal neurons (CPNs) and thalamic neurons occurs in HD patients, and cognitive, somatosensory, and attention deficits precede motor abnormalities. However, the role of thalamocortical pathways in HD progression has been understudied. Here, we measured single unit activity and local field potentials (LFPs) from electrode arrays implanted in the thalamus and primary motor cortex of 4-5 month-old male and female Q175 mice. We assessed neuronal activity under baseline conditions as well as during presentation of rewards delivered via actuation of an audible solenoid valve. HD mice showed a significantly delayed licking response to the reward stimulus. At the same time, neuronal activation to the reward was delayed in thalamic neurons, CPNs and fast-spiking cortical interneurons (FSIs) of HD mice. In addition, thalamocortical coherence increased at lower frequencies in HD relative to wildtype mice. Together, these data provide evidence that impaired cortical and thalamic responses to reward stimuli, and impaired thalamocortical coherence, may play an important early role in motor, cognitive, and learning deficits in HD patients.

Mutant huntingtin reduction in astrocytes slows disease progression in the BACHD conditional Huntington's disease mouse model.

Neuronal and non-neuronal cells express the huntingtin (HTT) protein, yet neurodegeneration in Huntington's disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length human mutant HTT (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis. To directly assess the necessity of fl-mHTT in astrocytes for HD pathogenesis, we used a mouse genetic approach and bred the conditional mHTT-expressing BACHD mouse model with GFAP-CreERT2 mice. We show that GFAP-CreERT2 expression in these mice is highly selective for astrocytes, and we are able to significantly reduce the expression of fl-mHTT protein in the striatum and cortex of BACHD/GFAP-CreERT2-tam mice. We performed behavioral, electrophysiological and neuropathological analyses of BACHD and BACHD/GFAP-CreERT2-tam mice. Behavioral analyses of BACHD/GFAP-CreERT2-tam mice demonstrate significant improvements in motor and psychiatric-like phenotypes. We observe improvements in neuropathological and electrophysiological phenotypes in BACHD/GFAP-CreERT2-tam mice compared to BACHD mice. We observed a restoration of the normal level αB-crystallin in the striatum of the BACHD/GFAP-CreERT2 mice, indicating a cell autonomous effect of mHTT on its expression. Taken together, this work indicates that astrocytes are important contributors to the progression of the behavioral and neuropathological phenotypes observed in HD.

Cortical Network Dynamics Is Altered in Mouse Models of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric disturbances. Although evidence indicates that projections from motor cortical areas play a key role in the development of dysfunctional striatal activity and motor phenotype, little is known about the changes in cortical microcircuits and their role in the development of the HD phenotype. Here we used two-photon laser-scanning microscopy to evaluate network dynamics of motor cortical neurons in layers II/III in behaving transgenic R6/2 and knock-in Q175+/- mice. Symptomatic R6/2 mice displayed increased motion manifested by a significantly greater number of motion epochs, whereas symptomatic Q175 mice displayed decreased motion. In both models, calcium transients in symptomatic mice displayed reduced amplitude, suggesting decreased bursting activity. Changes in frequency were genotype- and time-dependent; for R6/2 mice, the frequency was reduced during both motion and nonmotion, whereas in symptomatic Q175 mice, the reduction only occurred during nonmotion. In presymptomatic Q175 mice, frequency was increased during both behavioral states. Interneuronal correlation coefficients were generally decreased in both models, suggesting disrupted interneuronal communication in HD cerebral cortex. These results indicate similar and contrasting effects of the HD mutation on cortical ensemble activity depending on mouse model and disease stage.

Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients.

Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22-9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250-500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.

Mechanisms underlying the enhancement of γ-aminobutyric acid responses in the external globus pallidus of R6/2 Huntington's disease model mice.

In Huntington's disease (HD), the output of striatal indirect pathway medium-sized spiny neurons (MSNs) is altered in its target region, the external globus pallidus (GPe). In a previous study we demonstrated that selective optogenetic stimulation of indirect pathway MSNs induced prolonged decay time of γ-aminobutyric acid (GABA) responses in GPe neurons. Here we identified the mechanism underlying this alteration. Electrophysiological recordings in slices from symptomatic R6/2 and wildtype (WT) mice were used to evaluate, primarily, the effects of GABA transporter (GAT) antagonists on responses evoked by optogenetic activation of indirect pathway MSNs. In addition, immunohistochemistry (IHC) and Western blots (WBs) were used to examine GAT-3 expression in HD and WT mice. A GAT-3 blocker (SNAP5114) increased decay time of GABA responses in WT and HD GPe neurons, but the effect was significantly greater in WT neurons. In contrast, a GAT-1 antagonist (NO-711) or a GABAB receptor antagonist (CGP 54626) produced small increases in decay time but no differential effects between genotypes. IHC and WBs showed reduction of GAT-3 expression in the GPe of HD mice. Thus, reduced expression or dysfunction of GAT-3 could underlie alterations of GPe responses to GABA inputs from striatum and could be a target for therapeutic intervention.

Striatal Direct and Indirect Pathway Output Structures Are Differentially Altered in Mouse Models of Huntington's Disease.

The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre recombination, optogenetics, and whole-cell patch-clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 d) and presymptomatic (2 months) or symptomatic (10-12 months) YAC128 mice. Cell membrane capacitance was decreased, whereas input resistance was increased in SNr neurons from R6/2, but not YAC128 mice. The amplitude of GABAergic responses evoked by optogenetic stimulation of direct pathway terminals was reduced in SNr neurons of symptomatic mice of both models. A decrease in spontaneous GABA synaptic activity, in particular large-amplitude events, in SNr neurons also was observed. Passive membrane properties of GPe neurons were not different between R6/2 or YAC128 mice and their control littermates. Similarly, the amplitude of GABA responses evoked by activation of indirect pathway MSN terminals and the frequency of spontaneous GABA synaptic activity were similar in HD and control animals. In contrast, the decay time of the evoked GABA response was significantly longer in cells from HD mice. Interestingly, activation of indirect pathway MSNs within the striatum evoked larger-amplitude responses in direct pathway MSNs. Together, these results demonstrate differential alterations in responses evoked by direct and indirect pathway terminals in SNr and GPe leading to striatal output imbalance and motor dysfunction.SIGNIFICANCE STATEMENT Previous work on Huntington's disease (HD) focused on striatal medium-sized spiny neurons (MSNs) almost exclusively. Little is known about the effects that alterations in the striatum have on output structures of the direct and indirect pathways, the substantia nigra pars reticulata (SNr) and the external segment of the globus pallidus (GPe), respectively. We combined electrophysiological and optogenetic methods to examine responses evoked by selective activation of terminals of direct and indirect pathway MSNs in SNr and GPe neurons in two mouse models of HD. We show a differential disruption of synaptic communication between the direct and indirect output pathways of the striatum with their target regions leading to an imbalance of striatal output, which will contribute to motor dysfunction.

Neural Deletion of Glucose Transporter Isoform 3 Creates Distinct Postnatal and Adult Neurobehavioral Phenotypes.

We created a neural-specific conditional murine glut3 (Slc2A3) deletion (glut3flox/flox/nestin-Cre+) to examine the effect of a lack of Glut3 on neurodevelopment. Compared with age-matched glut3flox/flox = WT and heterozygotes (glut3flox/+/nestin-Cre+), we found that a >90% reduction in male and female brain Glut3 occurred by postnatal day 15 (PN15) in glut3flox/flox/nestin-Cre+ This genetic manipulation caused a diminution in brain weight and cortical thickness at PN15, a reduced number of dendritic spines, and fewer ultrasonic vocalizations. Patch-clamp recordings of cortical pyramidal neurons revealed increased frequency of bicuculline-induced paroxysmal discharges as well as reduced latency, attesting to a functional synaptic and cortical hyperexcitability. Concomitant stunting with lower glucose concentrations despite increased milk intake shortened the lifespan, failing rescue by a ketogenic diet. This led to creating glut3flox/flox/CaMK2α-Cre+ mice lacking Glut3 in the adult male limbic system. These mice had normal lifespan, displayed reduced IPSCs in cortical pyramidal neurons, less anxiety/fear, and lowered spatial memory and motor abilities but heightened exploratory and social responses. These distinct postnatal and adult phenotypes, based upon whether glut3 gene is globally or restrictively absent, have implications for humans who carry copy number variations and present with neurodevelopmental disorders.SIGNIFICANCE STATEMENT Lack of the key brain-specific glucose transporter 3 gene found in neurons during early postnatal life results in significant stunting, a reduction in dendritic spines found on neuronal processes and brain size, heightened neuronal excitability, along with a shortened lifespan. When occurring in the adult and limited to the limbic system alone, lack of this gene in neurons reduces the fear of spatial exploration and socialization but does not affect the lifespan. These features are distinct heralding differences between postnatal and adult phenotypes based upon whether the same gene is globally or restrictively lacking. These findings have implications for humans who carry copy number variations pertinent to this gene and have been described to present with neurodevelopmental disorders.

Striatal GABAergic interneuron dysfunction in the Q175 mouse model of Huntington's disease.

The pathological hallmark of Huntington's disease (HD) is the massive loss of striatal and cortical neurons. Until recently, it was believed that striatal interneurons were spared from degeneration. This view has changed after the demonstration that parvalbumin (PV)-expressing interneurons also are vulnerable in humans. Here we compared morphological and functional changes of striatal fast-spiking interneurons (FSIs) and low-threshold spiking (LTS) interneurons in the Q175 mouse model of HD at presymptomatic (2 months) and symptomatic (12 months) stages of the disease. Electrophysiological intrinsic and synaptic properties of FSIs were significantly altered in symptomatic mice compared to wild-type (WT) littermates. Overall, FSIs became more excitable with disease progression. Sholl analysis also revealed a significant loss of dendritic complexity and excitatory synaptic inputs. The basic membrane and synaptic properties of LTS interneurons were similar in Q175 and WT mice regardless of disease stage. The resilience of LTS interneurons could be related to their sparsity of excitatory synaptic inputs compared with FSIs. However, in symptomatic mice, a subpopulation of LTS interneurons displayed an increase in action potential firing within oscillating bursts. Thus, we conclude that while both FSI and LTS interneurons demonstrate increases in excitability, the HD mutation differentially affects their membrane and synaptic properties as well as their ability to respond to compensatory challenges presented during the late stage of the disease. Alterations in GABAergic interneuron intrinsic activity and responsiveness to incoming signals may significantly affect SPN output thus contributing to abnormal motor movements in patients afflicted with HD.

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

Basolateral Amygdala to Orbitofrontal Cortex Projections Enable Cue-Triggered Reward Expectations.

To make an appropriate decision, one must anticipate potential future rewarding events, even when they are not readily observable. These expectations are generated by using observable information (e.g., stimuli or available actions) to retrieve often quite detailed memories of available rewards. The basolateral amygdala (BLA) and orbitofrontal cortex (OFC) are two reciprocally connected key nodes in the circuitry supporting such outcome-guided behaviors. But there is much unknown about the contribution of this circuit to decision making, and almost nothing known about the whether any contribution is via direct, monosynaptic projections, or the direction of information transfer. Therefore, here we used designer receptor-mediated inactivation of OFC→BLA or BLA→OFC projections to evaluate their respective contributions to outcome-guided behaviors in rats. Inactivation of BLA terminals in the OFC, but not OFC terminals in the BLA, disrupted the selective motivating influence of cue-triggered reward representations over reward-seeking decisions as assayed by Pavlovian-to-instrumental transfer. BLA→OFC projections were also required when a cued reward representation was used to modify Pavlovian conditional goal-approach responses according to the reward's current value. These projections were not necessary when actions were guided by reward expectations generated based on learned action-reward contingencies, or when rewards themselves, rather than stored memories, directed action. These data demonstrate that BLA→OFC projections enable the cue-triggered reward expectations that can motivate the execution of specific action plans and allow adaptive conditional responding.SIGNIFICANCE STATEMENT Deficits anticipating potential future rewarding events are associated with many psychiatric diseases. Presently, we know little about the neural circuits supporting such reward expectation. Here we show that basolateral amygdala to orbitofrontal cortex projections are required for expectations of specific available rewards to influence reward seeking and decision making. The necessity of these projections was limited to situations in which expectations were elicited by reward-predictive cues. These projections therefore facilitate adaptive behavior by enabling the orbitofrontal cortex to use environmental stimuli to generate expectations of potential future rewarding events.

A Basic Phase Diagram of Neuronal Dynamics.

The extreme complexity of the brain has attracted the attention of neuroscientists and other researchers for a long time. More recently, the neuromorphic hardware has matured to provide a new powerful tool to study neuronal dynamics. Here, we study neuronal dynamics using different settings on a neuromorphic chip built with flexible parameters of neuron models. Our unique setting in the network of leaky integrate-and-fire (LIF) neurons is to introduce a weak noise environment. We observed three different types of collective neuronal activities, or phases, separated by sharp boundaries, or phase transitions. From this, we construct a rudimentary phase diagram of neuronal dynamics and demonstrate that a noise-induced chaotic phase (N-phase), which is dominated by neuronal avalanche activity (intermittent aperiodic neuron firing), emerges in the presence of noise and its width grows with the noise intensity. The dynamics can be manipulated in this N-phase. Our results and comparison with clinical data is consistent with the literature and our previous work showing that healthy brain must reside in the N-phase. We argue that the brain phase diagram with further refinement may be used for the diagnosis and treatment of mental disease and also suggest that the dynamics may be manipulated to serve as a means of new information processing (e.g., for optimization). Neuromorphic chips, similar to the one we used but with a variety of neuron models, may be used to further enhance the understanding of human brain function and accelerate the development of neuroscience research.

Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a fatal genetic disorder characterized by cell death of medium-sized spiny neurons (MSNs) in the striatum, traditionally attributed to excessive glutamate inputs and/or receptor sensitivity. While changes in corticostriatal projections have typically been studied in mouse models of HD, morphological and functional alterations in thalamostriatal projections have received less attention. In this study, an adeno-associated virus expressing channelrhodopsin-2 under the calcium/calmodulin-dependent protein kinase IIα promoter was injected into the sensorimotor cortex or the thalamic centromedian-parafascicular nuclear complex in the R6/2 mouse model of HD, to permit selective activation of corticostriatal or thalamostriatal projections, respectively. In symptomatic R6/2 mice, peak amplitudes and areas of corticostriatal glutamate AMPA and NMDA receptor-mediated responses were reduced. In contrast, although peak amplitudes of AMPA and NMDA receptor-mediated thalamostriatal responses also were reduced, the areas remained unchanged due to an increase in response decay times. Blockade of glutamate reuptake further increased response areas and slowed rise and decay times of NMDA responses. These effects appeared more pronounced at thalamostriatal synapses of R6/2 mice, suggesting increased activation of extrasynaptic NMDA receptors. In addition, the probability of glutamate release was higher at thalamostriatal than corticostriatal synapses, particularly in R6/2 mice. Morphological studies indicated that the density of all excitatory synaptic contacts onto MSNs was reduced, which matches the basic electrophysiological findings of reduced amplitudes. There was a consistent reduction in the area of spines but little change in presynaptic terminal size, indicating that the postsynaptic spine may be more significantly affected than presynaptic terminals. These results highlight the significant and differential contribution of the thalamostriatal projection to glutamate excitotoxicity in HD.

WONOEP appraisal: Development of epilepsy biomarkers-What we can learn from our patients?

OBJECTIVE: Current medications for patients with epilepsy work in only two of three patients. For those medications that do work, they only suppress seizures. They treat the symptoms, but do not modify the underlying disease, forcing patients to take these drugs with significant side effects, often for the rest of their lives. A major limitation in our ability to advance new therapeutics that permanently prevent, reduce the frequency of, or cure epilepsy comes from a lack of understanding of the disease coupled with a lack of reliable biomarkers that can predict who has or who will get epilepsy. METHODS: The main goal of this report is to present a number of approaches for identifying reliable biomarkers from observing patients with brain disorders that have a high probability of producing epilepsy. RESULTS: A given biomarker, or more likely a profile of biomarkers, will have both a quantity and a time course during epileptogenesis that can be used to predict who will get the disease, to confirm epilepsy as a diagnosis, to identify coexisting pathologies, and to monitor the course of treatments. SIGNIFICANCE: Additional studies in patients and animal models could identify common and clinically valuable biomarkers to successfully translate animal studies into new and effective clinical trials.

Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington's disease.

In mouse models of Huntington's disease (HD), striatal neuron properties are significantly altered. These alterations predict changes in striatal output regions. However, little is known about alterations in those regions. The present study examines changes in passive and active membrane properties of neurons in the external globus pallidus (GPe), the first relay station of the indirect pathway, in the R6/2 mouse model of juvenile HD at presymptomatic (1 month) and symptomatic (2 month) stages. In GPe, two principal types of neurons can be distinguished based on firing properties and the presence (type A) or absence (type B) of Ih currents. In symptomatic animals (2 month), cell membrane capacitance and input resistance of type A neurons were increased compared with controls. In addition, action potential afterhyperpolarization amplitude was reduced. Although the spontaneous firing rate of GPe neurons was not different between control and R6/2 mice, the number of spikes evoked by depolarizing current pulses was significantly reduced in symptomatic R6/2 animals. In addition, these changes were accompanied by altered firing patterns evidenced by increased interspike interval variation and increased number of bursts. Blockade of GABAA receptors facilitated bursting activity in R6/2 mice but not in control littermates. Thus, alterations in firing patterns could be caused by changes in intrinsic membrane conductances and modulated by synaptic inputs. © 2016 Wiley Periodicals, Inc.