Local Neural Circuits Research Articles

Intrinsic Bipolar Head-Direction Cells in the Medial Entorhinal Cortex.

Head-direction (HD) cells are a fundamental component in the hippocampal-entorhinal circuit for spatial navigation and help maintain an internal sense of direction to anchor the orientation in space. A classical HD cell robustly increases its firing rate when the head is oriented toward a specific direction, with each cell tuned to only one direction. Although unidirectional HD cells are reported broadly across multiple brain regions, computation modelling has predicted the existence of multiple equilibrium states of HD network, which has yet to be proven. In this study, a novel HD variant of bipolar HD cells in the medial entorhinal cortex (MEC) are identified that exhibit stable double-peaked directional tuning properties. The bipolar patterns remain stable in the darkness and across environments of distinct geometric shapes. Moreover, bipolar HD cells co-rotate coherently with unipolar HD cells to anchor the external visual cue. The discovery reveals a new spatial cell type of bipolar HD cells, whose unique activity patterns may comprise a potential building block for a sophisticated local neural circuit configuration for the internal representation of direction. These findings may contribute to the understanding of how the brain processes spatial information by shedding light on the role of bipolar HD cells in this process.

Multitask learning of a biophysically-detailed neuron model.

The human brain operates at multiple levels, from molecules to circuits, and understanding these complex processes requires integrated research efforts. Simulating biophysically-detailed neuron models is a computationally expensive but effective method for studying local neural circuits. Recent innovations have shown that artificial neural networks (ANNs) can accurately predict the behavior of these detailed models in terms of spikes, electrical potentials, and optical readouts. While these methods have the potential to accelerate large network simulations by several orders of magnitude compared to conventional differential equation based modelling, they currently only predict voltage outputs for the soma or a select few neuron compartments. Our novel approach, based on enhanced state-of-the-art architectures for multitask learning (MTL), allows for the simultaneous prediction of membrane potentials in each compartment of a neuron model, at a speed of up to two orders of magnitude faster than classical simulation methods. By predicting all membrane potentials together, our approach not only allows for comparison of model output with a wider range of experimental recordings (patch-electrode, voltage-sensitive dye imaging), it also provides the first stepping stone towards predicting local field potentials (LFPs), electroencephalogram (EEG) signals, and magnetoencephalography (MEG) signals from ANN-based simulations. While LFP and EEG are an important downstream application, the main focus of this paper lies in predicting dendritic voltages within each compartment to capture the entire electrophysiology of a biophysically-detailed neuron model. It further presents a challenging benchmark for MTL architectures due to the large amount of data involved, the presence of correlations between neighbouring compartments, and the non-Gaussian distribution of membrane potentials.

Neuronal functional connectivity is impaired in a layer dependent manner near chronically implanted intracortical microelectrodes in C57BL6 wildtype mice

Objective. This study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near chronically implanted microelectrodes. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how the FBR affects the functional stability of neural circuits near implanted brain–computer interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders. Approach. This study utilized single-shank, 16-channel,100 µm site-spacing Michigan-style microelectrodes (3 mm length, 703 µm2 site area) that span all cortical layers and the hippocampal CA1 region. Sex balanced C57BL6 wildtype mice (11–13 weeks old) received perpendicularly implanted microelectrode in left primary visual cortex. Electrophysiological recordings were performed during both spontaneous activity and visual sensory stimulation. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of local field potential (LFP) and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation. Main results. The study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations. Significance. This study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our study’s understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

Abnormal gamma phase-amplitude coupling in the parahippocampal cortex is associated with network hyperexcitability in Alzheimer's disease.

While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls (n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.

Neural repair and regeneration interfaces: a comprehensive review.

Neural interfaces play a pivotal role in neuromodulation, as they enable precise intervention into aberrant neural activity and facilitate recovery from neural injuries and resultant functional impairments by modulating local immune responses and neural circuits. This review outlines the development and applications of these interfaces and highlights the advantages of employing neural interfaces for neural stimulation and repair, including accurate targeting of specific neural populations, real-time monitoring and control of neural activity, reduced invasiveness, and personalized treatment strategies. Ongoing research aims to enhance the biocompatibility, stability, and functionality of these interfaces, ultimately augmenting their therapeutic potential for various neurological disorders. The review focuses on electrophysiological and optophysiology neural interfaces, discussing functionalization and power supply approaches. By summarizing the techniques, materials, and methods employed in this field, this review aims to provide a comprehensive understanding of the potential applications and future directions for neural repair and regeneration devices.

Monosynaptic Rabies Viral Tracing Reveals Subiculum Circuit Connectivity Alterations in Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly and causes progressive memory and behavioral impairment. Examining the changes in neural circuitry using AD model mice is an emerging strategy for a better understanding of AD neural mechanisms toward discovering new therapeutic targets. Our recent work indicates the disruption of long-range and local neural circuit connections in the hippocampus using an AD mouse model. The subiculum is the major output structure of the hippocampus and is among the earliest AD-impacted brain regions. We hypothesize that age-progressive alterations also occur in the neural circuit organization of the subiculum in the 5xFAD mouse model. To comprehensively map cell-type-specific circuit inputs, we utilized the novel viral-genetic tool of monosynaptic rabies tracing. We quantitatively assessed and compared the circuit connectivity of subiculum excitatory neurons in age-matched C57BL6 control and 5xFAD model mice at young and middle ages (3-4 months vs 8-9 months) in both sexes. The major subiculum input brain regions mapped by rabies tracing include hippocampal subregions, medial septum and diagonal band (MS-DB), subiculum (SUB), post subiculum (post SUB), visual (VIS) cortex, auditory (AUD) cortex, entorhinal cortex (EC), thalamus, and temporal association cortex (TeA). Our results reveal significant alterations in local and long-range circuit connections to the subiculum in AD model mice. The overall brain-wide connectivity strengths of subiculum inputs in aged AD model mice are weaker than in wild type mice. There are significant age and sex differences in the connectivity strengths of multiple input regions, including the hippocampal CA1, CA2, MS-DB, thalamus, RSC, VIS, AUD, and TeA. Our work provides new insights into subiculum- directed neural circuit mechanisms during AD progression and supports neural circuit disruptions as a prominent feature of AD.

Dual action of serotonin on local excitatory and inhibitory neural circuits regulating the corticotropin-releasing factor neurons in the paraventricular nucleus of the hypothalamus.

Serotonergic neurons originating from the raphe nuclei have been proposed to regulate corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVH). Since glutamate- and γ-aminobutyric acid (GABA)-containing neurons, constituting the hypothalamic local circuits, innervate PVH CRF neurons, we examined whether they mediate the actions of serotonin (5-hydroxytryptamine [5-HT]) on CRF neurons. Spontaneous excitatory postsynaptic currents (sEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in PVH CRF neurons, under whole cell patch-clamp, using the CRF-modified yellow fluorescent protein (Venus) ΔNeo mouse. Serotonin elicited an increase in the frequency of sEPSCs in 77% of the cells and a decrease in the frequency of sIPSCs in 71% of the cells, tested in normal medium. Neither the amplitude nor decay time of sEPSC and sIPSC was affected, thus the site(s) of action of serotonin may be presynaptic. In the presence of tetrodotoxin (TTX), serotonin had no significant effects on either parameter of sEPSC or sIPSC, indicating that the effects of serotonin are action potential-dependent, and that the presynaptic interneurons are largely intact within the slice; distant neurons may exist, though, since some 20%-30% of neurons did not respond to serotonin without TTX. We next examined through what receptor subtype(s) serotonin exerts its effects on presynaptic interneurons. DOI (5-HT2A/2C agonist) mimicked the action of serotonin on the sIPSCs, and the serotonin-induced decrease in sIPSC frequency was inhibited by a selective 5-HT2C antagonist RS102221. 8-OH-DPAT (5-HT1A/7 agonist) mimicked the action of serotonin on the sEPSCs, and the serotonin-induced increase in sEPSC frequency was inhibited by a selective 5-HT7 antagonist SB269970. Thus, serotonin showed a dual action on PVH CRF neurons, by upregulating glutamatergic- and downregulating GABAergic interneurons; the former may partly be mediated by 5-HT7 receptors, whereas the latter by 5-HT2C receptors. The CRF-Venus ΔNeo mouse was useful for the electrophysiological examination.

Cortical circuit dynamics underlying motor skill learning: from rodents to humans.

Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning.

Two-photon live imaging of direct glia-to-neuron conversion in the mouse cortex.

JOURNAL/nrgr/04.03/01300535-202408000-00032/figure1/v/2023-12-16T180322Z/r/image-tiff Over the past decade, a growing number of studies have reported transcription factor-based in situ reprogramming that can directly convert endogenous glial cells into functional neurons as an alternative approach for neuroregeneration in the adult mammalian central nervous system. However, many questions remain regarding how a terminally differentiated glial cell can transform into a delicate neuron that forms part of the intricate brain circuitry. In addition, concerns have recently been raised around the absence of astrocyte-to-neuron conversion in astrocytic lineage-tracing mice. In this study, we employed repetitive two-photon imaging to continuously capture the in situ astrocyte-to-neuron conversion process following ectopic expression of the neural transcription factor NeuroD1 in both proliferating reactive astrocytes and lineage-traced astrocytes in the mouse cortex. Time-lapse imaging over several weeks revealed the step-by-step transition from a typical astrocyte with numerous short, tapered branches to a typical neuron with a few long neurites and dynamic growth cones that actively explored the local environment. In addition, these lineage-converting cells were able to migrate radially or tangentially to relocate to suitable positions. Furthermore, two-photon Ca2+ imaging and patch-clamp recordings confirmed that the newly generated neurons exhibited synchronous calcium signals, repetitive action potentials, and spontaneous synaptic responses, suggesting that they had made functional synaptic connections within local neural circuits. In conclusion, we directly visualized the step-by-step lineage conversion process from astrocytes to functional neurons in vivo and unambiguously demonstrated that adult mammalian brains are highly plastic with respect to their potential for neuroregeneration and neural circuit reconstruction.

Targeting operational regimes of interest in recurrent neural networks.

Neural computations emerge from local recurrent neural circuits or computational units such as cortical columns that comprise hundreds to a few thousand neurons. Continuous progress in connectomics, electrophysiology, and calcium imaging require tractable spiking network models that can consistently incorporate new information about the network structure and reproduce the recorded neural activity features. However, for spiking networks, it is challenging to predict which connectivity configurations and neural properties can generate fundamental operational states and specific experimentally reported nonlinear cortical computations. Theoretical descriptions for the computational state of cortical spiking circuits are diverse, including the balanced state where excitatory and inhibitory inputs balance almost perfectly or the inhibition stabilized state (ISN) where the excitatory part of the circuit is unstable. It remains an open question whether these states can co-exist with experimentally reported nonlinear computations and whether they can be recovered in biologically realistic implementations of spiking networks. Here, we show how to identify spiking network connectivity patterns underlying diverse nonlinear computations such as XOR, bistability, inhibitory stabilization, supersaturation, and persistent activity. We establish a mapping between the stabilized supralinear network (SSN) and spiking activity which allows us to pinpoint the location in parameter space where these activity regimes occur. Notably, we find that biologically-sized spiking networks can have irregular asynchronous activity that does not require strong excitation-inhibition balance or large feedforward input and we show that the dynamic firing rate trajectories in spiking networks can be precisely targeted without error-driven training algorithms.

Astrocyte heterogeneity and interactions with local neural circuits.

Astrocytes are ubiquitous within the central nervous system (CNS). These cells possess many individual processes which extend out into the neuropil, where they interact with a variety of other cell types, including neurons at synapses. Astrocytes are now known to be active players in all aspects of the synaptic life cycle, including synapse formation and elimination, synapse maturation, maintenance of synaptic homeostasis and modulation of synaptic transmission. Traditionally, astrocytes have been studied as a homogeneous group of cells. However, recent studies have uncovered a surprising degree of heterogeneity in their development and function, suggesting that astrocytes may be matched to neurons to support local circuits. Hence, a better understanding of astrocyte heterogeneity and its implications are needed to understand brain function.

Research progress of neural circuit reconstruction after spinal cord injury

<p indent="0mm">Spinal cord repair and regeneration in adult mammalians is a complicated and unresolved challenge after spinal cord injury (SCI). The incidence of SCI is increasing worldwide with the growing global economy. Motor and sensory functions can be permanently impaired after SCI, bringing huge economic pressure and psychological burden to paraplegic patients and their families. Therefore, there is an urgent need to discover effective strategies for the treatment of SCI. In recent years, the exogenous or endogenous neuronal relay therapy has provided new perspectives for local neural circuit reconstruction after SCI. The application of grafts such as stem cells or biomaterials to the lesion area can improve the local microenvironment and induce neural stem cells to differentiate into neurons, which has become a promising method to promote neural circuit reconstruction and functional recovery. This review focuses on the application of cell transplantation therapy, engineering strategies and gene regulation in repairing the neural network after SCI, it also discusses whether newborn neurons can have potential functional integration to rebuild neural circuits and restore motor and sensory functions after SCI.

In Vivo Wide-Field and Two-Photon Calcium Imaging from a Mouse using a Large Cranial Window.

Wide-field calcium imaging from the mouse's neocortex allows one to observe cortex-wide neural activity related to various brain functions. On the other hand, two-photon imaging can resolve the activity of local neural circuits at the single-cell level. It is critical to make a large cranial window to perform multiple-scale analysis using both imaging techniques in the same mouse. To achieve this, one must remove a large section of the skull and cover the exposed cortical surface with transparent materials. Previously, glass skulls and polymer-based cranial windows have been developed for this purpose, but these materials are not easily fabricated. The present protocol describes a simple method for making a large cranial window consisting of commercially available polyvinylidene chloride (PVDC) wrapping film, a transparent silicone plug, and a cover glass. For imaging the dorsal surface of an entire hemisphere, the window size was approximately 6 x 3 mm2. Severe brain vibrations were not observed regardless of such a large window. Importantly, the condition of the brain surface did not deteriorate for more than one month. Wide-field imaging of a mouse expressing a genetically-encoded calcium indicator (GECI), GCaMP6f, specifically in astrocytes, revealed synchronized responses in a few millimeters. Two-photon imaging of the same mouse showed prominent calcium responses in individual astrocytes over several seconds. Furthermore, a thin layer of an adeno-associated virus was applied to the PVDC film and successfully expressed GECI in cortical neurons over the cranial window. This technique is reliable and cost-effective for making a large cranial window and facilitates the investigation of the neural and glial dynamics and their interactions during behavior at the macroscopic and microscopic levels.

&lt;em&gt;In Vivo&lt;/em&gt; Wide-Field and Two-Photon Calcium Imaging from a Mouse Using a Large Cranial Window

Wide-field calcium imaging from the mouse's neocortex allows one to observe cortex-wide neural activity related to various brain functions. On the other hand, two-photon imaging can resolve the activity of local neural circuits at the single-cell level. It is critical to make a large cranial window to perform multiple-scale analysis using both imaging techniques in the same mouse. To achieve this, one must remove a large section of the skull and cover the exposed cortical surface with transparent materials. Previously, glass skulls and polymer-based cranial windows have been developed for this purpose, but these materials are not easily fabricated. The present protocol describes a simple method for making a large cranial window consisting of commercially available polyvinylidene chloride (PVDC) wrapping film, a transparent silicone plug, and a cover glass. For imaging the dorsal surface of an entire hemisphere, the window size was approximately 6 x 3 mm2. Severe brain vibrations were not observed regardless of such a large window. Importantly, the condition of the brain surface did not deteriorate for more than one month. Wide-field imaging of a mouse expressing a genetically-encoded calcium indicator (GECI), GCaMP6f, specifically in astrocytes, revealed synchronized responses in a few millimeters. Two-photon imaging of the same mouse showed prominent calcium responses in individual astrocytes over several seconds. Furthermore, a thin layer of an adeno-associated virus was applied to the PVDC film and successfully expressed GECI in cortical neurons over the cranial window. This technique is reliable and cost-effective for making a large cranial window and facilitates the investigation of the neural and glial dynamics and their interactions during behavior at the macroscopic and microscopic levels.

Adult neurogenesis of the median eminence contributes to structural reconstruction and recovery of body fluid metabolism in hypothalamic self-repair after pituitary stalk lesion.

Body fluid homeostasis is critical to survival. The integrity of the hypothalamo-neurohypophysial system (HNS) is an important basis of the precise regulation of body fluid metabolism and arginine vasopressin (AVP) hormone release. Clinically, some patients with central diabetes insipidus (CDI) due to HNS lesions can experience recovery compensation of body fluid metabolism. However, whether the hypothalamus has the potential for structural plasticity and self-repair under pathological conditions remains unclear. Here, we report the repair and reconstruction of a new neurohypophysis-like structure in the hypothalamic median eminence (ME) after pituitary stalk electrical lesion (PEL). We show that activated and proliferating adult neural progenitor cells differentiate into new mature neurons, which then integrate with remodeled AVP fibers to reconstruct the local AVP hormone release neural circuit in the ME after PEL. We found that the transcription factor of NK2 homeobox 1 (NKX2.1) and the sonic hedgehog signaling pathway, mediated by NKX2.1, are the key regulators of adult hypothalamic neurogenesis. Taken together, our study provides evidence that adult ME neurogenesis is involved in the structural reconstruction of the AVP release circuit and eventually restores body fluid metabolic homeostasis during hypothalamic self-repair.

Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at two different ages (3–4 vs. 10–11 months old). We quantitatively mapped the connectivity strengths of neural circuit inputs to hippocampal CA1 excitatory neurons from brain regions including hippocampal subregions, medial septum, subiculum and entorhinal cortex, comparing different age groups and genotypes. We focused on hippocampal CA1 because of its clear relationship with learning and memory and that the hippocampal formation shows clear neuropathological changes in human AD. Our results reveal alterations in circuit connectivity of hippocampal CA1 in AD model mice. Overall, we find weaker extrinsic CA1 input connectivity strengths in AD model mice compared with control mice, including sex differences of reduced subiculum to CA1 inputs in aged female AD mice compared with aged male AD mice. Unexpectedly, we find a connectivity pattern shift with an increased proportion of inputs from the CA3 region to CA1 excitatory neurons when comparing young and old AD model mice, as well as old wild-type mice and old AD model mice. These unexpected shifts in CA3-CA1 input proportions in this AD mouse model suggest the possibility that compensatory circuit increases may occur in response to connectivity losses in other parts of the hippocampal circuits. We expect that this work provides new insights into the neural circuit mechanisms of AD pathogenesis.

A developmental switch between electrical and neuropeptide communication in the ventromedial hypothalamus

Dissecting neural connectivity patterns within local brain regions is an essential step to understanding the function of the brain.1 Neural microcircuits in brain regions, such as the neocortex and the hippocampus, have been extensively studied.2 By contrast, the microcircuit in the hypothalamus remains largely uncharacterized. The hypothalamus is crucial for animals' survival and reproduction.3 Knowledge of how different hypothalamic nuclei coordinate with each other and outside brain regions for hypothalamus-related functions has been significantly advanced.4-9 Although there are limited studies on the neural microcircuit in the lateral hypothalamus (LHA)10,11 and the suprachiasmatic nucleus (SCN),12,13 the patterns of neural microcircuits in most of the given hypothalamic nuclei remain largely unknown. This study applied combinatory approaches to address the local neural circuit pattern in the ventromedial hypothalamus (VMH) and other hypothalamic nuclei. We discovered a unique neural circuit design in the VMH. Neurons in the VMH were electrically coupled at the early postnatal stage like ones in the neocortex.14 However, unlike neocortical neurons,14,15 they developed very few chemical synapses after the disappearance of electrical synapses. Instead, VMH neurons communicated with neuropeptides. The similar scarceness of synaptic connectivity found in other hypothalamic nuclei further indicated that the lack of synaptic connections is a unique feature for local neural circuits in most adult hypothalamic nuclei. Thus, our findings provide a solid synaptic basis at the cellular level to understand hypothalamic functions better.

Transcutaneous spinal direct current stimulation (tsDCS) does not affect postural sway of young and healthy subjects during quiet upright standing.

Transcutaneous spinal direct current stimulation (tsDCS) is an effective non-invasive spinal cord electrical stimulation technique to induce neuromodulation of local and distal neural circuits of the central nervous system (CNS). Applied to the spinal cord lumbosacral region, tsDCS changes electrophysiological responses of the motor, proprioceptive and nociceptive pathways, alters the performance of some lower limb motor tasks and can even modulate the behavior of supramedullary neuronal networks. In this study an experimental protocol was conducted to verify if tsDCS (5 mA, 20 minutes) of two different polarizations, applied over the lumbosacral region (tenth thoracic vertebrae (T10)), can induce changes in postural sway oscillations of young healthy individuals during quiet standing. A novel initialization of the electrical stimulation was developed to improve subject blinding to the different stimulus conditions including the sham trials. Measures of postural sway, both global and structural, were computed before, during and following the DC stimulation period. The results indicated that, for the adopted conditions, tsDCS did not induce statistically significant changes in postural sway of young healthy individuals during quiet standing.

Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.

Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD‐like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg‐AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell‐specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell‐specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell‐specific transcriptomic data revealed that multiple AD‐associated signaling pathways were disrupted by hTau N368, including reduction of synapse‐associated proteins, inhibition of AKT and activation of glycogen synthase kinase‐3β. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368‐induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD‐like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell‐related spatial memory loss but also provides a mouse model of Mossy cell‐specific hTau accumulation for drug development in AD and the related tauopathies.

Imaging neural circuit pathology of autism spectrum disorders: autism-associated genes, animal models and the application of in vivo two-photon imaging.

Recent advances in human genetics identified genetic variants involved in causing autism spectrum disorders (ASDs). Mouse models that mimic mutations found in patients with ASD exhibit behavioral phenotypes consistent with ASD symptoms. These mouse models suggest critical biological factors of ASD etiology. Another important implication of ASD genetics is the enrichment of ASD risk genes in molecules involved in developing synapses and regulating neural circuit function. Sophisticated in vivo imaging technologies applied to ASD mouse models identify common synaptic impairments in the neocortex, with genetic-mutation-specific defects in local neural circuits. In this article, we review synapse- and circuit-level phenotypes identified by in vivo two-photon imaging in multiple mouse models of ASD and discuss the contributions of altered synapse properties and neural circuit activity to ASD pathogenesis.