Neurons In Somatosensory Cortex Research Articles

Systemic exposure to COVID-19 virus-like particles modulates firing patterns of cortical neurons in the living mouse brain.

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) causes a systemic infection that affects the central nervous system. We used virus-like particles (VLPs) to explore how exposure to the SARS-CoV-2 proteins affects brain activity patterns in wild-type (WT) mice and in mice that express the wild-type human tau protein (htau mice). VLP exposure elicited dose-dependent changes in corticosterone and distinct chemokine levels. Longitudinal two-photon microscopy recordings of primary somatosensory and motor cortex neurons that express the jGCaMP7s calcium sensor tracked modifications of neuronal activity patterns following exposure to VLPs. There was a substantial short-term increase in stimulus-evoked activity metrics in both WT and htau VLP-injected mice, while htau mice showed also increased spontaneous activity metrics and increase activity in the vehicle-injected group. Over the following weeks, activity metrics in WT mice subsided, but remained above baseline levels. For htau mice, activity metrics either remain elevated or decreased to lower levels than baseline. Overall, our data suggest that exposure to the SARS-CoV-2 VLPs leads to strong short-term disruption of cortical activity patterns in mice with long-term residual effects. The htau mice, which have a more vulnerable genetic background, exhibited more severe pathobiology that may lead to more adverse outcomes.

Somatosensory Mapping Using a Novel Sensory Discrimination Task: Technical Note.

Although diffuse gliomas in the primary somatosensory cortex (S1) are often considered resectable, gliomas in the primary motor cortex require motor mapping to preserve motor function. Recent evidence indicates that some somatosensory cortex neurons may trigger motor responses, necessitating refined somatosensory mapping techniques. Using piezoelectric tactile stimulators on patients' faces and hands, we delivered 25 Hz vibrations and prompted patients to discriminate between dermatomes. Testing included areas contralateral to tumor-infiltrated and to non-tumor-infiltrated cortical regions. Sensory thresholds were determined by reducing stimulus intensity based on performance. Intraoperatively, electrocorticography electrode arrays were used to map sensory responses, and postoperative assessments evaluated sensory outcomes. The high-grade glioma case involved a 61-year-old man with right-sided weakness and numbness with a left parietal mass on MRI. Preoperative testing showed that the average vibratory detection threshold of the hand contralateral to the suspected tumor site was significantly higher than that of the hand contralateral to healthy cortex (P < .001). Intraoperative mapping confirmed the absence of functional involvement in cortical structures overlying the tumor. Postoperative imaging confirmed gross total resection, and sensory vibratory thresholds were normalized (P = .51). The low-grade glioma case included a 54-year-old man with a left parietal nonenhancing mass on MRI. No baseline sensory impairments were found on preoperative testing. Intraoperative mapping identified motor and sensory cortices, guiding tumor resection while preserving motor function. Postoperative MRI confirmed near-total resection, but new sensory impairments were noted in the hand and face contralateral to the resection site (P < .001). These deficits resolved by postoperative day 11, with no evidence of tumor progression on follow-up imaging. The sensory discrimination task provides a quantifiable method for assessing sensory changes and functional outcomes related to glioma. This technique enhances our understanding of how glioma infiltration remodels sensory systems and affects clinical outcomes in patients.

Motor Control of Distinct Layer 6 Corticothalamic Feedback Circuits.

Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extrasensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in CT neurons projecting to the dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) located in lower L6a than VPm-only-projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements.

Transient enhancement of stimulus-evoked activity in neocortex during sensory learning.

Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not clear. Here, we used longitudinal in vivo Ca2+ imaging in the barrel cortex of awake mice to test the hypothesis that increased excitatory synaptic strength during the learning of a whisker-dependent sensory-association task would be correlated with enhanced stimulus-evoked firing. To isolate stimulus-evoked responses from dynamic, task-related activity, imaging was performed outside of the training context. Although prior studies indicate that multiwhisker stimuli drive robust subthreshold activity, we observed sparse activation of L2/3 pyramidal (Pyr) neurons in both control and trained mice. Despite evidence for excitatory synaptic strengthening at thalamocortical and intracortical synapses in this brain area at the onset of learning-indeed, under our imaging conditions thalamocortical axons were robustly activated-we observed that L2/3 Pyr neurons in somatosensory (barrel) cortex displayed only modest increases in stimulus-evoked activity that were concentrated at the onset of training. Activity renormalized over longer training periods. In contrast, when stimuli and rewards were uncoupled in a pseudotraining paradigm, stimulus-evoked activity in L2/3 Pyr neurons was significantly suppressed. These findings indicate that sensory-association training but not sensory stimulation without coupled rewards may briefly enhance sensory-evoked activity, a phenomenon that might help link sensory input to behavioral outcomes at the onset of learning.

A noradrenergic pathway for the induction of pain by sleep loss

An epidemic of sleep loss currently affects modern societies worldwide and is implicated in numerous physiological disorders, including pain sensitization, although few studies have explored the brain pathways affected by active sleep deprivation (ASD; e.g., due to recreation). Here, we describe a neural circuit responsible for pain sensitization in mice treated with 9-h non-stress ASD. Using a combination of advanced neuroscience methods, we found that ASD stimulates noradrenergic inputs from locus coeruleus (LCNA) to glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HLGlu). Moreover, artificial inhibition of this LCNA→S1HLGlu pathway alleviates ASD-induced pain sensitization in mice, while chemogenetic activation of this pathway recapitulates the pain sensitization observed following ASD. Our study thus implicates activation of the LCNA→S1HLGlu pathway in ASD-induced pain sensitization, expanding our fundamental understanding of the multisystem interplay involved in pain processing.

Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice.

To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

Age- and region-dependent cortical excitability in the zQ175 Huntington disease mouse model.

The neurodegenerative disorder, Huntington disease (HD), manifests as disorders of movement, cognition and mood. Although studies report abnormal corticostriatal synaptic function early in HD mouse models, less is known about cortical-cortical activity across brain regions and disease stages. Recently, we reported enhanced mesoscale spread of cortical responses to sensory stimulation in vivo at early-manifest stages of two HD mouse models. Here, we investigated cortical excitability of zQ175 HD-model mice compared to their wild-type littermates across different cell types, ages and/or cortical regions using ex vivo electrophysiology. Cortical pyramidal neurons (CPNs) in somatosensory cortex of zQ175 mice showed intrinsic hyper-excitability at 3-4months, but hypo-excitability at early-manifest stage (8-9months); reduced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was seen at both ages. In contrast, motor cortex CPNs in early-manifest zQ175 mice showed increased intrinsic excitability and sEPSC frequency. Large-amplitude excitatory discharges recorded from CPNs in early-manifest zQ175 mice showed increased frequency only in somatosensory cortex, suggesting the intrinsic hypo-excitability of these CPNs may be compensatory against cortical network hyper-excitability. Similarly, in early-manifest zQ175 mice, region-dependent differences were seen in fast-spiking interneurons (FSIs): somatosensory but not motor FSIs from early-manifest zQ175 mice had reduced intrinsic excitability. Moreover, CPNs showed decreased frequency of spontaneous inhibitory postsynaptic currents and increased excitatory-inhibitory (E-I) balance of evoked synaptic currents in somatosensory cortex. Aberrant large-amplitude discharges and reduced inhibitory drive may therefore underlie E-I imbalances that result in circuit changes and synaptic dysfunction in early-manifest HD.

Comparative influence of mesenchymal stromal cells of different origin on DNA fragmentation of neuronal nuclei during ischemia-reperfusion of the somatosensory cortex of the rat brain

Relevance: One of the main causes of stroke in acute cerebrovascular accident (ACVA) is ischemia, which begins with the formation of an acute neuronal energy deficit with subsequent activation of the "ischemic cascade" reactions that lead to irreversible damage to nervous tissue. Aim: To compare the effect of mesenchymal stromal cells (MSCs) of different origin and human MSCs from Wharton's jelly lysate on neuroapoptotic changes in the somatosensory cortex of the rat brain in conditions of model ischemia-reperfusion (IR) performed by ductal cytoflowmetry. Materials and methods: The experiment was carried out using 165 four-month-old male Wistar rats weighing 160-190 g, which were subjected to bilateral 20-minute transient ischemia-reperfusion (IR) of the internal carotid arteries. After modeling the pathology, the animals were injected into the femoral vein (iv) with MSCs obtained from umbilical cord Wharton jelly, human and rat adipose tissue in the amount of 106 cells/animal. Other groups of experimental animals were intravenously injected with fetal rat fibroblasts in the amount of 106 cells/animal (in 0.2 ml of physiological solution) and MSCs from umbilical cord Wharton's jelly lysate in a dose of 0.2 ml/animal. Control animals were injected intravenously with 0.2 ml of physiological solution. The level of DNA fragmentation in the nuclei of neurons of the somatosensory cortex of rats on the 7th day after ischemia-reperfusion was studied by flow cytometry. The research was carried out on a flow cytometer "Partech РАС" of the company Partech, Germany. The statistical significance of the differences was assessed by Student's t-test. Results: The study noted an increase in the level of fragmented DNA in a group of animals with IR by 3.25 times 7 days after model IR. The performed treatment showed that in groups with transplanted MSCs of various origins and MSC lysate from human Wharton's jelly cells, the intensity of DNA fragmentation in the nuclei of neurons in rat brain somatosensory cortex reliably decreased in1.8-2. 6 times compared with the group of control pathology (IR without treatment). Conclusions: Experimental 20-minute IR of the brain of rats forms a persistent focus of necrotic and apoptotic death of neurons, which is manifested by an increase in fragmented DNA (3.25 times). Intravenous transplantation of MSCs of various origin and lysate of MSCs from human Wharton jelly has a therapeutic effect in model IR, which is manifested by a decrease in the processes of neuro-destruction and neuroapoptosis in the area of ischemic brain damage Such effect is a link to the polytrophic mechanism of MSCs neuro-protective action.

VIP interneurons in sensory cortex encode sensory and action signals but not direct reward signals

Vasoactive intestinal peptide (VIP) interneurons in sensory cortex modulate sensory responses based on global exploratory behavior and arousal state, but their function during non-exploratory, goal-directed behavior is not well understood. In particular, whether VIP cells are activated by sensory cues, reward-seeking actions, or directly by reinforcement is unclear. We trained mice on a Go/NoGo whisker touch detection task that included a delay period and other features designed to separate sensory-evoked, action-related, and reward-related neural activity. Mice had to lick in response to a whisker stimulus to receive a variable-sized reward. Using two-photon calcium imaging, we measured ΔF/F responses of L2/3 VIP neurons in whisker somatosensory cortex (S1) during behavior. In both expert and novice mice, VIP cells were strongly activated by whisker stimuli and goal-directed actions (licking), but not by reinforcement. VIP cells showed somatotopic whisker tuning that was spatially organized relative to anatomical columns in S1, unlike lick-related signals which were spatially widespread. In expert mice, lick-related VIP responses were suppressed, not enhanced, when a reward was delivered, and the amount of suppression increased with reward size. This reward-related suppression was not seen in novice mice, where reward delivery was not yoked to licking. These results indicate that besides arousal and global state variables, VIP cells are activated by local sensory features and goal-directed actions, but not directly by reinforcement. Instead, our results are consistent with a role for VIP cells in encoding the expectation of reward associated with motor actions.

Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical invivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

A direct spino-cortical circuit bypassing the thalamus modulates nociception.

Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus define these neurons as spino-cortical recipient neurons (SCRNs). Morphological studies revealed that the branches from spinal ascending axons formed a kind of disciform structure with the descending axons from SCRNs in the basilar pontine nucleus (BPN). Electron microscopy and calcium imaging further confirmed that the axon terminals from spinal ascending neurons and SCRNs made functional synaptic contacts in the BPN, linking the ascending sensory pathway to the descending motor control pathway. Furthermore, behavioral tests indicated that the spino-cortical connection in the BPN was involved in nociceptive responses. In vivo calcium imaging showed that SCRNs responded to peripheral noxious stimuli faster than neighboring layer 4 cortical neurons in awake mice. Manipulating activities of SCRNs could modulate nociceptive behaviors. Therefore, this direct spino-cortical circuit represents a noncanonical pathway, allowing a fast sensory-motor transition of the brain in response to noxious stimuli.

Hippocampal output profoundly impacts the interpretation of tactile input patterns in SI cortical neurons

Due to continuous state variations in neocortical circuits, individual somatosensory cortex (SI) neurons invivo display a variety of intracellular responses to the exact same spatiotemporal tactile input pattern. To manipulate the internal cortical state, we here used brief electrical stimulation of the output region of the hippocampus, which preceded the delivery of specific tactile afferent input patterns to digit 2 of the anesthetized rat. We find that hippocampal output had a diversified, remarkably strong impact on the intracellular response types displayed by each neuron in the primary SI to each given tactile input pattern. Qualitatively, this impact was comparable to that previously described for cortical output, which was surprising given the widely assumed specific roles of the hippocampus, such as in cortical memory formation. The findings show that hippocampal output can profoundly impact the state-dependent interpretation of tactile inputs and hence influence perception, potentially with affective and semantic components.

Microstimulation of sensory cortex engages natural sensory representations

Cortical activity patterns occupy a small subset of possible network states. If this is due to intrinsic network properties, microstimulation of sensory cortex should evoke activity patterns resembling those observed during natural sensory input. Here, we use optical microstimulation of virally transfected layer 2/3 pyramidal neurons in the mouse primary vibrissal somatosensory cortex to compare artificially evoked activity with natural activity evoked by whisker touch and movement ("whisking"). We find that photostimulation engages touch- but not whisking-responsive neurons more than expected by chance. Neurons that respond to photostimulation and touch or to touch alone exhibit higher spontaneous pairwise correlations than purely photoresponsive neurons. Exposure to several days of simultaneous touch and optogenetic stimulation raises both overlap and spontaneous activity correlations among touch and photoresponsive neurons. We thus find that cortical microstimulation engages existing cortical representations and that repeated co-presentationof natural and artificial stimulation enhances this effect.

Motor cortex gates distractor stimulus encoding in sensory cortex

Suppressing responses to distractor stimuli is a fundamental cognitive function, essential for performing goal-directed tasks. A common framework for the neuronal implementation of distractor suppression is the attenuation of distractor stimuli from early sensory to higher-order processing. However, details of the localization and mechanisms of attenuation are poorly understood. We trained mice to selectively respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of whisker motor cortex increased the overall tendency to respond and the detection of distractor whisker stimuli. Within sensory cortex, optogenetic inhibition of whisker motor cortex enhanced the propagation of distractor stimuli into target-preferring neurons. Single unit analyses revealed that whisker motor cortex (wMC) decorrelates target and distractor stimulus encoding in target-preferring primary somatosensory cortex (S1) neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from wMC to S1, through the differential activation of putative excitatory and inhibitory neurons before stimulus onset. Overall, our studies support a contribution of motor cortex to sensory selection, in suppressing behavioral responses to distractor stimuli by gating distractor stimulus propagation within sensory cortex.

Heterozygous GABAA receptor β3 subunit N110D knock-in mice have epileptic spasms.

Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock-in mouse with the human infantile spasms-associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock-in mouse as a model of infantile spasms syndrome. We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock-in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi-unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. The infantile spasms-associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock-in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. The Gabrb3+/N110D knock-in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits.

Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain

Increased low frequency cortical oscillations are observed in people with neuropathic pain, but the cause of such elevated cortical oscillations and their impact on pain development remain unclear. By imaging neuronal activity in a spared nerve injury (SNI) mouse model of neuropathic pain, we show that neurons in dorsal root ganglia (DRG) and somatosensory cortex (S1) exhibit synchronized activity after peripheral nerve injury. Notably, synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations. This DRG synchrony is initiated by axotomized neurons and mediated by local purinergic signaling at the site of nerve injury. We further show that synchronized DRG activity after SNI is responsible for increasing low frequency cortical oscillations and synaptic remodeling in S1, as well as for inducing animals’ pain-like behaviors. In naive mice, enhancing the synchrony, not the level, of DRG neuronal activity causes synaptic changes in S1 and pain-like behaviors similar to SNI mice. Taken together, these results reveal the critical role of synchronized DRG neuronal activity in increasing cortical plasticity and oscillations in a neuropathic pain model. These findings also suggest the potential importance of detection and suppression of elevated cortical oscillations in neuropathic pain states.

Combined neuromuscular electrical stimulation and transcutaneous spinal direct current stimulation increases motor cortical plasticity in healthy humans.

Neuromuscular electrical stimulation (NMES) induces neural plasticity of the central nervous system (CNS) and improves motor function in patients with CNS lesions. However, the extended stimulus duration of NMES reduces its clinical applicability. Transcutaneous spinal direct current stimulation (tsDCS), which increases afferent input, may enhance the effects and reduce the stimulus duration of NMES. This study investigated the excitability of the motor cortex, somatosensory cortex, and spinal motor neurons after the combined stimulation of NMES and tsDCS. Among the 55 participants in this study, 24 were allocated to experiment 1, 15 to experiment 2, and 16 to experiment 3. They received intervention for 20 min on different days: (1) NMES combined with tsDCS (NMES + tsDCS), (2) NMES combined with sham tsDCS (NMES + sham tsDCS), and (3) sham NMES combined with tsDCS (sham NMES + tsDCS). NMES was delivered to the right common peroneal nerve at 25 Hz with the intensity at 120% of the motor threshold. For tsDCS, the cathodal electrode was positioned on the thoracic 10th-12th vertebral levels, and the anodal electrode was located on the right shoulder. The stimulus intensity was 2.5 mA. In experiment 1, motor evoked potentials (MEPs) and short-latency intracortical inhibition (SICI) were measured by transcranial magnetic stimulation up to 60 min after stimulation. The spinal motor neurons' excitability was assessed by recording the posterior root muscle reflex (PRMR) induced via transcutaneous spinal cord stimulation in experiment 2, and the primary somatosensory cortex excitability was evaluated by recording the somatosensory evoked potentials (SEPs) in experiment 3 up to 15 min after stimulation. Compared to before the stimulation, NMES + tsDCS significantly increased MEP for 60 min or more, and significantly decreased SICI immediately after. Conversely contrast, the PRMR significantly decreased immediately after, and SEPs were unchanged. These results suggest that simultaneous afferent inputs from different stimulus positions critically induce primary motor cortex plasticity. The combined stimulation of NMES with tsDCS may facilitate the development of a new neurorehabilitation technique.

Dexmedetomidine Preserves Activity of Neurons in Primary Somatosensory Cortex Compared to Propofol and Ketamine.

General anesthesia has been shown to induce significant changes in the functional connectivity of the cerebral cortex. However, traditional methods such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) lack the spatial resolution to study the effects of general anesthesia on individual cortical neurons. This study aimed to use high-resolution two-photon imaging, which can provide single-neuron resolution, to investigate the characteristics of consciousness under general anesthesia. We used C57BL/6J and Thy1-GCamp6s mice and found that at similar levels of sedation, as measured by EEG, dexmedetomidine did not significantly inhibit the spontaneous activity of neuronal somata in the S1 cortex, but preserved the frequency of calcium events in neuronal spines. In contrast, propofol and ketamine dramatically inhibited the spontaneous activity of both neuronal somata and spines. The S1 cortex still responded to whisker stimulation under dexmedetomidine anesthesia, but not under propofol or ketamine anesthesia. Our results suggest that dexmedetomidine anesthesia has unique neuronal properties associated with its ability to facilitate easy awakening in the clinic. These findings provide insights into the development of more effective strategies for monitoring consciousness during general anesthesia.

Quantitative Fluorescence Analysis Reveals Dendrite-Specific Thalamocortical Plasticity in L5 Pyramidal Neurons during Learning.

High-throughput anatomic data can stimulate and constrain new hypotheses about how neural circuits change in response to experience. Here, we use fluorescence-based reagents for presynaptic and postsynaptic labeling to monitor changes in thalamocortical synapses onto different compartments of layer 5 (L5) pyramidal (Pyr) neurons in somatosensory (barrel) cortex from mixed-sex mice during whisker-dependent learning (Audette et al., 2019). Using axonal fills and molecular-genetic tags for synapse identification in fixed tissue from Rbp4-Cre transgenic mice, we found that thalamocortical synapses from the higher-order posterior medial thalamic nucleus showed rapid morphologic changes in both presynaptic and postsynaptic structures at the earliest stages of sensory association training. Detected increases in thalamocortical synaptic size were compartment specific, occurring selectively in the proximal dendrites onto L5 Pyr and not at inputs onto their apical tufts in L1. Both axonal and dendritic changes were transient, normalizing back to baseline as animals became expert in the task. Anatomical measurements were corroborated by electrophysiological recordings at different stages of training. Thus, fluorescence-based analysis of input- and target-specific synapses can reveal compartment-specific changes in synapse properties during learning.SIGNIFICANCE STATEMENT Synaptic changes underlie the cellular basis of learning, experience, and neurologic diseases. Neuroanatomical methods to assess synaptic plasticity can provide critical spatial information necessary for building models of neuronal computations during learning and experience but are technically and fiscally intensive. Here, we describe a confocal fluorescence microscopy-based analytical method to assess input, cell type, and dendritic location-specific synaptic plasticity in a sensory learning assay. Our method not only confirms prior electrophysiological measurements but allows us to predict functional strength of synapses in a pathway-specific manner. Our findings also indicate that changes in primary sensory cortices are transient, occurring during early learning. Fluorescence-based synapse identification can be an efficient and easily adopted approach to study synaptic changes in a variety of experimental paradigms.

Up-regulation of HCN2 channels in a thalamocortical circuit mediates allodynia in mice.

Chronic pain is a significant problem that afflicts individuals and society, and for which the current clinical treatment is inadequate. In addition, the neural circuit and molecular mechanisms subserving chronic pain remain largely uncharacterized. Herein we identified enhanced activity of a glutamatergic neuronal circuit that encompasses projections from the ventral posterolateral nucleus (VPLGlu) to the glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HLGlu), driving allodynia in mouse models of chronic pain. Optogenetic inhibition of this VPLGlu→S1HLGlu circuit reversed allodynia, whereas the enhancement of its activity provoked hyperalgesia in control mice. In addition, we found that the expression and function of the HCN2 (hyperpolarization-activated cyclic nucleotide-gated channel 2) were increased in VPLGlu neurons under conditions of chronic pain. Using in vivo calcium imaging, we demonstrated that downregulation of HCN2 channels in the VPLGlu neurons abrogated the rise in S1HLGlu neuronal activity while alleviating allodynia in mice with chronic pain. With these data, we propose that dysfunction in HCN2 channels in the VPLGlu→S1HLGlu thalamocortical circuit and their upregulation occupy essential roles in the development of chronic pain.