Population Of Inhibitory Interneurons Research Articles

Postsynaptic GABAB-receptor mediated currents in diverse dentate gyrus interneuron types.

The processing of rich synaptic information in the dentate gyrus (DG) relies on a diverse population of inhibitory GABAergic interneurons to regulate cellular and circuit activity, in a layer-specific manner. Metabotropic GABAB-receptors (GABABRs) provide powerful inhibition to the DG circuit, on timescales consistent with behavior and learning, but their role in controlling the activity of interneurons is poorly understood with respect to identified cell types. We hypothesize that GABABRs display cell type-specific heterogeneity in signaling strength, which will have direct ramifications for signal processing in DG networks. To test this, we perform in vitro whole-cell patch-clamp recordings from identified DG principal cells and interneurons, followed by GABABR pharmacology, photolysis of caged GABA, and extracellular stimulation of endogenous GABA release to classify the cell type-specific inhibitory potential. Based on our previous classification of DG interneurons, we show that postsynaptic GABABR-mediated currents are present on all interneuron types albeit at different amplitudes, dependent largely on soma location and synaptic targets. GABABRs were coupled to inwardly-rectifying K+ channels that strongly reduced the excitability of those interneurons where large currents were observed. These data provide a systematic characterization of GABABR signaling in the rat DG to provide greater insight into circuit dynamics.

Cell type- and layer-specific plasticity of olfactory bulb interneurons following olfactory sensory neuron ablation

Lifelong neurogenesis endows the mouse olfactory system with a capacity for regeneration that is unique in the mammalian nervous system. Throughout life, olfactory sensory neurons (OSNs) are generated from olfactory epithelium (OE) stem cells in the nose, while the subventricular zone generates neuroblasts that migrate to the olfactory bulb (OB) and differentiate into multiple populations of inhibitory interneurons. Methimazole (MMZ) selectively ablates OSNs, but OE neurogenesis enables OSN repopulation and gradual recovery of OSN input to the OB within 6 weeks. However, it is not known how OB interneurons are affected by this loss and subsequent regeneration of OSN input following MMZ treatment. We found that dopaminergic neuron density was significantly reduced 7–14 days post-MMZ but recovered substantially at 35 days. The density of parvalbumin-expressing interneurons was unaffected by MMZ; however, their soma size was significantly reduced at 7–14 days post-MMZ, recovering by 35 days. Surprisingly, we found a transient increase in the density of calretinin-expressing neurons in the glomerular and external plexiform layers, but not the granule cell layer, 7 days post-MMZ. This could not be accounted for by increased neurogenesis but may result from increased calretinin expression. Together, our data demonstrate cell type- and layer-specific changes in OB interneuron density and morphology after MMZ treatment, providing new insight into the range of plasticity mechanisms employed by OB circuits during loss and regeneration of sensory input.

Conservation, alteration, and redistribution of mammalian striatal interneurons.

Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1-4. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons5. However, there has not yet been a detailed analysis of the spatial and phylogenetic distribution of this population. Here, we profile single cell gene expression in the developing pig (an ungulate) and ferret (a carnivore), representing 94 million years divergence from primates, and assign newborn inhibitory neurons to initial classes first specified during development6. We find that the initial class of TAC3 interneurons represents an ancestral striatal population that is also deployed towards the cortex in pig and ferret. In adult mouse, we uncover a rare population expressing Tac2, the ortholog of TAC3, in ventromedial striatum, prompting a reexamination of developing mouse striatal interneuron initial classes by targeted enrichment of their precursors. We conclude that the TAC3 interneuron initial class is conserved across Boreoeutherian mammals, with the mouse population representing Th striatal interneurons, a subset of which expresses Tac2. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.

Single-cell multiregion dissection of Alzheimer’s disease

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1–3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Role of interneuron subtypes in controlling trial-by-trial output variability in the neocortex

Trial-by-trial variability is a ubiquitous property of neuronal activity in vivo which shapes the stimulus response. Computational models have revealed how local network structure and feedforward inputs shape the trial-by-trial variability. However, the role of input statistics and different interneuron subtypes in this process is less understood. To address this, we investigate the dynamics of stimulus response in a cortical microcircuit model with one excitatory and three inhibitory interneuron populations (PV, SST, VIP). Our findings demonstrate that the balance of inputs to different neuron populations and input covariances are the primary determinants of output trial-by-trial variability. The effect of input covariances is contingent on the input balances. In general, the network exhibits smaller output trial-by-trial variability in a PV-dominated regime than in an SST-dominated regime. Importantly, our work reveals mechanisms by which output trial-by-trial variability can be controlled in a context, state, and task-dependent manner.

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling.

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

Inhibitory control of sharp-wave ripple duration during learning in hippocampal recurrent networks.

Recurrent excitatory connections in hippocampal regions CA3 and CA2 are thought to play a key role in the generation of sharp-wave ripples (SWRs), electrophysiological oscillations tightly linked with learning and memory consolidation. However, it remains unknown how defined populations of inhibitory interneurons regulate these events during behavior. Here, we use large-scale, three-dimensional calcium imaging and retrospective molecular identification in the mouse hippocampus to characterize molecularly identified CA3 and CA2 interneuron activity during SWR-associated memory consolidation and spatial navigation. We describe subtype- and region-specific responses during behaviorally distinct brain states and find that SWRs are preceded by decreased cholecystokinin-expressing interneuron activity and followed by increased parvalbumin-expressing basket cell activity. The magnitude of these dynamics correlates with both SWR duration and behavior during hippocampal-dependent learning. Together these results assign subtype- and region-specific roles for inhibitory circuits in coordinating operations and learning-related plasticity in hippocampal recurrent circuits.

Organizational Principles of the Centrifugal Projections to the Olfactory Bulb.

Centrifugal projections in the olfactory system are critical to both olfactory processing and behavior. The olfactory bulb (OB), the first relay station in odor processing, receives a substantial number of centrifugal inputs from the central brain regions. However, the anatomical organization of these centrifugal connections has not been fully elucidated, especially for the excitatory projection neurons of the OB, the mitral/tufted cells (M/TCs). Using rabies virus-mediated retrograde monosynaptic tracing in Thy1-Cre mice, we identified that the three most prominent inputs of the M/TCs came from the anterior olfactory nucleus (AON), the piriform cortex (PC), and the basal forebrain (BF), similar to the granule cells (GCs), the most abundant population of inhibitory interneurons in the OB. However, M/TCs received proportionally less input from the primary olfactory cortical areas, including the AON and PC, but more input from the BF and contralateral brain regions than GCs. Unlike organizationally distinct inputs from the primary olfactory cortical areas to these two types of OB neurons, inputs from the BF were organized similarly. Furthermore, individual BF cholinergic neurons innervated multiple layers of the OB, forming synapses on both M/TCs and GCs. Taken together, our results indicate that the centrifugal projections to different types of OB neurons may provide complementary and coordinated strategies in olfactory processing and behavior.

α2-Adrenergic modulation of Ih in adult-born granule cells in the olfactory bulb.

In the olfactory bulb (OB), a large population of axon-less inhibitory interneurons, the granule cells (GCs), coordinate network activity and tune the output of principal neurons, the mitral and tufted cells (MCs), through dendrodendritic interactions. Furthermore, GCs undergo neurogenesis throughout life, providing a source of plasticity to the neural network of the OB. The function and integration of GCs in the OB are regulated by several afferent neuromodulatory signals, including noradrenaline (NA), a state-dependent neuromodulator that plays a crucial role in the regulation of cortical function and task-specific decision processes. However, the mechanisms by which NA regulates GC function are not fully understood. Here, we show that NA modulates hyperpolarization-activated currents (Ih) via the activation of α2-adrenergic receptors (ARs) in adult-born GCs (abGCs), thus directly acting on channels that play essential roles in regulating neuronal excitability and network oscillations in the brain. This modulation affects the dendrodendritic output of GCs leading to an enhancement of lateral inhibition onto the MCs. Furthermore, we show that NA modulates subthreshold resonance in GCs, which could affect the temporal integration of abGCs. Together, these results provide a novel mechanism by which a state-dependent neuromodulator acting on Ih can regulate GC function in the OB.

Structural spine plasticity: Learning and forgetting of odor-specific subnetworks in the olfactory bulb.

Learning to discriminate between different sensory stimuli is essential for survival. In rodents, the olfactory bulb, which contributes to odor discrimination via pattern separation, exhibits extensive structural synaptic plasticity involving the formation and removal of synaptic spines, even in adult animals. The network connectivity resulting from this plasticity is still poorly understood. To gain insight into this connectivity we present here a computational model for the structural plasticity of the reciprocal synapses between the dominant population of excitatory principal neurons and inhibitory interneurons. It incorporates the observed modulation of spine stability by odor exposure. The model captures the striking experimental observation that the exposure to odors does not always enhance their discriminability: while training with similar odors enhanced their discriminability, training with dissimilar odors actually reduced the discriminability of the training stimuli. Strikingly, this differential learning does not require the activity-dependence of the spine stability and occurs also in a model with purely random spine dynamics in which the spine density is changed homogeneously, e.g., due to a global signal. However, the experimentally observed odor-specific reduction in the response of principal cells as a result of extended odor exposure and the concurrent disinhibition of a subset of principal cells arise only in the activity-dependent model. Moreover, this model predicts the experimentally testable recovery of odor response through weak but not through strong odor re-exposure and the forgetting of odors via exposure to interfering odors. Combined with the experimental observations, the computational model provides strong support for the prediction that odor exposure leads to the formation of odor-specific subnetworks in the olfactory bulb.

Mice With Monoallelic GNAO1 Loss Exhibit Reduced Inhibitory Synaptic Input to Cerebellar Purkinje Cells

GNAO1 encodes Gαo, a heterotrimeric G protein alpha subunit in the Gi/o family. Gαo, the most abundant membrane protein in the brain, mediates downstream signaling pathways by itself, or via regulating free Gβγ subunits. To determine the role of Gαo protein in regulating synaptic transmission, we use electrophysiology to study cerebellar molecular layer interneuron ‐ Purkinje cell synaptic transmission in a haploinsufficient loss‐of‐function (LOF) Gnao1 mouse model, manifest with movement abnormalities and enhanced seizure susceptibility. We hypothesize that a LOF Gαo protein will increase GABA release through presynaptic Gαo ‐ coupled receptors.Inhibitory post synaptic currents (IPSCs) and excitatory post synaptic currents (EPSCs) were recorded using standard patch clamp techniques. Spontaneous IPSCs (sIPSCs) were isolated with glutamatergic receptor inhibitors CNQX and AP‐5. Spontaneous EPSCs (sEPSCs) were isolated with the GABAergic receptor inhibitor bicuculline. Miniature PSCs were isolated with the additional perfusion of tetrodotoxin. Cerebellar molecular layer inhibitory neurons were labeled with the Kit‐eGFP method and observed under an inverted epifluorescence microscope. Gαo and Gβ protein expression levels from flash‐frozen mouse brain tissues were determined using Western Blot.Instead of increase, we observe a significant reduction in both sIPSC (40%) and mIPSC (75%) frequency but not amplitude in the Gnao1 mutant mouse model. Both frequency and amplitude of sEPSCs and mEPSCs remain unchanged. On Western blots, levels of Gαo were reduced by about half, as expected, while Gβ levels were unchanged from control. To determine whether this reduction is due to the loss of cerebellar inhibitory interneuron populations, we compare cerebellar interneuron number in the cerebellar molecular layer between Gnao1 mutant mice and their wildtype littermate control. There is a modest reduction (13%) in interneuron number of cerebellar molecular layer in the Gnao1 mutant mouse.The observed reduction in IPSC frequency is not related to Gαo ‐ coupled GABAergic receptors. Also, the modest change in cerebellar interneuron counts does not seem to account for the marked reduction in IPSC frequency. These observations, and the reduced Gαo expression in brain with the normal levels of Gβ, strongly support that a model with a haploinsufficient LOF Gnao1 mutant mainly functions through receptor‐independent regulation of free Gβγ subunits to suppress inhibitory neurotransmitter release in Gnao1 mutant cerebellum.

Excitatory and Inhibitory Neurons of the Spinal Cord Superficial Dorsal Horn Diverge in Their Somatosensory Responses and Plasticity in Vivo.

The superficial dorsal horn (SDH) of the spinal cord represents the first site of integration between innocuous and noxious somatosensory stimuli. According to gate control theory, diverse populations of excitatory and inhibitory interneurons within the SDH are activated by distinct sensory afferents, and their interplay determines the net nociceptive output projecting to higher pain centers. Although specific SDH cell types are ill defined, numerous classifications schemes find that excitatory and inhibitory neurons fundamentally differ in their morphology, electrophysiology, neuropeptides, and pain-associated plasticity; yet little is known about how these neurons respond over a range of natural innocuous and noxious stimuli. To address this question, we applied an in vivo imaging approach in male mice where the genetically encoded calcium indicator GCaMP6s was expressed either in vGluT2-positive excitatory or vIAAT-positive inhibitory neurons. We found that inhibitory neurons were markedly more sensitive to innocuous touch than excitatory neurons but still responded dynamically over a wide range of noxious mechanical stimuli. Inhibitory neurons were also less sensitive to thermal stimuli than their excitatory counterparts. In a capsaicin model of acute pain sensitization, the responses of excitatory neurons were significantly potentiated to innocuous and noxious mechanical stimuli, whereas inhibitory neural responses were only depressed to noxious stimuli. These in vivo findings show that excitatory and inhibitory SDH neurons diverge considerably in their somatosensory responses and plasticity, as postulated by gate control theory.SIGNIFICANCE STATEMENT Gate control theory posits that opposing spinal excitatory and inhibitory neurons, differently tuned across somatosensory modalities, determine the net nociceptive output to higher pain centers. Little is known about how natural stimuli activate these two neural populations. This study applied an in vivo calcium imaging approach to genetically target these neurons and contrast their responses over a range of innocuous and noxious mechanical and thermal stimuli. Compared with excitatory neurons, we found that inhibitory neurons are more sensitive to innocuous touch and far less sensitive to thermal stimuli. An acute model of pain also revealed that these subtypes undergo divergent mechanosensory plasticity. Our data provide important and novel insights for gate-control inspired models of pain processing.

Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons.

The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-positive interneurons does not require the activation of GluN2A-containing NMDARs but does rely on the activation of NMDARs containing GluN2B and GluN2D subunits.

NDNF is selectively expressed by neocortical, but not habenular neurogliaform cells.

The lateral habenula (LHb) is a brain structure which is known to be pathologically hyperactive in depression, whereby it shuts down the brains' reward systems. Interestingly, inhibition of the LHb has been shown to have an antidepressant effect, hence making the LHb a fascinating subject of study for developing novel antidepressant therapies. Despite this however, the exact mechanisms by which inhibitory signalling is processed within the LHb remain incompletely understood. Some studies have proposed the existence of locally targeting inhibitory interneuron populations within the LHb. One such population is believed to be akin to neocortical neurogliaform cells, yet specific molecular markers for studying these neurons are sparse and hence their function remains elusive. Recently, neuron-derived neurotrophic factor (NDNF) has been proposed as one such marker for neocortical neurogliaform cells. Using a combination of histological, physiological and optogenetic tools, we hence sought to first validate if NDNF was selectively expressed by such inhibitory neurons within the neocortex, and then if it was confined to a similar population within the LHb. While we report this to be true for the neocortex, we find no such evidence within the LHb; rather that NDNF is expressed without restriction to a particular neuronal subpopulation. These results hence indicate that molecular markers can represent broadly diverse populations of neurons on a region-to-region basis and that therefore each population as defined by molecular marker expression should be validated in each brain structure.

Chronic pain‐mediated Regulator of G protein signaling 4 (RGS4) gene expression in superficial dorsal horn of spinal cord

Regulator of G protein signaling 4 (RGS4) is a potent negative regulator of G-protein coupled receptor signaling duration. Recent studies have identified RGS4 as a key gene in the maintenance of mechanical and cold allodynia associated with chronic pain states in mice. RGS4 is abundantly expressed across the pain matrix, and several studies have demonstrated upregulation of RGS4 mRNA in response to both peripheral inflammation and nerve injury. Here, we tested the hypothesis that peripheral nerve injury alters RGS4 neuronal expression broadly, and with specific expression-patterning among excitatory and inhibitory interneuron populations within the superficial dorsal horn of the mouse spinal cord. Chronic neuropathic pain was induced in C57BL/6 male mice via spared-nerve injury (SNI). At 2.5 months post-surgery (SNI vs sham), animals were sacrificed and lumbar spinal cords were harvested for tissue processing. RNAScope, an ultrasensitive RNA ISH method, was used to visualize and quantify single-molecule expression of RGS4, prodynorphin/PDYN (exclusively expressed by inhibitory dorsal horn interneurons), and somatostatin/SST (expressed by excitatory interneurons) within the cellular topography of the lumbar superficial dorsal horn. RGS4 expression increased significantly in the dorsal horn following spared-nerve injury (P =0.0384). RGS4 mRNA remained unchanged (SNI vs sham) among expression-positive dorsal horn neurons (p=0.6327). In sham-treated mice, there were no differences in cell-type specific (PDYN vs. SST) RGS4 expression patterns in the dorsal horn (p=0.4170). Cell-type specific RGS4 expression in the dorsal horn was significantly different (F (2,27) = 8.353; P =0.0015; one-way ANOVA) following spared-nerve injury. SNI-induced RGS4 expression was significantly enriched in PDYN vs SST-expressing interneurons (p=0.0300), and overall RGS4 expression was significantly downregulated in SST-expressing cells compared to all cells (p=0.0012). These data demonstrate that nerve injury induces upregulation of RGS4 in the superficial dorsal horn, and suggest that RGS4-positive inhibitory interneurons may be implicated in influencing persistent pain signaling within the dorsal horn of the spinal cord.

Ethanol-Induced Adaptations to Inhibitory Microcircuits in the Mouse Prefrontal Cortex

Prefrontal cortex (PFC) dysfunction is a central component of the etiology of alcohol use disorder (AUD) and other addictions. While mechanistic studies have revealed many adaptations to PFC pyramidal cells in models of binge drinking and ethanol dependence, relatively little research has focused on alterations to defined populations of inhibitory interneurons.

Spinal Inhibitory Interneurons: Gatekeepers of Sensorimotor Pathways.

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.