Somatostatin-expressing Cells Research Articles

Hypothalamic regulation of hippocampal CA1 interneurons by the supramammillary nucleus

The hypothalamic supramammillary nucleus (SuM) projects heavily to the hippocampus to regulate hippocampal activity and plasticity. Although the projections from the SuM to the dentate gyrus (DG) and CA2 have been extensively studied, whether the SuM projects to CA1, the main hippocampal output region, is unclear. Here, we report a glutamatergic pathway from the SuM that selectively excites CA1 interneurons in the border between the stratum radiatum (SR) and the stratum lacunosum-moleculare (SLM). We find that the SuM projects selectively to a narrow band in the CA1 SR/SLM and monosynaptically excites SR/SLM interneurons, including vasoactive intestinal peptide-expressing (VIP+) and neuron-derived neurotrophic factor-expressing (NDNF+) cells, but completely avoids making monosynaptic contacts with CA1 pyramidal neurons (PNs) or parvalbumin-expressing (PV+) or somatostatin-expressing (SOM+) cells. Moreover, SuM activation drives spikes in most SR/SLM interneurons to suppress CA1 PN excitability. Taken together, our findings reveal that the SuM can directly regulate hippocampal output region CA1, bypassing CA2, CA3, and the DG.

Subfield-specific interneuron circuits govern the hippocampal response to novelty in male mice

The hippocampus is the brain’s center for episodic memories. Its subregions, the dentate gyrus and CA1-3, are differentially involved in memory encoding and recall. Hippocampal principal cells represent episodic features like movement, space, and context, but less is known about GABAergic interneurons. Here, we performed two-photon calcium imaging of parvalbumin- and somatostatin-expressing interneurons in the dentate gyrus and CA1-3 of male mice exploring virtual environments. Parvalbumin-interneurons increased activity with running-speed and reduced it in novel environments. Somatostatin-interneurons in CA1-3 behaved similar to parvalbumin-expressing cells, but their dentate gyrus counterparts increased activity during rest and in novel environments. Congruently, chemogenetic silencing of dentate parvalbumin-interneurons had prominent effects in familiar contexts, while silencing somatostatin-expressing cells increased similarity of granule cell representations between novel and familiar environments. Our data indicate unique roles for parvalbumin- and somatostatin-positive interneurons in the dentate gyrus that are distinct from those in CA1-3 and may support routing of novel information.

Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

AbstractOpioid drugs are widely used as analgesics but cause respiratory depression, a potentially lethal side effect with overdose, by acting on μ-opioid receptors (MORs) expressed in brainstem regions involved in the control of breathing. Although many brainstem regions have been shown to regulate opioid-induced respiratory depression, the types of neurons involved have not been identified. Somatostatin is a major neuropeptide found in brainstem circuits regulating breathing, but it is unknown whether somatostatin-expressing circuits regulate respiratory depression by opioids. We examined the coexpression ofSst(gene encoding somatostatin) andOprm1(gene encoding MORs) mRNAs in brainstem regions involved in respiratory depression. Interestingly,Oprm1mRNA expression was found in the majority (>50%) ofSst-expressing cells in the preBötzinger Complex, the nucleus tractus solitarius, the nucleus ambiguus, and the Kölliker–Fuse nucleus. We then compared respiratory responses to fentanyl between wild-type andOprm1full knock-out mice and found that the lack of MORs prevented respiratory rate depression from occurring. Next, using transgenic knock-out mice lacking functional MORs specifically inSst-expressing cells, we compared respiratory responses to fentanyl between control and the conditional knock-out mice. We found that respiratory rate depression by fentanyl was preserved when MORs were deleted only inSst-expressing cells. Our results show that despite coexpression ofSstandOprm1in respiratory circuits and the importance of somatostatin-expressing cells in the regulation of breathing, these cells do not mediate opioid-induced respiratory rate depression. Instead, MORs found in respiratory cell populations other thanSst-expressing cells likely contribute to the respiratory effects of fentanyl.

The β2V287L nicotinic subunit linked to sleep-related epilepsy differently affects fast-spiking and regular spiking somatostatin-expressing neurons in murine prefrontal cortex.

Mutant subunits of the neuronal nicotinic ACh receptor (nAChR) can cause Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE), characterized by frontal seizures during non-rapid eye movement (NREM) sleep. We studied the cellular bases of the pathogenesis in brain slices from mice conditionally expressing the ADSHE-linked β2V287L nAChR subunit. β2V287L mice displayed minor structural alterations, except for a ~10% decrease of prefrontal cortex thickness. However, they showed a substantial decrease of the excitatory input to layer V fast-spiking (FS) interneurons, despite a concomitant increase in the number of glutamatergic terminals around the cell soma. Hence, prefrontal hyperexcitability may depend on a permanent impairment of surround inhibition. The effect disappeared when β2V287L was silenced until postnatal day 15th, suggesting that the transgene selectively affects the maturation of glutamatergic synapses on FS neurons. The other main population of interneurons in layer V was constituted by somatostatin-expressing regular spiking cells. When tested with 10µM nicotine, these displayed larger somatic nicotinic currents in transgenic mice. Thus, during wakefulness, activation of β2V287L-containing nAChRs by the high cholinergic tone may counteract hyperexcitability by promoting local inhibition by somatostatin-expressing cells and decreasing the effect of glutamatergic deficit in FS neurons. This interpretation was tested in networks disinhibited by 2μM bicuculline. Slices expressing β2V287L were more susceptible to develop synchronized activity in the absence of nicotine. Addition of the drug boosted excitability in the controls, but had little effect in β2V287L. Our findings suggest why NREM sleep favors ADSHE seizures and nicotine can be palliative in patients.

Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome

BackgroundFragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice.MethodsWe used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons.ResultsDe novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities.LimitationsThe mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors.ConclusionsOur findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS.

Conversion of Gastrointestinal Somatostatin-Expressing D Cells Into Insulin-Producing Beta-Like Cells Upon Pax4 Misexpression.

Type 1 diabetes results from the autoimmune-mediated loss of insulin-producing beta-cells. Accordingly, important research efforts aim at regenerating these lost beta-cells by converting pre-existing endogenous cells. Following up on previous results demonstrating the conversion of pancreatic somatostatin delta-cells into beta-like cells upon Pax4 misexpression and acknowledging that somatostatin-expressing cells are highly represented in the gastrointestinal tract, one could wonder whether this Pax4-mediated conversion could also occur in the GI tract. We made use of transgenic mice misexpressing Pax4 in somatostatin cells (SSTCrePOE) to evaluate a putative Pax4-mediated D-to-beta-like cell conversion. Additionally, we implemented an ex vivo approach based on mice-derived gut organoids to assess the functionality of these neo-generated beta-like cells. Our results outlined the presence of insulin+ cells expressing several beta-cell markers in gastrointestinal tissues of SSTCrePOE animals. Further, using lineage tracing, we established that these cells arose from D cells. Lastly, functional tests on mice-derived gut organoids established the ability of neo-generated beta-like cells to release insulin upon stimulation. From this study, we conclude that the misexpression of Pax4 in D cells appears sufficient to convert these into functional beta-like cells, thus opening new research avenues in the context of diabetes research.

CTCF in parvalbumin-expressing neurons regulates motor, anxiety and social behavior and neuronal identity

CCCTC-binding factor (CTCF) is a regulator of chromatin organization and has direct effects on gene transcription. Mutations in CTCF have been identified in individuals with neurodevelopmental conditions. There are wide range of behaviors associated with these mutations, including intellectual disabilities, changes in temperament, and autism. Previous mice-model studies have identified roles for CTCF in excitatory neurons in specific behaviors, particularly in regards to learning and memory. However, the role of CTCF in inhibitory neurons is less well defined. In the current study, specific knockout of CTCF in parvalbumin-expressing neurons, a subset of inhibitory neurons, induced a specific behavioral phenotype, including locomotor abnormalities, anxiolytic behavior, and a decrease in social behavior. The anxiolytic and social abnormalities are detected before the onset of locomotor abnormalities. Immunohistochemical analysis revealed a disbalance in parvalbumin-expressing and somatostatin-expressing cells in these mice. Single nuclei RNA sequencing identified changes in gene expression in parvalbumin-expressing neurons that are specific to inhibitory neuronal identity and function. Electrophysiology analysis revealed an enhanced inhibitory tone in the hippocampal pyramidal neurons in knockout mice. These findings indicate that CTCF in parvalbumin-expressing neurons has a significant role in the overall phenotype of CTCF-associated neurodevelopmental deficits.

Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.

SummaryDuctal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/− diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.

Comprehensive characterization of oscillatory signatures in a model circuit with PV- and SOM-expressing interneurons

Neural circuits contain a wide variety of interneuron types, which differ in their biophysical properties and connectivity patterns. The two most common interneuron types, parvalbumin-expressing and somatostatin-expressing cells, have been shown to be differentially involved in many cognitive functions. These cell types also show different relationships with the power and phase of oscillations in local field potentials. The mechanisms that underlie the emergence of different oscillatory rhythms in neural circuits with more than one interneuron subtype, and the roles specific interneurons play in those mechanisms, are not fully understood. Here, we present a comprehensive analysis of all possible circuit motifs and input regimes that can be achieved in circuits comprised of excitatory cells, PV-like fast-spiking interneurons and SOM-like low-threshold spiking interneurons. We identify 18 unique motifs and simulate their dynamics over a range of input strengths. Using several characteristics, such as oscillation frequency, firing rates, phase of firing and burst fraction, we cluster the resulting circuit dynamics across motifs in order to identify patterns of activity and compare these patterns to behaviors that were generated in circuits with one interneuron type. In addition to the well-known PING and ING gamma oscillations and an asynchronous state, our analysis identified three oscillatory behaviors that were generated by the three-cell-type motifs only: theta-nested gamma oscillations, stable beta oscillations and theta-locked bursting behavior, which have also been observed in experiments. Our characterization provides a map to interpret experimental activity patterns and suggests pharmacological manipulations or optogenetics approaches to validate these conclusions.

Somatostatin and Astroglial Involvement in the Human Limbic System in Alzheimer's Disease.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-β peptide (Aβ) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer’s disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aβ and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aβ peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer’s disease pathogenesis.

Central amygdala circuitry modulates nociceptive processing through differential hierarchical interaction with affective network dynamics

The central amygdala (CE) emerges as a critical node for affective processing. However, how CE local circuitry interacts with brain wide affective states is yet uncharted. Using basic nociception as proxy, we find that gene expression suggests diverging roles of the two major CE neuronal populations, protein kinase C δ-expressing (PKCδ+) and somatostatin-expressing (SST+) cells. Optogenetic (o)fMRI demonstrates that PKCδ+/SST+ circuits engage specific separable functional subnetworks to modulate global brain dynamics by a differential bottom-up vs. top-down hierarchical mesoscale mechanism. This diverging modulation impacts on nocifensive behavior and may underly CE control of affective processing.

Flexible Frequency Switching in Adult Mouse Visual Cortex Is Mediated by Competition Between Parvalbumin and Somatostatin Expressing Interneurons.

Neuronal networks in rodent primary visual cortex (V1) can generate oscillations in different frequency bands depending on the network state and the level of visual stimulation. High-frequency gamma rhythms, for example, dominate the network's spontaneous activity in adult mice but are attenuated upon visual stimulation, during which the network switches to the beta band instead. The spontaneous local field potential (LFP) of juvenile mouse V1, however, mainly contains beta rhythms and presenting a stimulus does not elicit drastic changes in network oscillations. We study, in a spiking neuron network model, the mechanism in adult mice allowing for flexible switches between multiple frequency bands and contrast this to the network structure in juvenile mice that lack this flexibility. The model comprises excitatory pyramidal cells (PCs) and two types of interneurons: the parvalbumin-expressing (PV) and the somatostatinexpressing (SOM) interneuron. In accordance with experimental findings, the pyramidal-PV and pyramidal-SOM cell subnetworks are associated with gamma and beta oscillations, respectively. In our model, they are both generated via a pyramidal-interneuron gamma (PING) mechanism, wherein the PCs drive the oscillations. Furthermore, we demonstrate that large but not small visual stimulation activates SOM cells, which shift the frequency of resting-state gamma oscillations produced by the pyramidal-PV cell subnetwork so that beta rhythms emerge. Finally, we show that this behavior is obtained for only a subset of PV and SOM interneuron projection strengths, indicating that their influence on the PCs should be balanced so that they can compete for oscillatory control of the PCs. In sum, we propose a mechanism by which visual beta rhythms can emerge from spontaneous gamma oscillations in a network model of the mouse V1; for this mechanism to reproduce V1 dynamics in adult mice, balance between the effective strengths of PV and SOM cells is required.

A circuit of mossy cells controls the efficacy of memory retrieval by Gria2I inhibition of Gria2

Mossy cells (MCs) are a unique group of excitatory neurons in the hippocampus, a brain region important for emotion, learning, and memory. Due to the lack of a reliable method to isolate MCs from other cell types, how MCs integrate neural information and convey it to their synaptic targets for engaging a specific function are still unknown. Here, we report that MCs control the efficacy of spatial memory retrieval by synapsing directly onto local somatostatin-expressing (SST) cells. MC-SST synaptic transmission undergoes long-term potentiation (LTP), requiring Gria2-lacking Ca2+-permeable anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (Ca2+AR). A long noncoding RNA (Gria2I) is associated with Gria2 transcriptional repressors in SST cells. Silencing Gria2I induces Gria2 transcription, blocks LTP of MCs-SST synaptic transmission, and reduces the efficacy of memory retrieval. Thus, MCs directly and functionally innervate local SST neurons, and this innervation controls the efficacy of spatial memory retrieval by Gria2I inhibition of Gria2 transcription.

Dentate Gyrus Somatostatin Cells are Required for Contextual Discrimination During Episodic Memory Encoding.

Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

Head Movements Control the Activity of Primary Visual Cortex in a Luminance-Dependent Manner

The vestibular system broadcasts head-movement-related signals to sensory areas throughout the brain, including visual cortex. These signals are crucial for the brain's ability to assess whether motion of the visual scene results from the animal's head movements. However, how head movements affect visual cortical circuits remains poorly understood. Here, we discover that ambient luminance profoundly transforms how mouse primary visual cortex (V1) processes head movements. While in darkness, head movements result in overall suppression of neuronal activity; in ambient light, the same head movements trigger excitation across all cortical layers. This light-dependent switch in how V1 processes head movements is controlled by somatostatin-expressing (SOM) inhibitory neurons, which are excited by head movements in dark, but not in light. This study thus reveals a light-dependent switch in the response of V1 to head movements and identifies a circuit in which SOM cells are key integrators of vestibular and luminance signals.

Characterizing the morphology of somatostatin-expressing interneurons and their synaptic innervation pattern in the barrel cortex of the GFP-expressing inhibitory neurons mouse.

Somatostatin-expressing (SST+) cells form the second largest subpopulation of neocortical GABAergic neurons that contain diverse subtypes, which participate in layer-specific cortical circuits. Martinotti cells, as the most abundant subtype of SST+ interneurons, are mainly located in layers II/III and V/VI, and are characterized by dense axonal arborizations in layer I. GFP-expressing inhibitory neurons (GIN), representing a fraction of mainly upper layer SST+ interneurons in various cortical areas, were recently claimed to include both Martinotti cells and non-Martinotti cells. This makes it necessary to examine in detail the morphology and synaptic innervation pattern of the GIN cells, in order to better predict their functional implications. In our study, we characterized the neurochemical specificity, somatodendritic morphology, synaptic ultrastructure as well as synaptic innervation pattern of GIN cells in the barrel cortex in a layer-specific manner. We showed that GIN cells account for 44% of the SST+ interneurons in layer II/III and around 35% in layers IV and Va. There are 29% of GIN cells coexpressing calretinin with 54% in layer II/III, 8% in layer IV, and 13% in layer V. They have diverse somatodendritic configurations and form relatively small synapses across all examined layers. They almost exclusively innervate dendrites of excitatory cells, preferentially targeting distal apical dendrites and apical dendritic tufts of pyramidal neurons in layer I, and rarely target other inhibitory neurons. In summary, our study reveals unique features in terms of the morphology and output of GIN cells, which can help to better understand their diversity and structure-function relationships.

Somatostatin-Expressing Interneurons Form Axonal Projections to the Contralateral Hippocampus.

Conscious memories are critically dependent upon bilateral hippocampal formation, and interhemispheric commissural projections made by mossy cells and CA3 pyramidal cells. GABAergic interneurons also make long-range axonal projections, but little is known regarding their commissural, inter-hippocampal connections. We used retrograde and adeno-associated viral tracing, immunofluorescence and electron microscopy, and in vitro optogenetics to assess contralateral projections of neurochemically defined interneuron classes. We found that contralateral-projecting interneurons were 24-fold less common compared to hilar mossy cells, and mostly consisted of somatostatin- and parvalbumin-expressing types. Somatostatin-expressing cells made denser contralateral axonal projections than parvalbumin-expressing cells, although this was typically 10-fold less than the ipsilateral projection density. Somatostatin-expressing cells displayed a topographic-like innervation according to the location of their somata, whereas parvalbumin-expressing cells mostly innervated CA1. In the dentate gyrus molecular layer, commissural interneuron post-synaptic targets were predominantly putative granule cell apical dendrites. In the hilus, varicosities in close vicinity to various interneuron subtypes, as well as mossy cells, were observed, but most contralateral axon varicosities had no adjacent immunolabeled structure. Due to the relative sparsity of the connection and the likely distal dendritic location of their synapses, commissural projections made by interneurons were found to be weak. We postulate that these projections may become functionally active upon intense network activity during tasks requiring increased memory processing.

Ectopic expression of Pax4 in pancreatic δ cells results in β-like cell neogenesis.

The recent demonstration that pancreatic α cells can be continuously regenerated and converted into β-like cells upon ectopic expression of Pax4 opened new avenues of research in the endocrine cell differentiation and diabetes fields. To determine whether such plasticity was also shared by δ cells, we generated and characterized transgenic animals that express Pax4 specifically in somatostatin-expressing cells. We demonstrate that the ectopic expression of Pax4 in δ cells is sufficient to induce their conversion into functional β-like cells. Importantly, this conversion induces compensatory mechanisms involving the reactivation of endocrine developmental processes that result in dramatic β-like cell hyperplasia. Importantly, these β-like cells are functional and can partly reverse the consequences of chemically induced diabetes.

Dedicated Hippocampal Inhibitory Networks for Locomotion and Immobility.

Network activity is strongly tied to animal movement; however, hippocampal circuits selectively engaged during locomotion or immobility remain poorly characterized. Here we examined whether distinct locomotor states are encoded differentially in genetically defined classes of hippocampal interneurons. To characterize the relationship between interneuron activity and movement, we used in vivo, two-photon calcium imaging in CA1 of male and female mice, as animals performed a virtual-reality (VR) track running task. We found that activity in most somatostatin-expressing and parvalbumin-expressing interneurons positively correlated with locomotion. Surprisingly, nearly one in five somatostatin or one in seven parvalbumin interneurons were inhibited during locomotion and activated during periods of immobility. Anatomically, the somata of somatostatin immobility-activated neurons were smaller than those of movement-activated neurons. Furthermore, immobility-activated interneurons were distributed across cell layers, with somatostatin-expressing cells predominantly in stratum oriens and parvalbumin-expressing cells mostly in stratum pyramidale. Importantly, each cell's correlation between activity and movement was stable both over time and across VR environments. Our findings suggest that hippocampal interneuronal microcircuits are preferentially active during either movement or immobility periods. These inhibitory networks may regulate information flow in "labeled lines" within the hippocampus to process information during distinct behavioral states.SIGNIFICANCE STATEMENT The hippocampus is required for learning and memory. Movement controls network activity in the hippocampus but it's unclear how hippocampal neurons encode movement state. We investigated neural circuits active during locomotion and immobility and found interneurons were selectively active during movement or stopped periods, but not both. Each cell's response to locomotion was consistent across time and environments, suggesting there are separate dedicated circuits for processing information during locomotion and immobility. Understanding how the hippocampus switches between different network configurations may lead to therapeutic approaches to hippocampal-dependent dysfunctions, such as Alzheimer's disease or cognitive decline.

Activation of cortical somatostatin interneurons prevents the development of neuropathic pain.

Neuropathic pain involves long-lasting modifications of pain pathways that result in abnormal cortical activity. How cortical circuits are altered and contribute to the intense sensation associated with allodynia is unclear. Here we report a persistent elevation of layer V pyramidal neuron activity in the somatosensory cortex of a mouse model of neuropathic pain. This enhanced pyramidal neuron activity was caused in part by increases of synaptic activity and NMDA-receptor-dependent calcium spikes in apical tuft dendrites. Furthermore, local inhibitory interneuron networks shifted their activity in favor of pyramidal neuron hyperactivity: somatostatin-expressing and parvalbumin-expressing inhibitory neurons reduced their activity, whereas vasoactive intestinal polypeptide–expressing interneurons increased their activity. Pharmacogenetic activation of somatostatin-expressing cells reduced pyramidal neuron hyperactivity and reversed mechanical allodynia. These findings reveal cortical circuit changes that arise during the development of neuropathic pain and identify the activation of specific cortical interneurons as therapeutic targets for chronic pain treatment.