Subset Of Neurons Research Articles

Dynamic Organization of Neuronal Extracellular Matrix Revealed by HaloTag-HAPLN1.

The brain's extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows a net-like structure around a subset of neurons, a ring-like structure at the nodes of Ranvier, and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to hyaluronan proteoglycan link protein 1, which links hyaluronan and proteoglycans. Expression or application of the probe in primary rat neuronal cultures enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in mouse brains of either sex reveals detailed ECM architectures around excitatory neurons and developmentally regulated dendritic ECM. Our study uncovers extensive structural features of the brain's ECM, suggesting diverse roles in regulating neuronal plasticity.

Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells

Gene therapy is emerging as an alternative option for individuals with drug-resistant focal epilepsy. Here, we explore the potential of a novel gene therapy based on Neuropeptide Y (NPY), a well-known endogenous anticonvulsant. We develop a lentiviral vector co-expressing NPY with its inhibitory receptor Y2 in which, for the first time, both transgenes are placed under the control of the minimal CamKIIa(0.4) promoter, biasing expression toward excitatory neurons and allowing autoregulation of neuronal excitability by Y2 receptor-mediated inhibition. Vector-induced NPY and Y2 expression and safety are first assessed in cultures of hippocampal neurons. In vivo experiments demonstrate efficient and nearly selective overexpression of both genes in granule cell mossy fiber terminals following vector administration in the dentate gyrus. Telemetry video-EEG monitoring reveals a reduction in the frequency and duration of seizures in the synapsin triple KO model. This study shows that targeting a small subset of neurons (hippocampal granule cells) with a combined overexpression of NPY and Y2 receptor is sufficient to reduce the occurrence of spontaneous seizures.

Abstract P352: Transcriptomic Effects of Prolonged Diet-Induced Obesity in Subtypes of Agouti-Related Peptide Neurons of the Hypothalamic Arcuate Nucleus

Obesity is the greatest impediment to improving cardiovascular health. Despite many methods to lose weight, few people can keep it off in the long-term. The adaptation (suppression) of resting metabolic rate (RMR) appears to mediate weight re-gain after weight loss, yet the neurobiology that controls RMR remains unclear. Previously we published that the angiotensin II type 1 receptor (AT 1 R/ Agtr1a ) within Agouti-related peptide (AgRP/ Agrp ) neurons of the arcuate nucleus of the hypothalamus (ARC) is critical for integrative control of RMR. In the ARC, AT 1 R is only expressed by a subset of AgRP neurons (“Type 1”). In lean animals, AT 1 R inhibits this cell via a β-arrestin-1/Gαi-coupled cascade ("Type 1i”). Prolonged diet-induced obesity (DIO) causes RMR adaptation and is associated with a spontaneous G protein cascade switch by AT 1 R in the Type 1 neuron, in which AT 1 R activation begins stimulating the cell via the Gαq-coupled cascade (“Type 1s”). Our ongoing work aims to clarify the molecular mechanisms that govern AT 1 R coupling to Gαi versus Gαq within Type 1 AgRP neurons. First, using a dual-reporter mouse with tdTomato in AT 1 R-expressing cells plus green fluorescent protein in somatostatin (SST/ Sst )-expressing cells, we confirmed that SST expression is a selective marker of the Type 1 subtype of ARC AgRP neurons. Second, we reanalyzed our previously published single-nucleus RNA sequencing dataset describing the mouse ARC following prolonged DIO (PMC7347451) to explore the effects of DIO upon the transcriptomic profiles of AgRP neuron subtypes. Of 26 cell types initially identified, one cluster strongly expressed both Sst and Agrp (Cluster 5). Sub-clustering of Cluster 5 identified four cell types with strong Agrp expression (subclusters 0, 2, 5, and 6). Subcluster 6 may represent the Type 1i subtype due to high Sst expression, as well as enrichment for signatures of Gαi signaling events . Subcluster 6 also had very few DIO-induced differentially expressed genes (up=3, down=2). Interestingly, Subcluster 2 was comprised almost exclusively of nuclei from the DIO group (95%). Subcluster 2 was more closely related to Subcluster 6 than the other Agrp subclusters in the cluster phylogenetic tree, leading us to hypothesize that this cluster represents the DIO-induced Type 1s subtype. These data identify novel markers of AgRP neuron subtypes within the ARC, and a possible transcriptomic signature of subtype switching induced by prolonged DIO.

NS-Pten knockout mice exhibit sex and hippocampal subregion-specific increases in microglia/macrophage density

Seizures induce hippocampal subregion dependent enhancements in microglia/macrophage phagocytosis and cytokine release that may contribute to the development of epilepsy. As a model of hyperactive mTOR induced epilepsy, neuronal subset specific phosphatase and tensin homolog (NS-Pten) knockout (KO) mice exhibit hyperactive mTOR signaling in the hippocampus, seizures that progress with age, and enhanced hippocampal microglia/macrophage activation. However, it is unknown where microglia/macrophages are most active within the hippocampus of NS-Pten KO mice. We quantified the density of IBA1 positive microglia/macrophages in the CA1, CA2/3, and dentate gyrus of NS-Pten KO and wildtype (WT) male and female mice at 4, 10, and 15 weeks of age. NS-Pten KO mice exhibited an overall increase in the number of IBA1 positive microglia/macrophages in each subregion and in the entire hippocampus. After accounting for differences in size, the whole hippocampus of NS-Pten KO mice still exhibited an increased density of IBA1 positive microglia/macrophages. Subregion analyses showed that this increase was restricted to the dentate gyrus of both male and female NS-Pten KO mice and to the CA1 of male NS-Pten KO mice. These data suggest enhanced microglia/macrophage activity may occur in the NS-Pten KO mice in a hippocampal subregion and sex-dependent manner. Future work should seek to determine whether these region-specific increases in microgliosis play a role in the progression of epilepsy in this model.

Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain.

The development and maintenance of chronic pain involves the reorganization of spinal nociceptive circuits. The mechanistic target of rapamycin complex 2 (mTORC2), a central signaling hub that modulates both actin-dependent structural changes and mTORC1-dependent mRNA translation, plays key roles in hippocampal synaptic plasticity and memory formation. However, its function in spinal plasticity and chronic pain is poorly understood. Here we show that pharmacological activation of spinal mTORC2 induces pain hypersensitivity, whereas its inhibition, using downregulation of the mTORC2-defining component Rictor, alleviates both inflammatory and neuropathic pain. Cell-type-specific deletion of Rictor showed that the selective inhibition of mTORC2 in a subset of excitatory neurons impairs spinal synaptic potentiation and alleviates inflammation-induced mechanical and thermal hypersensitivity, and nerve injury-induced heat hyperalgesia. The ablation of mTORC2 in inhibitory interneurons strongly alleviated nerve injury-induced mechanical hypersensitivity. Our findings reveal the role of mTORC2 in chronic pain and highlight its cell-type-specific functions in mediating pain hypersensitivity in response to peripheral inflammation and nerve injury.

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism.

Developmental and Epileptic Encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Na v ) regulator, we observed no effect of Fgf13 ablation in interneurons on Na v s but rather a marked reduction in K + channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K + channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13- related seizures and expand our understanding of FGF13 functions in different neuron subsets.

Single neuron responses to perceptual difficulty in the mouse auditory cortex.

Perceptual learning leads to improvement in behavioral performance, yet how the brain supports challenging perceptual demands is unknown. We used two photon imaging in the mouse primary auditory cortex during behavior in a Go-NoGo task designed to test perceptual difficulty. Using general linear model analysis, we found a subset of neurons that increased their responses during high perceptual demands. Single neurons increased their responses to both Go and NoGo sounds when mice were engaged in the more difficult perceptual discrimination. This increased responsiveness contributes to enhanced cortical network discriminability for the learned sounds. Under passive listening conditions, the same neurons responded weaker to the more similar sound pairs of the difficult task, and the training protocol by itself induced specific suppression to the learned sounds. Our findings identify how neuronal activity in auditory cortex is modulated during high perceptual demands, which is a fundamental feature associated with perceptual improvement.

Intricate response dynamics enhances stimulus discrimination in the resource-limited C. elegans chemosensory system

BackgroundSensory systems evolved intricate designs to accurately encode perplexing environments. However, this encoding task may become particularly challenging for animals harboring a small number of sensory neurons. Here, we studied how the compact resource-limited chemosensory system of Caenorhabditis elegans uniquely encodes a range of chemical stimuli.ResultsWe find that each stimulus is encoded using a small and unique subset of neurons, where only a portion of the encoding neurons sense the stimulus directly, and the rest are recruited via inter-neuronal communication. Furthermore, while most neurons show stereotypical response dynamics, some neurons exhibit versatile dynamics that are either stimulus specific or network-activity dependent. Notably, it is the collective dynamics of all responding neurons which provides valuable information that ultimately enhances stimulus identification, particularly when required to discriminate between closely related stimuli.ConclusionsTogether, these findings demonstrate how a compact and resource-limited chemosensory system can efficiently encode and discriminate a diverse range of chemical stimuli.

Population coding of predator imminence in the hypothalamus.

Distinct subsets of VMHdm SF1 neurons encode multiple predator-evoked internal states. Anti-correlated subsets encode safety vs. threat in a bi-directional mannerA population code for predator imminence is identified using a novel assay VMHdm SF1 dynamics correlate with individual variation in predator defensiveness.

Convergent Comodulation Reduces Interindividual Variability of Circuit Output.

Ionic current levels of identified neurons vary substantially across individual animals. Yet, under similar conditions, neural circuit output can be remarkably similar, as evidenced in many motor systems. All neural circuits are influenced by multiple neuromodulators, which provide flexibility to their output. These neuromodulators often overlap in their actions by modulating the same channel type or synapse, yet have neuron-specific actions resulting from distinct receptor expression. Because of this different receptor expression pattern, in the presence of multiple convergent neuromodulators, a common downstream target would be activated more uniformly in circuit neurons across individuals. We therefore propose that a baseline tonic (non-saturating) level of comodulation by convergent neuromodulators can reduce interindividual variability of circuit output. We tested this hypothesis in the pyloric circuit of the crab, Cancer borealis Multiple excitatory neuropeptides converge to activate the same voltage-gated current in this circuit, but different subsets of pyloric neurons have receptors for each peptide. We quantified the interindividual variability of the unmodulated pyloric circuit output by measuring the activity phases, cycle frequency, and intraburst spike number and frequency. We then examined the variability in the presence of different combinations and concentrations of three neuropeptides. We found that at mid-level concentration (30 nM) but not at near-threshold (1 nM) or saturating (1 µM) concentrations, comodulation by multiple neuropeptides reduced the circuit output variability. Notably, the interindividual variability of response properties of an isolated neuron was not reduced by comodulation, suggesting that the reduction of output variability may emerge as a network effect.

Dysfunctional Parvalbumin Neurons in Schizophrenia and the Pathway to the Clinical Application of Kv3 Channel Modulators.

Based on the pathophysiological changes observed in schizophrenia, the gamma-aminobutyric acid (GABA) hypothesis may facilitate the development of targeted treatments for this disease. This hypothesis, mainly derived from postmortem brain results, postulates dysfunctions in a subset of GABAergic neurons, particularly parvalbumin-containing interneurons. In the cerebral cortex, the fast spike firing of parvalbumin-positive GABAergic interneurons is regulated by the Kv3.1 and Kv3.2 channels, which belong to a potassium channel subfamily. Decreased Kv3.1 levels have been observed in the prefrontal cortex of patients with schizophrenia, prompting the investigation of Kv3 channel modulators for the treatment of schizophrenia. However, biomarkers that capture the dysfunction of parvalbumin neurons are required for these modulators to be effective in the pharmacotherapy of schizophrenia. Electroencephalography and magnetoencephalography studies have demonstrated impairments in evoked gamma oscillations in patients with schizophrenia, which may reflect the dysfunction of cortical parvalbumin neurons. This review summarizes these topics and provides an overview of how the development of therapeutics that incorporate biomarkers could innovate the treatment of schizophrenia and potentially change the targets of pharmacotherapy.

Single-cell Profiling Uncovers Evolutionary Divergence of Hypocretin/Orexin Neuronal Subpopulations.

Brain nuclei are traditionally defined by their anatomy, activity, and expression of specific markers. The hypothalamus contains discrete neuronal populations that coordinate fundamental behavioral functions, including sleep and wakefulness, in all vertebrates. Particularly, the diverse roles of hypocretin/orexin (Hcrt)-releasing neurons suggest functional heterogeneity among Hcrt neurons. Using single-cell RNA sequencing (scRNA-seq) and high-resolution imaging of the adult male and female zebrafish hypothalamic periventricular zone (PVZ), we identified 21 glutamatergic and 28 GABAergic cell types. Integration of zebrafish and mouse scRNA-seq revealed evolutionary conserved and divergent hypothalamic cell types. The expression of specific genes, including npvf, which encodes a sleep-regulating neuropeptide, was enriched in subsets of glutamatergic Hcrt neurons in both larval and adult zebrafish. The genetic profile, activity, and neurite processing of the neuronal subpopulation that co-expresses both Hcrt and Npvf (Hcrt+Npvf+) differ from other Hcrt neurons. These inter-species findings provide a unified annotation of hypothalamic cell types, and suggest that the heterogeneity of Hcrt neurons enables multi-functionality, such as consolidation of both wake and sleep by the Hcrt- and Npvf-releasing neuronal subpopulation.Significance Statement The study reveals the intricate heterogeneity within the hypothalamic periventricular zone (PVZ) of zebrafish, identifying 21 glutamatergic and 28 GABAergic cell types through single-cell RNA sequencing (scRNA-seq) and high-resolution imaging. Comparative analysis with mouse scRNA-seq data revealed conserved and divergent cell types, transcriptional regulatory mechanisms, and neuropeptide localization. Notably, we identified a unique neuronal subpopulation co-expressing both hypocretin/orexin (Hcrt) and neuropeptide VF (Npvf) neuropeptides in zebrafish. The distinct genetic profiles, activity patterns, and neurite processing of this subpopulation suggest a role in regulating both sleep and wakefulness.

Identification of a stress-responsive subregion of the basolateral amygdala in male rats.

The basolateral amygdala (BLA) is reliably activated by psychological stress and hyperactive in conditions of pathological stress or trauma; however, subsets of BLA neurons are also readily activated by rewarding stimuli and can suppress fear and avoidance behaviours. The BLA is highly heterogeneous anatomically, exhibiting continuous molecular and connectivity gradients throughout the entire structure. A critical gap remains in understanding the anatomical specificity of amygdala subregions, circuits, and cell types explicitly activated by acute stress and how they are dynamically activated throughout stimulus exposure. Using a combination of topographical mapping for the activity-responsive protein FOS and fiber photometry to measure calcium transients in real-time, we sought to characterize the spatial and temporal patterns of BLA activation in response to a range of novel stressors (shock, swim, restraint, predator odour) and non-aversive, but novel stimuli (crackers, citral odour). We report four main findings: (1) the BLA exhibits clear spatial activation gradients in response to novel stimuli throughout the medial-lateral and dorsal-ventral axes, with aversive stimuli strongly biasing activation towards medial aspects of the BLA; (2) novel stimuli elicit distinct temporal activation patterns, with stressful stimuli exhibiting particularly enhanced or prolonged temporal activation patterns; (3) changes in BLA activity are associated with changes in behavioural state; and (4) norepinephrine enhances stress-induced activation of BLA neurons via the ß-noradrenergic receptor. Moving forward, it will be imperative to combine our understanding of activation gradients with molecular and circuit-specificity.

Neural Control of Naturalistic Behavior Choices.

In the natural world, animals make decisions on an ongoing basis, continuously selecting which action to undertake next. In the lab, however, the neural bases of decision processes have mostly been studied using artificial trial structures. New experimental tools based on the genetic toolkit of model organisms now make it experimentally feasible to monitor and manipulate neural activity in small subsets of neurons during naturalistic behaviors. We thus propose a new approach to investigating decision processes, termed reverse neuroethology. In this approach, experimenters select animal models based on experimental accessibility and then utilize cutting-edge tools such as connectomes and genetically encoded reagents to analyze the flow of information through an animal's nervous system during naturalistic choice behaviors. We describe how the reverse neuroethology strategy has been applied to understand the neural underpinnings of innate, rapid decision making, with a focus on defensive behavioral choices in the vinegar fly Drosophila melanogaster.

Distinct basal forebrain-originated neural circuits promote homoeostatic feeding and suppress hedonic feeding in male mice.

Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.

Arcuate dopaminergic/GABAergic neurons project within the hypothalamus and to the median eminence.

Cotransmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-aminobutyric acid (GABA) are known to coexpress in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also cotransmit GABA. However, the extent of cotransmission, and the projection patterns of these neurons have not been fully revealed. Here, we used a genetic intersectional reporter expression approach to selectively label cells that express both tyrosine hydroxylase (TH) and vesicular GABA transporter (VGAT). Through this approach, we identified cells capable of both DA and GABA cotransmission in the Arc, periventricular (Pe), paraventricular (Pa), ventromedial, and the dorsolateral hypothalamic nuclei, in addition to a novel population in the caudate putamen. The highest density of labeled cells was in the Arc, 6.68% of DAPI-labeled cells at Bregma -2.06 mm, and in the Pe, 2.83% of DAPI-labeled cells at Bregma -1.94 mm. Next, we evaluated the projections of these DA/GABA cells by injecting an mCherry virus that fluoresces in DA/GABA cells. We observed a cotransmitting DA/GABA population, with projections within the Arc, and to the Pa and ME. These data suggest DA/GABA Arc neurons are involved in prolactin release as a subset of TIDA neurons. Further investigation will elucidate the interactions of dopamine and GABA in the hypothalamus.NEW & NOTEWORTHY Cotransmitting dopaminergic (DA) and γ-aminobutyric acid (GABA)ergic (DA/GABA) neurons contribute to the complexity of neural circuits. Using a new genetic technique, we characterized the locations, density, and projections of hypothalamic DA/GABA neurons. DA/GABA cells are mostly in the arcuate nucleus (Arc), from which they project locally within the arcuate, to the median eminence (ME), and to the paraventricular (Pa) nucleus. There is also a small and previously unreported group of DA/GABA cells in the caudate putamen.

Parvalbumin expression does not account for discrete electrophysiological profiles of glutamatergic ventral pallidal subpopulations

The ventral pallidum (VP) has emerged as a critical node in the mesolimbic reward system. Modulating the VP can impact the subjective valuation of rewards, reward motivation, and reward seeking under conflict, making it an attractive target for clinical neuromodulation therapies that manage substance use disorders. To understand how to rationally modulate the VP, we need a better understanding of the electrophysiological properties of VP neurons and the molecular and biophysical determinants of these properties. Here, we used patch-clamp electrophysiology to characterize the intrinsic properties of glutamatergic VP (VPGlu) neurons and observed two distinct electrophysiological profiles: VPGlu neurons that undergo depolarization block in response to progressively increasing current injection amplitudes and those that were resistant to depolarization block. To explore the mechanisms that could contribute to these distinct profiles, we used targeted ribosome affinity purification to identify ion channel subunits and regulatory proteins by isolating actively transcribed mRNA selectively from VPGlu neurons. We then used this transcriptomic information to implement a Markov Chain Monte Carlo method to parameterize a large population of biophysically distinct multicompartment models of VPGlu neurons conforming to either subpopulation. Based on prior literature suggesting parvalbumin (PV) is expressed in a subset of VPGlu neurons, and that PV expression governs the firing properties of those neurons, we tested the hypothesis that PV expression accounted for differences in subgroups, by increasing the maximal firing frequency and conferring resistance to depolarization block. In contrast, our model determined that PV expression at physiological levels had no effect on maximum firing rate. However, supraphysiological expression levels of PV appeared to induce a depolarization block in previously depolarization block-resistant neuron models, suggesting that other intracellular calcium-binding proteins could play a role in determining the firing phenotype of VPGlu neurons. We corroborated this result with single-cell patch-clamp RT-PCR, which confirmed that PV expression did not distinguish the two electrophysiologically distinct subpopulations. Together, these findings establish that VPGlu neurons are composed of biophysically distinct subpopulations that have not been appreciated in prior studies interrogating the function of this population. With the advent of novel tools for cell-type specific pharmacology and targeted neurostimulation, this understanding will be critical for developing strategies to rationally modulate VPGlu cells to treat disorders characterized by maladaptive reward seeking.

A chemogenetic screen reveals that Trpv1-expressing neurons control regulatory T cells in the gut.

Neuroimmune cross-talk participates in intestinal tissue homeostasis and host defense. However, the matrix of interactions between arrays of molecularly defined neuron subsets and of immunocyte lineages remains unclear. We used a chemogenetic approach to activate eight distinct neuronal subsets, assessing effects by deep immunophenotyping, microbiome profiling, and immunocyte transcriptomics in intestinal organs. Distinct immune perturbations followed neuronal activation: Nitrergic neurons regulated T helper 17 (TH17)-like cells, and cholinergic neurons regulated neutrophils. Nociceptor neurons, expressing Trpv1, elicited the broadest immunomodulation, inducing changes in innate lymphocytes, macrophages, and RORγ+ regulatory T (Treg) cells. Neuroanatomical, genetic, and pharmacological follow-up showed that Trpv1+ neurons in dorsal root ganglia decreased Treg cell numbers via the neuropeptide calcitonin gene-related peptide (CGRP). Given the role of these neurons in nociception, these data potentially link pain signaling with gut Treg cell function.

A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis

Orchestrating complex behaviors, such as approaching and consuming food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also controls appetite and satiety. However, specific neuronal subtypes of the NAc that are involved and how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood. Here we decipher the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and define a dopamine receptor D1-expressing and Serpinb2-expressing subtype controlling food consumption in male mice. Chemogenetics and optogenetics-mediated regulation of Serpinb2+ neurons bidirectionally regulate food seeking and consumption specifically. Circuitry stimulation reveals that the NAcShSerpinb2→LHLepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2+ neuron ablation reduces food intake and upregulates energy expenditure, resulting in reduced bodyweight gain. Our study reveals a neural circuit consisting of a molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, providing a potential therapeutic target for eating disorders.

Patterns of neural activity in prelimbic cortex neurons correlate with attentional behavior in the rodent continuous performance test.

Sustained attention, the ability to focus on a stimulus or task over extended periods, is crucial for higher level cognition, and is impaired in individuals diagnosed with neuropsychiatric and neurodevelopmental disorders, including attention-deficit/hyperactivity disorder, schizophrenia, and depression. Translational tasks like the rodent continuous performance test (rCPT) can be used to study the cellular mechanisms underlying sustained attention. Accumulating evidence points to a role for the prelimbic cortex (PrL) in sustained attention, as electrophysiological single unit and local field (LFPs) recordings reflect changes in neural activity in the PrL in mice performing sustained attention tasks. While the evidence correlating PrL electrical activity with sustained attention is compelling, limitations inherent to electrophysiological recording techniques, including low sampling in single unit recordings and source ambivalence for LFPs, impede the ability to fully resolve the cellular mechanisms in the PrL that contribute to sustained attention. In vivo endoscopic calcium imaging using genetically encoded calcium sensors in behaving animals can address these questions by simultaneously recording up to hundreds of neurons at single cell resolution. Here, we used in vivo endoscopic calcium imaging to record patterns of neuronal activity in PrL neurons using the genetically encoded calcium sensor GCaMP6f in mice performing the rCPT at three timepoints requiring differing levels of cognitive demand and task proficiency. A higher proportion of PrL neurons were recruited during correct responses in sessions requiring high cognitive demand and task proficiency, and mice intercalated non-responsive-disengaged periods with responsive-engaged periods that resemble attention lapses. During disengaged periods, the correlation of calcium activity between PrL neurons was higher compared to engaged periods, suggesting a neuronal network state change during attention lapses in the PrL. Overall, these findings illustrate that cognitive demand, task proficiency, and task engagement differentially recruit activity in a subset of PrL neurons during sustained attention.