Developmental Cajal-Retzius cell death contributes to the maturation of layer 1 cortical inhibition and somatosensory processing.

The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally.

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here, we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels.

PV and SST neurons in the anterior cingulate cortex regulate social disorders in adulthood induced by sensory abnormalities in childhood.

OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.

Long-range inhibition from prelimbic to cingulate areas of the medial prefrontal cortex enhances network activity and response execution.

It is well established that the medial prefrontal cortex (mPFC) exerts top-down control of many behaviors, but little is known regarding how cross-talk between distinct areas of the mPFC influences top-down signaling. We performed virus-mediated tracing and functional studies in male mice, homing in on GABAergic projections whose axons are located mainly in layer 1 and that connect two areas of the mPFC, namely the prelimbic area (PrL) with the cingulate area 1 and 2 (Cg1/2). We revealed the identity of the targeted neurons that comprise two distinct types of layer 1 GABAergic interneurons, namely single-bouquet cells (SBCs) and neurogliaform cells (NGFs), and propose that this connectivity links GABAergic projection neurons with cortical canonical circuits. In vitro electrophysiological and in vivo calcium imaging studies support the notion that the GABAergic projection neurons from the PrL to the Cg1/2 exert a crucial role in regulating the activity in the target area by disinhibiting layer 5 output neurons. Finally, we demonstrated that recruitment of these projections affects impulsivity and mechanical responsiveness, behaviors which are known to be modulated by Cg1/2 activity.

Age-related decline in GABAergic intracortical inhibition can be counteracted by long-term learning of balance skills.

Ageing induces a decline in GABAergic intracortical inhibition, which seems to be associated not only with decremental changes in well-being, sleep quality, cognition and pain management but also with impaired motor control. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. Therefore, the present study investigated whether age-related cortical dis-inhibition could be reversed after 6 months of balance learning and whether improvements in postural control correlated with the extent of reversed dis-inhibition. The results demonstrated that intracortical inhibition can be upregulated in elderly subjects after long-term balance learning and revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition and may therefore be seminal for many pathologies in which the equilibrium between inhibitory and excitatory neurotransmitters is disturbed. KEY POINTS: Ageing induces a decline in GABAergic intracortical inhibition. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. After 6 months of balance learning, intracortical inhibition can be upregulated in elderly subjects. The results of this study also revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition.

Cholinergic modulation of interhemispheric inhibition in the mouse motor cortex.

Interhemispheric inhibition of the homotopic motor cortex is believed to be effective for accurate unilateral motor function. However, the cellular mechanisms underlying interhemispheric inhibition during unilateral motor behavior remain unclear. Furthermore, the impact of the neuromodulator acetylcholine on interhemispheric inhibition and the associated cellular mechanisms are not well understood. To address this knowledge gap, we conducted recordings of neuronal activity from the bilateral motor cortex of mice during the paw-reaching task. Subsequently, we analyzed interhemispheric spike correlation at the cell-pair level, classifying putative cell types to explore the underlying cellular circuitry mechanisms of interhemispheric inhibition. We found a cell-type pair-specific enhancement of the interhemispheric spike correlation when the mice were engaged in the reaching task. We also found that the interhemispheric spike correlation was modulated by pharmacological acetylcholine manipulation. The local field responses to contralateral excitation differed along the cortical depths, and muscarinic receptor antagonism enhanced the inhibitory component of the field response in deep layers. The muscarinic subtype M2 receptor is predominantly expressed in deep cortical neurons, including GABAergic interneurons. These results suggest that GABAergic interneurons expressing muscarinic receptors in deep layers mediate the neuromodulation of interhemispheric inhibition in the homotopic motor cortex.

Low-frequency RTMS attenuates social impairment in the VPA-induced mouse model.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions and repetitive behaviors. Despite its prevalence, effective treatments remain elusive. Recent studies have highlighted the importance of the balance between GABAergic and glutamatergic neuronal synaptic functions in ASD development. Repetitive transcranial magnetic stimulation (RTMS) is a painless and effective treatment allowed for use in depression and obsessive-compulsive disorder. However, its efficacy in treating autism is still under investigation. Low-frequency RTMS (LF-RTMS), which shows promise in reducing autism-like behaviors, is considered to regulate synaptic function. OBJECTIVE: We observed and recorded the behaviors of mice to assess the impact of RTMS on their social interactions and repetitive activities. Subsequently, we examined GABAergic and glutamatergic neuronal markers along with synaptic marker proteins to understand the underlying changes associated with these behaviors. METHODS: To evaluate behaviors associated with autism spectrum disorder (ASD), several behavioral tests were conducted, focusing on sociability, repetitive behaviors, locomotion, anxiety, and depression. Additionally, Western blot and immunofluorescence staining were employed to investigate the activity of GABAergic and glutamatergic neurons in the hippocampus, aiming to understand the synaptic mechanisms underlying these behaviors. RESULTS: LF-RTMS treatment effectively relieved the social disability and normalized synaptic function in the hippocampus of ASD mice model induced by valproate (VPA). Importantly, this treatment did not lead to any adverse effects on repetitive behavior, locomotion, anxiety, or depression. CONCLUSION: LF-RTMS attenuated social disability without affecting repetitive behavior, locomotion, anxiety, or depression. Changes in the expression of GABAergic and glutamatergic neuronal synaptic proteins in the hippocampus were also observed.

Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus.

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP mouse, in which humanized renilla green fluorescent protein (hrGFP) expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on several factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY on the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.NEW & NOTEWORTHY Across brain regions, neuropeptide Y (NPY) expression is dynamic and influenced by extrinsic and intrinsic factors. We previously showed that NPY is expressed by a class of inhibitory neurons in the auditory midbrain. Here, we find that this neuron class also includes neurons that previously expressed NPY, suggesting that NPY expression is dynamically regulated in the auditory midbrain. We also provide functional evidence that NPY neurons contribute to local inhibitory circuits in the auditory midbrain.

Specific and comprehensive genetic targeting reveals brain-wide distribution and synaptic input patterns of GABAergic axo-axonic interneurons.

Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remain poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta, and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal, and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.

Whether we are memorising facts or reacting to a loud noise, nerve cells in different brain areas must be able to communicate with one another through precise, meaningful signals. Specialized nerve cells known as interneurons act as "traffic lights" to precisely regulate when and where this information flows in neural circuits. Axo-axonic cells are a rare type of inhibitory interneuron that are thought to be particularly important for controlling the passage of information between different groups of excitatory neurons. This is because they only connect to one key part of their target cell ­ the axon-initial segment ­ where the electrical signals needed for brain communication (known as action potentials) are initiated. Since axo-axonic cells are inhibitory interneurons, this connection effectively allows them to 'veto' the generation of these signals at their source. Although axo-axonic cells have been identified in three brain regions using traditional anatomical methods, there were no 'tags' readily available that can reliably identify them. Therefore, much about these cells remained unknown, including how widespread they are in the mammalian brain. To solve this problem, Raudales et al. investigated which genes are switched on in axo-axonic cells but not in other cells, identifying a unique molecular signature that could be used to mark, record, and manipulate these cells. Microscopy imaging of brain tissue from mice in which axo-axonic cells had been identified revealed that they are present in many more brain areas than previously thought, including nearly all regions of the broadly defined cerebral cortex and even the hypothalamus, which controls many innate behaviors. Axo-axonic cells were also 'wired up' differently, depending on where they were located; for example, those in brain areas associated with memory and emotions had wider-ranging input connections than other areas. The finding of Raudales et al. provide, for the first time, a method to directly track and manipulate axo-axonic cells in the brain. Since dysfunction in axo-axonic cells is also associated with neurological disorders like epilepsy and schizophrenia, gaining an insight into their distribution and connectivity could help to develop better treatments for these conditions.

Thalamic cells and pathway for social memory processing and storage.

In this issue of Neuron, Wang et al.1 demonstrate that parvalbumin interneurons in the sensory thalamic reticular nucleus are necessary and sufficient for regulating social memory in mice, identify a novel cortico-reticular thalamic-parafascicular pathway for social cognition, and highlight an essential role of GABAergic inhibitory neurons in social memory engrams.

Tonically active GABAergic neurons in the dorsal periaqueductal gray control instinctive escape in mice.

Escape behavior is a set of locomotor actions that move an animal away from threat. While these actions can be stereotyped, it is advantageous for survival that they are flexible.1,2,3 For example, escape probability depends on predation risk and competing motivations,4,5,6,7,8,9,10,11 and flight to safety requires continuous adjustments of trajectory and must terminate at the appropriate place and time.12,13,14,15,16 This degree of flexibility suggests that modulatory components, like inhibitory networks, act on the neural circuits controlling instinctive escape.17,18,19,20,21,22 In mice, the decision to escape from imminent threats is implemented by a feedforward circuit in the midbrain, where excitatory vesicular glutamate transporter 2-positive (VGluT2+) neurons in the dorsal periaqueductal gray (dPAG) compute escape initiation and escape vigor.23,24,25 Here we tested the hypothesis that local GABAergic neurons within the dPAG control escape behavior by setting the excitability of the dPAG escape network. Using in vitro patch-clamp and in vivo neural activity recordings, we found that vesicular GABA transporter-positive (VGAT+) dPAG neurons fire action potentials tonically in the absence of synaptic inputs and are a major source of inhibition to VGluT2+ dPAG neurons. Activity in VGAT+ dPAG cells transiently decreases at escape onset and increases during escape, peaking at escape termination. Optogenetically increasing or decreasing VGAT+ dPAG activity changes the probability of escape when the stimulation is delivered at threat onset and the duration of escape when delivered after escape initiation. We conclude that the activity of tonically firing VGAT+ dPAG neurons sets a threshold for escape initiation and controls the execution of the flight action.

Convergence of inputs from the basal ganglia with layer 5 of motor cortex and cerebellum in mouse motor thalamus.

A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1L5), while another arises from the deep cerebellar nuclei (Cb). M1L5 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi), and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1L5 in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1L5 through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1L5. Separately, we also demonstrate that, perhaps unexpectedly, GABAergic GPi and SNr inputs converge with those from the Cb. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1L5 and Cb information to cortex.

GABAergic neurons of anterior thalamic reticular nucleus regulate states of consciousness in propofol- and isoflurane-mediated general anesthesia.

BACKGROUND: The thalamus system plays critical roles in the regulation of reversible unconsciousness induced by general anesthetics, especially the arousal stage of general anesthesia (GA). But the function of thalamus in GA-induced loss of consciousness (LOC) is little known. The thalamic reticular nucleus (TRN) is the only GABAergic neurons-composed nucleus in the thalamus, which is composed of parvalbumin (PV) and somatostatin (SST)-expressing GABAergic neurons. The anterior sector of TRN (aTRN) is indicated to participate in the induction of anesthesia, but the roles remain unclear. This study aimed to reveal the role of the aTRN in propofol and isoflurane anesthesia. METHODS: We first set up c-Fos straining to monitor the activity variation of aTRNPV and aTRNSST neurons during propofol and isoflurane anesthesia. Subsequently, optogenetic tools were utilized to activate aTRNPV and aTRNSST neurons to elucidate the roles of aTRNPV and aTRNSST neurons in propofol and isoflurane anesthesia. Electroencephalogram (EEG) recordings and behavioral tests were recorded and analyzed. Lastly, chemogenetic activation of the aTRNPV neurons was applied to confirm the function of the aTRN neurons in propofol and isoflurane anesthesia. RESULTS: c-Fos straining showed that both aTRNPV and aTRNSST neurons are activated during the LOC period of propofol and isoflurane anesthesia. Optogenetic activation of aTRNPV and aTRNSST neurons promoted isoflurane induction and delayed the recovery of consciousness (ROC) after propofol and isoflurane anesthesia, meanwhile chemogenetic activation of the aTRNPV neurons displayed the similar effects. Moreover, optogenetic and chemogenetic activation of the aTRN neurons resulted in the accumulated burst suppression ratio (BSR) during propofol and isoflurane GA, although they represented different effects on the power distribution of EEG frequency. CONCLUSION: Our findings reveal that the aTRN GABAergic neurons play a critical role in promoting the induction of propofol- and isoflurane-mediated GA.

GABAergic synaptic scaling is triggered by changes in spiking activity rather than AMPA receptor activation.

Homeostatic plasticity represents a set of mechanisms that are thought to recover some aspect of neural function. One such mechanism called AMPAergic scaling was thought to be a likely candidate to homeostatically control spiking activity. However, recent findings have forced us to reconsider this idea as several studies suggest AMPAergic scaling is not directly triggered by changes in spiking. Moreover, studies examining homeostatic perturbations in vivo have suggested that GABAergic synapses may be more critical in terms of spiking homeostasis. Here, we show results that GABAergic scaling can act to homeostatically control spiking levels. We found that perturbations which increased or decreased spiking in cortical cultures triggered multiplicative GABAergic upscaling and downscaling, respectively. In contrast, we found that changes in AMPA receptor (AMPAR) or GABAR transmission only influence GABAergic scaling through their indirect effect on spiking. We propose that GABAergic scaling represents a stronger candidate for spike rate homeostat than AMPAergic scaling.

Homeostatic regulation of rapid eye movement sleep by the preoptic area of the hypothalamus.

Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2→TMN neurons) are crucial for the homeostatic regulation of REMs in mice. POAGAD2→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs.

Parvalbumin-expressing basal forebrain neurons mediate learning from negative experience.

Parvalbumin (PV)-expressing GABAergic neurons of the basal forebrain (BFPVNs) were proposed to serve as a rapid and transient arousal system, yet their exact role in awake behaviors remains unclear. We performed bulk calcium measurements and electrophysiology with optogenetic tagging from the horizontal limb of the diagonal band of Broca (HDB) while male mice were performing an associative learning task. BFPVNs responded with a distinctive, phasic activation to punishment, but showed slower and delayed responses to reward and outcome-predicting stimuli. Optogenetic inhibition during punishment impaired the formation of cue-outcome associations, suggesting a causal role of BFPVNs in associative learning. BFPVNs received strong inputs from the hypothalamus, the septal complex and the median raphe region, while they synapsed on diverse cell types in key limbic structures, where they broadcasted information about aversive stimuli. We propose that the arousing effect of BFPVNs is recruited by aversive stimuli to serve crucial associative learning functions.

Regulation of the Mouse Ventral Tegmental Area by Melanin-Concentrating Hormone.

Melanin-concentrating hormone (MCH) acts via its sole receptor MCHR1 in rodents and is an important regulator of homeostatic behaviors like feeding, sleep, and mood to impact overall energy balance. The loss of MCH signaling by MCH or MCHR1 deletion produces hyperactive mice with increased energy expenditure, and these effects are consistently associated with a hyperdopaminergic state. We recently showed that MCH suppresses dopamine release in the nucleus accumbens, which principally receives dopaminergic projections from the ventral tegmental area (VTA), but the mechanisms underlying MCH-regulated dopamine release are not clearly defined. MCHR1 expression is widespread and includes dopaminergic VTA cells. However, as the VTA is a neurochemically diverse structure, we assessed Mchr1 gene expression at glutamatergic, GABAergic, and dopaminergic VTA cells and determined if MCH inhibited the activity of VTA cells and/or their local microcircuit. Mchr1 expression was robust in major VTA cell types, including most dopaminergic (78%) or glutamatergic cells (52%) and some GABAergic cells (38%). Interestingly, MCH directly inhibited dopaminergic and GABAergic cells but did not regulate the activity of glutamatergic cells. Rather, MCH produced a delayed increase in excitatory input to dopamine cells and a corresponding decrease in GABAergic input to glutamatergic VTA cells. Our findings suggested that MCH may acutely suppress dopamine release while disinhibiting local glutamatergic signaling to restore dopamine levels. This indicated that the VTA is a target of MCH action, which may provide bidirectional regulation of energy balance.

Cortico-cortical transfer of socially derived information gates emotion recognition.

Emotion recognition and the resulting responses are important for survival and social functioning. However, how socially derived information is processed for reliable emotion recognition is incompletely understood. Here, we reveal an evolutionarily conserved long-range inhibitory/excitatory brain network mediating these socio-cognitive processes. Anatomical tracing in mice revealed the existence of a subpopulation of somatostatin (SOM) GABAergic neurons projecting from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC). Through optogenetic manipulations and Ca2+ imaging fiber photometry in mice and functional imaging in humans, we demonstrate the specific participation of these long-range SOM projections from the mPFC to the RSC, and an excitatory feedback loop from the RSC to the mPFC, in emotion recognition. Notably, we show that mPFC-to-RSC SOM projections are dysfunctional in mouse models relevant to psychiatric vulnerability and can be targeted to rescue emotion recognition deficits in these mice. Our findings demonstrate a cortico-cortical circuit underlying emotion recognition.

Nr4a1 regulates cell-specific transcriptional programs in inhibitory GABAergic interneurons.

The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of parvalbumin- and somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in the basal forebrain.

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.