Probes for SST

Daily and annual changes in light are processed by central clock circuits that control the timing of behavior and physiology. The suprachiasmatic nucleus (SCN) in the anterior hypothalamus processes daily photic inputs and encodes changes in day length (i.e., photoperiod), but the SCN circuits that regulate circadian and photoperiodic responses to light remain unclear. Somatostatin (SST) expression in the hypothalamus is modulated by photoperiod, but the role of SST in SCN responses to light has not been examined. Our results indicate that SST signaling regulates daily rhythms in behavior and SCN function in a manner influenced by sex. First, we use cell-fate mapping to provide evidence that SST in the SCN is regulated by light via de novo Sst activation. Next, we demonstrate that Sst  -/- mice display enhanced circadian responses to light, with increased behavioral plasticity to photoperiod, jetlag, and constant light conditions. Notably, lack of Sst  -/- eliminated sex differences in photic responses due to increased plasticity in males, suggesting that SST interacts with clock circuits that process light differently in each sex. Sst  -/- mice also displayed an increase in the number of retinorecipient neurons in the SCN core, which express a type of SST receptor capable of resetting the molecular clock. Last, we show that lack of SST signaling modulates central clock function by influencing SCN photoperiodic encoding, network after-effects, and intercellular synchrony in a sex-specific manner. Collectively, these results provide insight into peptide signaling mechanisms that regulate central clock function and its response to light.

We elucidated neural mechanisms underlying sighing. Photostimulation of parafacial (pF) neuromedin B ( NMB) or gastrin releasing peptide (GRP) or preBötC NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from the preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.

Activity in the dorsal vagal complex (DVC) is essential to gastric motility regulation. We and others have previously shown that this activity is greatly influenced by local GABAergic signaling primarily due to somatostatin-expressing GABAergic neurons (SST). To further understand the network dynamics associated with gastric motility control in the DVC, we focused on another neuron prominently distributed in this complex, neuropeptide-Y (NPY) neurons. However, the effect of these neurons on gastric motility remains unknown. Here we investigate the anatomical and functional characteristics of the NPY neurons in the nucleus tractus solitarius (NTS) and their interactions with SST neurons using transgenic mice of both sexes. We sought to determine if NPY neurons influence the activity of gastric projecting neurons, synaptically interact with SST neurons, and affect end-organ function. Our results using combined neuroanatomy and optogenetic in vitro and in vivo show that NPY neurons: are part of the gastric vagal circuit as they are trans-synaptically labeled by a viral tracer from the gastric antrum; are primarily excitatory as optogenetic activation of these neurons evoke EPSCs in gastric-antrum projecting neurons; are functionally coupled to each other and reciprocally connected to SST neurons, whose stimulation has a potent inhibitory effect on the action potential firing of the NPY neurons; and affect gastric tone and motility as reflected by their robust optogenetic response in vivo. These findings indicate that interacting NPY and SST neurons are integral to the network that controls vagal transmission to the stomach.Significance StatementThe brainstem neurons in the dorsal nuclear complex are essential for regulating vagus nerve activity that affects the stomach via tone and motility. Two distinct non-overlapping populations of predominantly excitatory neuropeptide Y (NPY) neurons and predominantly inhibitory somatostatin (SST) neurons form reciprocal connections with each other in the nucleus of the tractus solitarius (NTS) and with premotor neurons in the dorsal motor nucleus of the vagus to control gastric mechanics. Light activation and inhibition of NTS. NPY neurons increased and decreased gastric motility, respectively, while both activation and inhibition of NTS SST neurons enhanced gastric motility.

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders. However, the neuronal circuit mechanisms underlying prosocial behavior are still elusive. Here we identify a causal role of the basal forebrain (BF) in the control of prosocial behavior via inhibitory projections that disinhibit the midbrain ventral tegmental area (VTA) dopamine (DA) neurons. Specifically, BF somatostatin-positive (SST) inhibitory neurons were robustly activated during social interaction. Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference. Electrophysiological examinations further revealed that SST neurons predominantly targeted VTA GABA neurons rather than DA neurons. Consistently, optical inhibition of SST neuron axon terminals in the VTA decreased DA release in the nucleus accumbens during social interaction, confirming a disinhibitory action. These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain's reward system.

The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means for emotion regulation upon stress exposure. However, it is unclear about the neurological mechanism on how repetitive behaviors affect emotion regulation to cope with stress. Here, we identify that excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPLSST neurons) control self-grooming and encode reward. MPLSST neuronal activity is responsible for self-grooming initiation and maintenance. Loss-of-function of MPLSST neurons attenuates both self-grooming motor actions and anxiety alleviation upon stress exposure. Activating MPLSST neurons generate reward and drive reinforcement through eliciting dopamine release in the downstream target of the ventral tegmental area (VTA), and neuropeptide SST facilitates the rewarding impact of MPLSST neurons. MPLSST neuron-mediated self-grooming is triggered by inputs from the central amygdala (CeA). Our study validates a CeA-MPLSST-VTADA circuit mediating the impact of self-grooming on emotion regulation to cope with stress through generating reward and pleasurable feelings.

Introduction Information processing in cortical cell microcircuits involves regulation of excitatory pyramidal (PYR) cells by inhibitory Somatostatin- (SST), Parvalbumin- (PV), and Vasoactive intestinal peptide- (VIP) expressing interneurons. Human post-mortem and rodent studies show impaired PYR-cell dendritic morphology and decreased SST-cell markers in MDD or after chronic stress. However, knowledge of coordinated changes across microcircuit cell-types is virtually absent. Methods We investigated the transcriptomic effects of unpredictable chronic mild stress (UCMS) on distinct microcircuit cell-types in the medial prefrontal cortex (Cingulate regions 24a/b and 32) in mice. C57Bl/6 mice, exposed to UCMS or control housing for five weeks, were assessed for anxiety- and depressive-like behaviors. Microcircuit cell-types were laser-microdissected and processed for RNA-sequencing. Results UCMS induced predicted elevations in behavioral emotionality in mice. DESeq2 analysis revealed unique differentially-expressed genes in each cell-type after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell-types, whereas nearly all cell-types showed downregulated post-synaptic gene signatures. Across the cortical microcircuit, we observed a shift from a distributed transcriptomic coordination across cell-types in controls towards UCMS-induced increased coordination between PYR-, SST- and PV-cells, and hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide coexpression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviors. Conclusions These findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cells regulating the cortical excitation-inhibition balance, suggesting increased coordinated regulation of PYR-cells by SST- and PV-cells.