SST Neurons Research Articles

Interactions between Brainstem Neurons That Regulate the Motility to the Stomach.

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 because of somatostatin (SST)-expressing GABAergic neurons. 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 anatomic 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 whether 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 STATEMENT The brainstem neurons in the dorsal nuclear complex are essential for regulating vagus nerve activity that affects the stomach via tone and motility. Two distinct nonoverlapping populations of predominantly excitatory NPY neurons and predominantly inhibitory SST neurons form reciprocal connections with each other in the 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, whereas both activation and inhibition of NTS SST neurons enhanced gastric motility.

Vigilance and Behavioral State-Dependent Modulation of Cortical Neuronal Activity throughout the Sleep/Wake Cycle.

GABAergic inhibitory neurons, through their molecular, anatomic, and physiological diversity, provide a substrate for the modulation of ongoing cortical circuit activity throughout the sleep/wake cycle. Here, we investigated neuronal activity dynamics of parvalbumin (PV), vasoactive intestinal polypeptide (VIP), and somatostatin (SST) neurons in naturally sleeping head-restrained mice at the level of layer 2/3 of the primary somatosensory barrel cortex of mice. Through calcium imaging and targeted single-unit loose-patch or whole-cell recordings, we found that PV action potential firing activity was largest during both rapid eye movement (REM) and nonrapid eye movement (NREM) sleep stages, that VIP neurons were most active during REM sleep, and that the overall activity of SST neurons remained stable throughout the sleep/wake cycle. Analysis of neuronal activity dynamics uncovered rapid decreases in PV cell firing at wake onset followed by a progressive recovery during wake. Simultaneous local field potential (LFP) recordings further revealed that except for SST neurons, a large proportion of neurons were modulated by ongoing delta and theta oscillations. During NREM sleep spindles, PV and SST activity increased and decreased, respectively. Finally, we uncovered the presence of whisking behavior in mice during REM sleep and show that the activity of VIP and SST is differentially modulated during awake and sleeping whisking bouts, which may provide a neuronal substrate for internal brain representations occurring during sleep.SIGNIFICANCE STATEMENT In the sensory cortex, the balance between excitation and inhibition is believed to be highly dynamic throughout the sleep/wake cycle, shaping the response of cortical circuits to external stimuli while allowing the formation of newly encoded memory. Using in vivo two-photon calcium imaging or targeted single-unit recordings combined with LFP recordings, we describe the vigilance state and whisking-behavior-dependent activity of excitatory pyramidal and inhibitory GABAergic neurons in the supragranular layers of mouse somatosensory cortex. Interneuronal activity was found to be differentially modulated by ongoing delta and theta waves, sleep spindles, and a novel type of whisking observed during REM sleep, potentially providing a neuronal substrate for internal brain representations occurring during sleep.

P536. Lower Somatostatin and Parvalbumin Transcript Level Without Deficit in Density of Either Neuronal Subtype in the Prefrontal Cortex of Schizophrenia

Transcript levels for markers of the somatostatin (SST) and parvalbumin (PV) subtypes of GABA neurons are lower in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. However, it is unclear whether these deficits in transcript levels reflect fewer SST or PV neurons and/or lower expression of each transcript per neuron.

Effects of the Isolated and Combined Ablation of Growth Hormone and IGF-1 Receptors in Somatostatin Neurons.

Hypophysiotropic somatostatin (SST) neurons in the periventricular hypothalamic area express growth hormone (GH) receptor (GHR) and are frequently considered as the key neuronal population that mediates the negative feedback loop controlling the hypothalamic-GH axis. Additionally, insulin-like growth factor-1 (IGF-1) may also act at the hypothalamic level to control pituitary GH secretion via long-loop negative feedback. However, to the best of our knowledge, no study so far has tested whether GHR or IGF-1 receptor (IGF1R) signaling specifically in SST neurons is required for the homeostatic control of GH secretion. Here we show that GHR ablation in SST neurons did not impact the negative feedback mechanisms that control pulsatile GH secretion or body growth in male and female mice. The sex difference in hepatic gene expression profile was only mildly affected by GHR ablation in SST neurons. Similarly, IGF1R ablation in SST neurons did not affect pulsatile GH secretion, body growth, or hepatic gene expression. In contrast, simultaneous ablation of both GHR and IGF1R in SST-expressing cells increased mean GH levels and pulse amplitude in male and female mice, and partially disrupted the sex differences in hepatic gene expression. Despite the increased GH secretion in double knockout mice, no alterations in body growth and serum or liver IGF-1 levels were observed. In summary, GHR and IGF1R signaling in SST neurons play a redundant role in the control of GH secretion. Furthermore, our results reveal the importance of GH/IGF-1 negative feedback mechanisms on SST neurons for the establishment of sex differences in hepatic gene expression profile.

The impairment of the hippocampal neuro-vascular unit precedes changes in spatial cognition in naturally aged rats

Ageing is the major risk factor for the most neurodegenerative diseases, such as Alzheimer’s disease (AD). Damage to neurovascular components (microvessels, glia, and neurons) occurs with ageing and is suspected to exacerbate or cause mild cognitive impairment (MCI), vascular dementia, and AD. However, whether vascular cells, glia, and neurons change synchronously or asynchronously during ageing is unclear, and the relationship between complex dynamic pathophysiological changes in the brain and cognitive ability needs to be further studied. We used male Sprague–Dawley (SD) rats of three different ages (2 months, 12 months, and 24 months) and explored changes in the neurovascular unit (cerebral vessels, microglia, astrocytes, and neurons) and spatial memory upon normal ageing by the Morris water maze (MWM) test and immunofluorescence staining. We found that the impairments of microvessels, glia, neurons, and spatial memory were age-dependent in the rat hippocampus. In middle-aged (12-month-old) rats, some neurovascular unit components have become abnormal: the density and length of microvessels, pyramidal neuron, and SST (Somatostatin) neuron number was decreased, the number of astrocytes was increased in the hippocampus. The diameter of microvessels and PV (Parvalbumin) neuron numbers were decreased, the microglial number was increased and spatial learning was deficit at 24 months of age. In conclusion, we found that the impairment of the hippocampal neuro-vascular unit precedes changes in spatial cognition in naturally aged rats.

The Organization of Somatostatin-Immunoreactive Cells in the Visual Cortex of the Gerbil.

Somatostatin (SST) is widely expressed in the brain and plays various, vital roles involved in neuromodulation. The purpose of this study is to characterize the organization of SST neurons in the Mongolian gerbil visual cortex (VC) using immunocytochemistry, quantitative analysis, and confocal microscopy. As a diurnal animal, the Mongolian gerbil provides us with a different perspective to other commonly used nocturnal rodent models. In this study, SST neurons were located in all layers of the VC except in layer I; they were most common in layer V. Most SST neurons were multipolar round/oval or stellate cells. No pyramidal neurons were found. Moreover, 2-color immunofluorescence revealed that only 33.50%, 24.05%, 16.73%, 0%, and 64.57% of SST neurons contained gamma-aminobutyric acid, calbindin-D28K, calretinin, parvalbumin, and calcium/calmodulin-dependent protein kinase II, respectively. In contrast, neuropeptide Y and nitric oxide synthase were abundantly expressed, with 80.07% and 75.41% in SST neurons, respectively. Our immunocytochemical analyses of SST with D1 and D2 dopamine receptors and choline acetyltransferase, α7 and β2 nicotinic acetylcholine receptors suggest that dopaminergic and cholinergic fibers contact some SST neurons. The results showed some distinguishable features of SST neurons and provided some insight into their afferent circuitry in the gerbil VC. These findings may support future studies investigating the role of SST neurons in visual processing.

Excitatory SST Neurons in the Medial Paralemniscal Nucleus Control Repetitive Self-Grooming and Encode Reward

Excitatory SST Neurons in the Medial Paralemniscal Nucleus Control Repetitive Self-Grooming and Encode Reward

Robust cell-type-specific associations with Alzheimer's disease within excitatory and inhibitory neuronal subclasses.

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, despite recent single-cell transcriptomic analyses of human AD brain tissue, it remains unclear which neuronal subtypes are most vulnerable to degeneration. Here we applied cell-type proportion estimation methods to multiple RNA sequencing (RNAseq) datasets derived from human postmortem brain to identify the neuronal subtypes most strongly associated with AD. Postmortem bulk-brain RNAseq data collected from three AD studies were analyzed (n=953), comprising six datasets of different neocortical regions. Relative cell type proportions were estimated for each brain sample using the markerGeneProfile package and marker genes for specific neuronal subtypes derived from ultra-high depth single-nucleus RNAseq (Hodge et al., 2019). Linear models were used to test associations of cell-type proportion estimations (CTPs) with AD diagnosis in each dataset separately, followed by random-effects meta-analysis. Pseudo-bulk investigation of the Mathys et al. (2019) single-nucleus RNAseq dataset was used to further validate findings. Follow-up in the Religious Orders Study and Memory and Aging Project (ROS/MAP) cohorts (n=593) permitted the identification of specific neuropathologies associated with each neuronal subtype. Meta-analysis revealed several neuronal subtypes significantly associated with AD, with the strongest signals from intra-telencephalic (IT) excitatory neurons (meta p=4.82x10-13 ) and somatostatin (SST) inhibitory neurons (meta p= 1.55x10-10 ). Pseudo-bulk single-nucleus analysis suggested that these signals are most likely due to differences in cell proportions rather than differences in expression of any predominant marker gene for each class. In-depth analysis of CTPs in ROS/MAP consistently implicated a decrease in IT and SST CTPs with increasing amyloid and tau neuropathology, as well as more severe cognitive decline prior to death. Decreases in SST and IT neuron subtypes, estimated from bulk RNAseq data, were significantly associated with AD diagnosis across multiple cortical regions. The SST signal in particular is robust to the exclusion of the SST mRNA from CTP calculations, suggesting the pathological relevance of a loss of SST-expressing neurons rather than a downregulation of the SST gene specifically. These findings support seminal work implicating somatostatin in the pathogenesis of AD and helps to re-focus our current understanding of neuronal vulnerability in AD.

Sphingosine-1-phosphate receptor 1 agonist SEW2871 alters membrane properties of late-firing somatostatin expressing neurons in the central lateral amygdala

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. Here, we sought to understand how S1P signaling affects neuronal excitability in the central amygdala (CeA), which is a brain region associated with fear learning, aversive memory, and the affective dimension of pain. Because the G-protein coupled S1P receptor 1 (S1PR1) has been shown to be the primary mediator of S1P signaling, we utilized S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR to determine a potential role of S1PR1 in altering the cellular physiology of neurons in the lateral division of the CeA (CeL) that share the neuronal lineage marker somatostatin (Sst). CeL-Sst neurons play a critical role in expression of conditioned fear and pain modulation. Here we used transgenic breeding strategies to identify fluorescently labeled CeL-Sst neurons for electrophysiological recordings. Using principal component analysis, we identified two primary subtypes of Sst neurons within the CeL in both male and female mice. We denoted the two types regular-firing (type A) and late-firing (type B) CeL-Sst neurons. In response to SEW2871 application, Type A neurons exhibited increased input resistance, while type B neurons displayed a depolarized resting membrane potential and voltage threshold, increased current threshold, and decreased voltage height. NIBR application had no effect on CeL Sst neurons, indicating the absence of tonic S1P-induced S1PR1. Our findings reveal subtypes of Sst neurons within the CeL that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal circuits.

Neurochemically distinct populations of the bed nucleus of stria terminalis modulate innate fear response to weak threat evoked by predator odor stimuli

Anxiety and trauma-related disorders are characterized by significant alterations in threat detection, resulting in inadequate fear responses evoked by weak threats or safety stimuli. Recent research pointed out the important role of the bed nucleus of stria terminalis (BNST) in threat anticipation and fear modulation under ambiguous threats, hence, exaggerated fear may be traced back to altered BNST function. To test this hypothesis, we chemogenetically inhibited specific BNST neuronal populations (corticotropin-releasing hormone - BNSTCRH and somatostatin - BNSTSST expressing neurons) in a predator odor-evoked innate fear paradigm. The rationale for this paradigm was threefold: (1) predatory cues are particularly strong danger signals for all vertebrate species evoking defensive responses on the flight-avoidance-freezing dimension (conservative mechanisms), (2) predator odor can be presented in a scalable manner (from weak to strong), and (3) higher-order processing of olfactory information including predatory odor stimuli is integrated by the BNST. Accordingly, we exposed adult male mice to low and high predatory threats presented by means of cat urine, or low- and high-dose of 2-methyl-2-thiazoline (2MT), a synthetic derivate of a fox anogenital product, which evoked low and high fear response, respectively. Then, we tested the impact of chemogenetic inhibition of BNSTCRH and BNSTSST neurons on innate fear responses using crh- and sst-ires-cre mouse lines. We observed that BNSTSST inhibition was effective only under low threat conditions, resulting in reduced avoidance and increased exploration of the odor source. In contrast, BNSTCRH inhibition had no impact on 2MT-evoked responses, but enhanced fear responses to cat odor, representing an even weaker threat stimulus. These findings support the notion that BNST is recruited by uncertain or remote, potential threats, and CRH and SST neurons orchestrate innate fear responses in complementary ways.

Somatostatin Neurons in the Mouse Pontine Nucleus Activate GABAA Receptor Mediated Synaptic Currents in Locus Coeruleus Neurons.

The pontine nuclei comprising the locus coeruleus (LC) and Barrington’s nucleus (BRN) amongst others form the neural circuitry(s) that coordinates arousal and voiding behaviors. However, little is known about the synaptic connectivity of neurons within or across these nuclei. These include corticotropin-releasing factor (CRF+) expressing neurons in the BRN that control bladder contraction and somatostatin expressing (SST+) neurons whose role in this region has not been discerned. To determine the synaptic connectivity of these neurons, we employed optogenetic stimulation with recordings from BRN and LC neurons in brain stem slices of channelrhodopsin-2 expressing SST or CRF neurons. Optogenetic stimulation of CRF+ BRN neurons of CrfCre;chr2-yfp mice had little effect on either CRF+ BRN neurons, CRF– BRN neurons, or LC neurons. In contrast, in SstCre;chr2-yfp mice light-activated inhibitory postsynaptic currents (IPSCs) were reliably observed in a majority of LC but not BRN neurons. The GABAA receptor antagonist, bicuculline, completely abolished the light-induced IPSCs. To ascertain if these neurons were part of the neural circuitry that controls the bladder, the trans-synaptic tracer, pseudorabies virus (PRV) was injected into the bladder wall of CrfCre;tdTomato or SstCre;tdTomato mice. At 68–72 h post-viral infection, PRV labeled neurons were present only in the BRN, being preponderant in CRF+ neurons with few SST+ BRN neurons labeled from the bladder. At 76 and 96 h post-virus injection, increased labeling was observed in both BRN and LC neurons. Our results suggest SST+ neurons rather than CRF+ neurons in BRN can regulate the activity of LC neurons.

Reliable Sensory Processing in Mouse Visual Cortex through Cooperative Interactions between Somatostatin and Parvalbumin Interneurons.

Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). However, under certain conditions, neurons can respond reliably with highly precise responses to the same visual stimuli from trial to trial. This suggests that there exists intrinsic neural circuit mechanisms that dynamically modulate the intertrial variability of visual cortical neurons. Here, we sought to elucidate the role of different inhibitory interneurons (INs) in reliable coding in mouse V1. To study the interactions between somatostatin-expressing interneurons (SST-INs) and parvalbumin-expressing interneurons (PV-INs), we used a dual-color calcium imaging technique that allowed us to simultaneously monitor these two neural ensembles while awake mice, of both sexes, passively viewed natural movies. SST neurons were more active during epochs of reliable pyramidal neuron firing, whereas PV neurons were more active during epochs of unreliable firing. SST neuron activity lagged that of PV neurons, consistent with a feedback inhibitory SST→PV circuit. To dissect the role of this circuit in pyramidal neuron activity, we used temporally limited optogenetic activation and inactivation of SST and PV interneurons during periods of reliable and unreliable pyramidal cell firing. Transient firing of SST neurons increased pyramidal neuron reliability by actively suppressing PV neurons, a proposal that was supported by a rate-based model of V1 neurons. These results identify a cooperative functional role for the SST→PV circuit in modulating the reliability of pyramidal neuron activity.SIGNIFICANCE STATEMENT Cortical neurons often respond to identical sensory stimuli with large variability. However, under certain conditions, the same neurons can also respond highly reliably. The circuit mechanisms that contribute to this modulation remain unknown. Here, we used novel dual-wavelength calcium imaging and temporally selective optical perturbation to identify an inhibitory neural circuit in visual cortex that can modulate the reliability of pyramidal neurons to naturalistic visual stimuli. Our results, supported by computational models, suggest that somatostatin interneurons increase pyramidal neuron reliability by suppressing parvalbumin interneurons via the inhibitory SST→PV circuit. These findings reveal a novel role of the SST→PV circuit in modulating the fidelity of neural coding critical for visual perception.

Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina.

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice. The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.

The Impact of SST and PV Interneurons on Nonlinear Synaptic Integration in the Neocortex.

Excitatory synaptic inputs arriving at the dendrites of a neuron can engage active mechanisms that nonlinearly amplify the depolarizing currents. This supralinear synaptic integration is subject to modulation by inhibition. However, the specific rules by which different subtypes of interneurons affect the modulation have remained largely elusive. To examine how inhibition influences active synaptic integration, we optogenetically manipulated the activity of the following two subtypes of interneurons: dendrite-targeting somatostatin-expressing (SST) interneurons; and perisomatic-targeting parvalbumin-expressing (PV) interneurons. In acute slices of mouse primary visual cortex, electrical stimulation evoked nonlinear synaptic integration that depended on NMDA receptors. Optogenetic activation of SST interneurons in conjunction with electrical stimulation resulted in predominantly divisive inhibitory gain control, reducing the magnitude of the supralinear response without affecting its threshold. PV interneuron activation, on the other hand, had a minimal effect on the supralinear response. Together, these results delineate the roles for SST and PV neurons in active synaptic integration. Differential effects of inhibition by SST and PV interneurons likely increase the computational capacity of the pyramidal neurons in modulating the nonlinear integration of synaptic output.

Somatostatin neurons control an alcohol binge drinking prelimbic microcircuit in mice

Somatostatin (SST) neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance use disorders, including alcohol use disorder (AUD), is not fully characterized. Here, we found that repeated cycles of alcohol binge drinking via the Drinking-in-the-Dark (DID) model led to hypoactivity of SST neurons in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. Alcohol binge drinking disinhibited pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations and reducing spontaneous inhibitory transmission onto pyramidal neurons. Pyramidal neurons additionally displayed increased intrinsic excitability. Direct inhibition of PL pyramidal neurons via hM4Di was sufficient to reduce alcohol binge drinking. Together these data revealed an SST-mediated microcircuit in the PL that modulates the inhibitory dynamics of pyramidal neurons, a major source of output to subcortical targets to drive reward-seeking behaviors and emotional response.

Joint cell segmentation and cell type annotation for spatial transcriptomics

RNA hybridization‐based spatial transcriptomics provides unparalleled detection sensitivity. However, inaccuracies in segmentation of image volumes into cells cause misassignment of mRNAs which is a major source of errors. Here, we develop JSTA, a computational framework for joint cell segmentation and cell type annotation that utilizes prior knowledge of cell type‐specific gene expression. Simulation results show that leveraging existing cell type taxonomy increases RNA assignment accuracy by more than 45%. Using JSTA, we were able to classify cells in the mouse hippocampus into 133 (sub)types revealing the spatial organization of CA1, CA3, and Sst neuron subtypes. Analysis of within cell subtype spatial differential gene expression of 80 candidate genes identified 63 with statistically significant spatial differential gene expression across 61 (sub)types. Overall, our work demonstrates that known cell type expression patterns can be leveraged to improve the accuracy of RNA hybridization‐based spatial transcriptomics while providing highly granular cell (sub)type information. The large number of newly discovered spatial gene expression patterns substantiates the need for accurate spatial transcriptomic measurements that can provide information beyond cell (sub)type labels.

Density of Somatostatin Neurons in the Dorsolateral Prefrontal Cortex of Schizophrenia Subjects

Cognitive dysfunction in schizophrenia is associated with altered GABA signaling markers in the prefrontal cortex (PFC). For example, levels of somatostatin (SST) mRNA, expressed in a subset of GABA neurons, are markedly lower in PFC gray matter in schizophrenia. The density of SST mRNA+ neurons is also lower in schizophrenia. However, whether schizophrenia is associated with fewer SST neurons or a failure of certain SST neurons to express detectable levels of SST mRNA remains unknown.

Gamma rhythms and visual information in mouse V1 specifically modulated by somatostatin+ neurons in reticular thalamus.

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here, we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1 and represent a novel circuit through which the nRT can influence representation of visual information.

Differential Short-Term Plasticity of PV and SST Neurons Accounts for Adaptation and Facilitation of Cortical Neurons to Auditory Tones.

Cortical responses to sensory stimuli are strongly modulated by temporal context. One of the best studied examples of such modulation is sensory adaptation. We first show that in response to repeated tones pyramidal (Pyr) neurons in male mouse auditory cortex (A1) exhibit facilitating and stable responses, in addition to adapting responses. To examine the potential mechanisms underlying these distinct temporal profiles, we developed a reduced spiking model of sensory cortical circuits that incorporated the signature short-term synaptic plasticity (STP) profiles of the inhibitory parvalbumin (PV) and somatostatin (SST) interneurons. The model accounted for all three temporal response profiles as the result of dynamic changes in excitatory/inhibitory balance produced by STP, primarily through shifts in the relative latency of Pyr and inhibitory neurons. Transition between the three response profiles was possible by changing the strength of the inhibitory PV→Pyr and SST→Pyr synapses. The model predicted that a unit's latency would be related to its temporal profile. Consistent with this prediction, the latency of stable units was significantly shorter than that of adapting and facilitating units. Furthermore, because of the history-dependence of STP the model generated a paradoxical prediction: that inactivation of inhibitory neurons during one tone would decrease the response of A1 neurons to a subsequent tone. Indeed, we observed that optogenetic inactivation of PV neurons during one tone counterintuitively decreased the spiking of Pyr neurons to a subsequent tone 400 ms later. These results provide evidence that STP is critical to temporal context-dependent responses in the sensory cortex.SIGNIFICANCE STATEMENT Our perception of speech and music depends strongly on temporal context, i.e., the significance of a stimulus depends on the preceding stimuli. Complementary neural mechanisms are needed to sometimes ignore repetitive stimuli (e.g., the tic of a clock) or detect meaningful repetition (e.g., consecutive tones in Morse code). We modeled a neural circuit that accounts for diverse experimentally-observed response profiles in auditory cortex (A1) neurons, based on known forms of short-term synaptic plasticity (STP). Whether the simulated circuit reduced, maintained, or enhanced its response to repeated tones depended on the relative dominance of two different types of inhibitory cells. The model made novel predictions that were experimentally validated. Results define an important role for STP in temporal context-dependent perception.

Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area

The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.