Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and hemichannel (HC)-mediated gliotransmitter release, its specific role in SCZ remains unclear. Here, we report elevated Cx43 expression in the prefrontal cortex of individuals with SCZ and investigate its functional relevance in an MK801-induced mouse model. In this model, medial prefrontal cortex (mPFC) Cx43 upregulation was associated with enhanced HC activity without affecting GJ coupling. Pharmacological blockade of Cx43 HC with TAT-Gap19 rescued SCZ-like behavioral and synaptic alterations, whereas astrocyte-specific Cx43 overexpression (Cx43 OE) in the mPFC of naive mice recapitulated behavioral abnormalities. Mechanistically, increased HC activity was linked to excessive astrocytic glutamate release, which was directly visualized using ex vivo two-photon imaging with an astrocyte-specific glutamate sensor and normalized by TAT-Gap19. Together, our results integrate human expression data with experimental evidence to implicate astrocytic Cx43 HC dysregulation in prefrontal circuit dysfunction relevant to SCZ and suggest that glial HC signaling warrants further investigation in SCZ pathophysiology.

Anxiety disorders pose a substantial threat to global mental health, with chronic stress identified as a major etiologic factor. Over the past few decades, extensive studies have revealed that chronic stress induces anxiety states through a distributed neuronal network of interconnected brain structures. However, the precise circuit mechanisms underlying the transition from chronic stress to anxiety remain incompletely understood. Employing the chronic social defeat stress (CSDS) paradigm in mice, we uncovered a critical role of the parasubthalamic nucleus (PSTh) in both the induction and expression of anxiety-like behavior. The anxiogenic effect was mediated by an excitatory trisynaptic circuitry involving the lateral parabrachial nucleus (LPB), PSTh, and bed nucleus of the stria terminalis (BNST). Furthermore, CSDS downregulated Kv4.3 channels in glutamatergic neurons of the PSTh. Reexpression of these channels dampened neuronal overexcitability and alleviated anxiety-like behavior in stressed animals. In parallel with the well-known anxiety network centered on the amygdala, here we identify a noncanonical LPB-PSTh-BNST pathway in the transformation of stress into anxiety. These findings suggest that the PSTh may serve as a potential therapeutic target for anxiety-related disorders.

Previous research on major depressive disorder (MDD) has largely focused on cognitive biases and abnormalities in cortico-limbic circuitry during emotional face processing. However, it remains unclear whether these abnormalities start at early perceptual stages via subcortical pathways and how comorbid social anxiety influences this process. Here, we investigated subcortical mechanisms in emotional face processing using a psychophysical method that measures monocular advantage (i.e., superior discrimination performance when two stimuli are presented to the same eye than to different eyes). Participants included clinical patients diagnosed with MDD (n = 32), patients with MDD comorbid with social anxiety (comorbid MDD-SAD, n = 32), and a control group of healthy participants (HC, n = 32). We assessed monocular advantage across different emotions (neutral, sad, angry) and among groups. Results indicated that individuals with MDD showed a stronger monocular advantage for sad expressions compared to neutral and angry expressions. In contrast, HC and comorbid MDD-SAD groups showed a greater monocular advantage for neural over negative expressions. Cross-group comparisons revealed that MDD group had a stronger monocular advantage for sad expressions than both HC and comorbid MDD-SAD groups. Additionally, self-reported depressive symptoms were positively correlated with monocular advantage for sad expressions, while social anxiety symptoms were negatively correlated with monocular advantage for negative expressions. These findings suggest atypical early perceptual processing of sadness in individuals with MDD via subcortical mechanisms, with comorbid social anxiety potentially counteracting this effect. This study may inform novel interventions targeting sensory processing and expand beyond cognitive bias modification.

The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments, including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified.Using a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are activated synchronously during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear.These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptoms often observed in many psychiatric disorders. Excessive social fear is a common symptom observed in many mental disorders. Tian et al. reveal a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a target to ameliorate social fear symptoms associated with psychiatric disorders.

Elucidating the neural basis of fear allows for more effective treatments for maladaptive fear often observed in psychiatric disorders. Although the basal forebrain (BF) has an essential role in fear learning, its function in fear expression and the underlying neuronal and circuit substrates are much less understood. Here we report that BF glutamatergic neurons are robustly activated by social stimulus following social fear conditioning in male mice. And cell-type-specific inhibition of those excitatory neurons largely reduces social fear expression. At the circuit level, BF glutamatergic neurons make functional contacts with the lateral habenula (LHb) neurons and these connections are potentiated in conditioned mice. Moreover, optogenetic inhibition of BF-LHb glutamatergic pathway significantly reduces social fear responses. These data unravel an important function of the BF in fear expression via its glutamatergic projection onto the LHb, and suggest that selective targeting BF-LHb excitatory circuitry could alleviate maladaptive fear in relevant disorders. Maladaptive fear is linked to many neuropsychiatric disorders, while its neural basis is not fully understood. Here, the authors show that the hyperactivity of the basal forebrain to lateral habenula glutamatergic circuit is crucial for social fear behavior.

OBJECTIVE:Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H2S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H2S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl-d-Aspartate (NMDA) receptor function. METHODS:Mice were immediately administered dl-propargylglycine (PAG) intragastrically as an H2S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. RESULTS:Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H2S-induced intestinal and cerebral injury. CONCLUSION:This experimental data suggests that H2S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.

Individuals with social anxiety often exhibit atypical processing of facial expressions. Previous research in social anxiety has primarily emphasized cognitive bias associated with face processing and the corresponding abnormalities in cortico-limbic circuitry, yet whether social anxiety influences early perceptual processing of emotional faces remains largely unknown. We used a psychophysical method to investigate the monocular advantage for face perception (i.e., face stimuli are better recognized when presented to the same eye compared to different eyes), an effect that is indicative of early, subcortical processing of face stimuli. We compared the monocular advantage for different emotional expressions (neutral, angry and sad) in three groups (N = 24 per group): individuals clinically diagnosed with social anxiety disorder (SAD), individuals with high social anxiety in subclinical populations (SSA), and a healthy control (HC) group of individuals matched for age and gender. Compared to SSA and HC groups, we found that individuals with SAD exhibited a greater monocular advantage when processing neutral and sad faces. While the magnitudes of monocular advantages were similar across three groups when processing angry faces, individuals with SAD performed better in this condition when the faces were presented to different eye. The former findings suggest that social anxiety leads to an enhanced role of subcortical structures in processing nonthreatening expressions. The latter findings, on the other hand, likely reflect an enhanced cortical processing of threatening expressions in SAD group. These distinct patterns of monocular advantage indicate that social anxiety altered representation of emotional faces at various stages of information processing, starting at an early stage of the visual system.

Eye size is a key parameter to visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor Sterol regulatory element-binding protein 2 (Srebp2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. Srebp2 transcriptionally represses Low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (Bmp2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by Srebp2 transcriptionally while activated by Lrp2. Over postnatal development, SREBP2 protein in the RPE decreases while Lrp2 and Bmp2 increase in expression, as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knockout. Together, our study showed that the rapid postnatal eye size increment is governed by an RPE-derived signaling pathway, which is composed of both positive and negative regulators of eye growth.

Although stem cell-based therapy is recognized as a promising therapeutic strategy for spinal cord injury (SCI), its efficacy is greatly limited by local reactive oxygen species (ROS)-abundant and hyper-inflammatory microenvironments. It is still a challenge to develop bioactive scaffolds with outstanding antioxidant capacity for neural stem cells (NSCs) transplantation. In this study, albumin biomimetic cerium oxide nanoparticles (CeO2 @BSA nanoparticles, CeNPs) are prepared in a simple and efficient manner and dispersed in gelatin methacryloyl to obtain the ROS-scavenging hydrogel (CeNP-Gel). CeNP-Gel synergistically promotes neurogenesis via alleviating oxidative stress microenvironments and improving the viability of encapsulated NSCs. More interestingly, in the presence of CeNP-Gel, microglial polarization to anti-inflammatory M2 subtype are obviously facilitated, which is further verified to be associated with phosphoinositide 3-kinase/protein kinase B pathway activation. Additionally, the injectable ROS-scavenging hydrogel is confirmed to induce the integration and neural differentiation of transplanted NSCs. Compared with the blank-gel group, the survival rate of NSCs in CeNP-Gel group is about 3.5 times higher, and the neural differentiation efficiency is about 2.1 times higher. Therefore, the NSCs-laden ROS-scavenging hydrogel represents a comprehensive strategy with great application prospect for the treatment of SCI through comprehensively modulating the adverse microenvironment.

Social anxiety is characterized by an intense fear of evaluation from others and/or withdrawal from social situations. Extreme social anxiety can lead to social anxiety disorder. There remains an urgent need to investigate the neural substrates of subclinical social anxiety for early diagnosis and intervention to reduce the risk to develop social anxiety disorder. Twenty-nine young adults were recruited (10 males/19 females; mean age (SD) = 20.34 (2.29)). Trait-like social anxiety was assessed by Liebowitz Social Anxiety Scale. Functional magnetic resonance imaging was used with an emotional face-matching paradigm to probe brain activation in response to emotional stimuli including angry, fearful, and happy faces, with shape-matching as a control condition. Behavioral results showed positive correlations between Liebowitz Social Anxiety Scale scores and the reaction time in both angry and fearful conditions. The activation of superficial amygdala and the deactivation of basal forebrain in response to angry condition showed positive correlations with the level of social anxiety. In addition, the resting-state functional connectivity between these two regions was negatively correlated with the level of social anxiety. These results may help to understand the individual difference and corresponding neural underpinnings of social anxiety in the subclinical population, and might provide some insight to develop strategies for early diagnosis and interventions of social anxiety to reduce the risk of deterioration from subclinical to clinical level of social anxiety.

Directional axon regeneration and remyelination are crucial for repair of spinal cord injury (SCI), but existing treatments do not effectively promote those processes. Here, we propose a strategy for construction of niche-specific spinal white matter-like tissue (WMLT) using decellularized optic nerve (DON) loaded with neurotrophin-3 (NT-3)-overexpressing oligodendrocyte precursor cells. A rat model with a white matter defect in the dorsal spinal cord of the T10 segment was used. The WMLT transplantation group showed significant improvement in coordinated motor functions compared with the control groups. WMLT transplants integrated well with host spinal cord white matter, effectively addressing several barriers to directional axonal regeneration and myelination during SCI repair. In WMLT, laminin was found to promote development of oligodendroglial lineage (OL) cells by binding to laminin receptors. Interestingly, laminin could also guide linear axon regeneration via interactions with specific integrins on the axon surface. The WMLT developed here utilizes the unique microstructure and bioactive matrix of DON to create a niche rich in laminin, NT-3 and OL cells to achieve significant structural repair of SCI. Our protocol can help to promote research on repair of nerve injury and construction of neural tissues and organoids that form specific cell niches.

EDITORIAL article Front. Neural Circuits, 29 July 2022 https://doi.org/10.3389/fncir.2022.938354

Social interactions and relationships are often rewarding, but the neural mechanisms through which social interaction drives positive experience remain poorly understood. In this study, we developed an automated operant conditioning system to measure social reward in mice and found that adult mice of both sexes display robust reinforcement of social interaction. Through cell-type-specific manipulations, we identified a crucial role for GABAergic neurons in the medial amygdala (MeA) in promoting the positive reinforcement of social interaction. Moreover, MeA GABAergic neurons mediate social reinforcement behavior through their projections to the medial preoptic area (MPOA) and promote dopamine release in the nucleus accumbens. Finally, activation of this MeA-to-MPOA circuit can robustly overcome avoidance behavior. Together, these findings establish the MeA as a key node for regulating social reward in both sexes, providing new insights into the regulation of social reward beyond the classic mesolimbic reward system.

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.

Humans are social animals. Social interaction accounts for a large amount of our daily life and is fundamental to our physical and mental health (Hawkley and Cacioppo 2010; Kahneman et al. 2004). On the other hand, social impairments are commonly observed in various neurodegenerative, neuropsychiatric, and neurodevelopmental disorders (Bicks et al. 2015; Hari and Kujala 2009; Hari et al. 2015). Deciphering the neural mechanisms underlying social interaction behavior is therefore of great importance in terms of both basic science and clinical medicine.

Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.

Prefrontal GABAergic interneurons (INs) are crucial for social behavior by maintaining excitation/inhibition balance. However, the underlying neuronal correlates and network computations are poorly understood. We identified distinct firing patterns of prefrontal parvalbumin (PV) INs and somatostatin (SST) INs upon social interaction. Moreover, social interaction closely correlated with elevated gamma rhythms particularly at low gamma band (20 to 50 Hz). Pharmacogenetic inhibition of PV INs, instead of SST INs, reduced low gamma power and impaired sociability. Optogenetic synchronization of either PV INs or SST INs at low gamma frequency improved sociability, whereas high gamma frequency or random frequency stimulation had no effect. These results reveal a functional differentiation among IN subtypes and suggest the importance of low gamma rhythms in social interaction behavior. Furthermore, our findings underscore previously unrecognized potential of SST INs as therapeutic targets for social impairments commonly observed in major neuropsychiatric disorders.

Neurovascular coupling represents the relationship between changes in neuronal activity and cerebral hemodynamics. Concurrent Electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) recording and integration analysis has emerged as a promising multi-modal neuroimaging approach to study the neurovascular coupling as it provides complementary properties with regard to high temporal and moderate spatial resolution of brain activity. In this study we developed an EEG-informed-fNIRS analysis framework to investigate the neuro-correlate between neuronal activity and cerebral hemodynamics by identifying specific EEG rhythmic modulations which contribute to the improvement of the fNIRS-based general linear model (GLM) analysis. Specifically, frequency-specific regressors derived from EEG were used to construct design matrices to guide the GLM analysis of the fNIRS signals collected during a hand grasp task. Our results showed that the EEG-informed fNIRS GLM analysis, especially the alpha and beta band, revealed significantly higher sensitivity and specificity in localizing the task-evoked regions compared to the canonical boxcar model, demonstrating the strong correlations between hemodynamic response and EEG rhythmic modulations. Results also indicated that analysis based on the deoxygenated hemoglobin (HbR) signal slightly outperformed the oxygenated hemoglobin (HbO)-based analysis. The findings in our study not only validate the feasibility of enhancing fNIRS GLM analysis using simultaneously recorded EEG signals, but also provide a new perspective to study the neurovascular coupling of brain activity.