Hong Lian

Anxiety disorders frequently accompany aggression, with their co-occurrence predicting greater functional impairment and poor prognosis. Nevertheless, the underlying neural mechanisms remain elusive, primarily due to a lack of appropriate animal models. Here, we designed a chronic conspecific outsider stress (CCS) model in which male mice underwent perceived social threats and exhibited increased anxiety-like behaviors accompanied by aggression. CCS led to Fos activation and hyperexcitability of GABAergic neurons in the medial preoptic area (mPOA). Inhibition of mPOA GABAergic (mPOAGad2) neurons rescued CCS-induced anxiety-like and aggressive behaviors, whereas activating these cells induced susceptibility to CCS. Moreover, CCS upregulated the mRNA and protein expression of the sexual-dimorphic gene, cholecystokinin A receptor (CCKAR)-encoding Cckar gene in the mPOA. Importantly, the knock-down and overexpression of CCKAR in the mPOAGad2 neurons had alleviating and promoting effects on anxiety-like and aggressive behaviors, aligning with decreased and increased excitability by the anxiolytic CCKAR antagonist MK-329 and the anxiogenic CCKAR agonist A71623 in mPOAGad2 neurons, respectively. Overall, our study characterizes a novel mouse model of anxiety disorders accompanied by aggression and the neuronal subpopulation and molecular mediator of the aberrant behaviors provide potential targets of intervention for anxiety disorders with aggression.

The mesolimbic dopamine system is crucial for drug reinforcement and reward learning, leading to addiction. We previously demonstrated that Arvcf was associated significantly with nicotine and alcohol addiction through genome-wide association studies. However, the role and mechanisms of Arvcf in dopamine-mediated drug reward processes were largely unknown. In this study, we first showed that Arvcf mediates nicotine-induced reward behavior by using conditioned place preference (CPP) model on Arvcf-knockout (Arvcf-KO) animal model. Then, we revealed that Arvcf was mainly expressed in VTA dopaminergic neurons whose expression could be upregulated by nicotine treatment. Subsequently, our SnRNA-seq analysis revealed that Arvcf was directly involved in dopamine biosynthesis in VTA dopaminergic neurons. Furthermore, we found that Arvcf-KO led to a significant reduction in both the dopamine synthesis and release in the nucleus accumbens (NAc) on nicotine stimulation. Specifically, we demonstrated that inhibition of Arvcf in VTA dopaminergic neurons decreased dopamine release within VTA-NAc circuit and suppressed nicotine reward-related behavior, while overexpression of Arvcf led to the opposite results. Taken together, these findings highlight the role of Arvcf in regulating dopamine signaling and reward learning, and its enhancement of dopamine release in the VTA-NAc circuit as a novel mechanism for nicotine reward.

The dorsal hippocampus plays a pivotal role in spatial memory. However, the role of subregion‐specific molecular pathways in spatial cognition remains unclear. We observed that the transcriptional coregulator C‐terminal binding protein 2 (CtBP2) presented CA3‐specific enrichment in expression. RNAi interference of CtBP2 in the dorsal CA3 (dCA3) neurons, but not the ventral CA3 (vCA3), specifically impaired spatial reference memory and reduced the expression of GluR2, the calcium permeability determinant subunit of AMPA receptors. Application of an antagonist for GluR2‐absent calcium permeable AMPA receptors rescued spatial memory deficits in dCA3 CtBP2 knockdown animals. Transcriptomic analysis suggest that CtBP2 may regulate GluR2 protein level through post‐translational mechanisms, especially by the endocytosis pathway which regulates AMPA receptor sorting. Consistently, CtBP2 deficiency altered the mRNA expression of multiple endocytosis‐regulatory genes, and CtBP2 knockdown in primary hippocampal neurons enhanced GluR2‐containing AMPA receptor endocytosis. Together, our results provide evidence that the dCA3 regulates spatial reference memory by the CtBP2/GluR2 pathway through the modulation of calcium permeable AMPA receptors.

Major depressive disorder (MDD) is a highly prevalent debilitating psychiatric disease and a serious public health problem worldwide. Brain structural MRI and postmortem studies on patients with depression have revealed changes in the anatomy and functionality in various brain regions, including the amygdala, thalamus, hippocampus, and prefrontal cortex (PFC). The alterations in these brain regions could be a result, in part, of the dysregulation of the neurotrophic factors. Neuregulin1 (NRG1) is one of the neurotrophic factors, and our previous study showed that the NRG1-ErbB4 signaling pathway plays a critical role in epilepsy. In this study, we established a chronic social defeat stress (CSDS) model to investigate the role of the NRG1-ErbB4 signaling pathway in depression-like behaviors. In CSDS mice, we found that the NRG1 protein expression levels were significantly decreased both in the medial prefrontal cortex (mPFC) and hippocampus, while phosphorylated ErbB4 only decreased in the mPFC. In addition, lateral ventricle NRG1 administration significantly rescued depression-like behaviors in the susceptible group. The current study suggests that the NRG1-ErbB4 signaling pathway may exert a protective role in MDD.

Cao SX, Zhang Y, Hu XY, Hong B, Sun P, He HY, Geng HY, Bao AM, Duan SM, Yang JM, Gao TM, Lian H, Li XM. 2018. ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines. eLife 7:e39907. doi: 10.7554/eLife.39907.

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of manic-depressive psychosis (MDP). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to MDP; however, how ErbB4 regulates NE neuronal function and contributes to MDP pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, ErbB4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.