A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.

Neural circuits that control aversion are essential for motivational regulation and survival in animals. The nucleus accumbens (NAc) plays an important role in predicting aversive events and translating motivations into actions. However, the NAc circuits that mediate aversive behaviors remain elusive. Here, we report that tachykinin precursor 1 (Tac1) neurons in the NAc medial shell regulate avoidance responses to aversive stimuli. We show that NAcTac1 neurons project to the lateral hypothalamic area (LH) and that the NAcTac1→LH pathway contributes to avoidance responses. Moreover, the medial prefrontal cortex (mPFC) sends excitatory inputs to the NAc, and this circuit is involved in the regulation of avoidance responses to aversive stimuli. Overall, our study reveals a discrete NAc Tac1 circuit that senses aversive stimuli and drives avoidance behaviors.

Nucleus Accumbens Tac1-Expressing Neurons Mediate Stress-Induced Anhedonia-like Behavior in Mice.

Major depressive disorder (MDD) presents with two primary symptoms: depressed mood and anhedonia, which suggests that distinct neuronal circuits may regulate MDD. However, the underlying circuits of these individual symptoms linked to depression remain elusive. Herein, we identify a discrete circuit of tachykinin precursor 1 (Tac1)-expressing neurons in the nucleus accumbens (NAc) lateral shell, which project to ventral pallidum and contribute to stress-induced anhedonia-like behavior. Selective inhibition and activation of Tac1NAc neurons bidirectionally modulate stress susceptibility, revealing that Tac1 neurons in the NAc are critical for regulating anhedonia-like behaviors. We find that a subpopulation of VP neurons receives inhibitory inputs from Tac1NAc neurons and exhibits decreased excitability in susceptible mice. Furthermore, the inhibition of the neurokinin 1 receptor promotes susceptibility to social stress. Overall, our study reveals a discrete circuit regulating anhedonia-like behavior in mice.

HuR in the Medial Prefrontal Cortex is Critical for Stress-Induced Synaptic Dysfunction and Depressive-Like Symptoms in Mice.

Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuRflox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.

Substance P plays a critical role in synaptic transmission in striatal neurons.

Substance P is one of the major neuropeptides released by striatal neurons; however, its function in the striatum remains unclear. In this study, we found substance P triggers spontaneous neurotransmitter release and rapid synaptic vesicle exocytosis in cultured striatal neurons, as substance P knockdown in these neurons impaired spontaneous neurotransmitter release and calcium-dependent rapid synaptic neurotransmission. Furthermore, treatment with exogenous substance P completely rescued the synaptic dysfunction phenotype in striatal neurons lacking this neuropeptide. On the other hand, substance P knockdown had no effect on the size of the readily releasable pool of synaptic vesicles, but decreased the probability of presynaptic release of synaptic vesicles in cultured striatal neurons. Treatment with CP96345, a NK1 receptor antagonist, also resulted in synaptic defects in cultured striatal neurons. In summary, we propose substance P is critical for synaptic transmission in striatal neurons.