Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. Here we show that, in a rodent anxiety model induced by chronic restraint stress (CRS), the dysregulation occurs in basolateral amygdala projection neurons receiving mono-directional inputs from dorsomedial prefrontal cortex (dmPFC→BLA PNs) rather than those reciprocally connected with dmPFC (dmPFC↔BLA PNs). Specifically, CRS shifts the dmPFC-driven excitatory-inhibitory balance towards excitation in the former, but not latter population. Such specificity is preferential to connections made by dmPFC, caused by enhanced presynaptic glutamate release, and highly correlated with the increased anxiety-like behavior in stressed mice. Importantly, low-frequency optogenetic stimulation of dmPFC afferents in BLA normalizes the enhanced prefrontal glutamate release onto dmPFC→BLA PNs and lastingly attenuates CRS-induced increase of anxiety-like behavior. Our findings thus reveal a target cell-based dysregulation of mPFC-to-amygdala transmission for stress-induced anxiety.

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BACKGROUND:The role of the amygdala in mediating stress coping has been long appreciated. However, baso-lateral amygdala (BLA) projection neurons (PNs) are organized into discrete output circuits, and it remains unclear whether stress differentially impacts these circuits. METHODS:Mice were exposed to acute restraint stress or chronic restraint stress (CRS), and cfos expression was measured as a proxy for neuronal activation in Retrobead retrogradely labeled dorsomedial prefrontal cortex-targeting PNs (BLA→dmPFC) and non-dmPFC-targeting PNs (BLA↛dmPFC). Next, the effects of CRS on neuronal firing and membrane potassium channel current were examined via ex vivo electrophysiology in these neuronal populations and correlated with anxiety-like behavior, as measured in the elevated plus maze and novel open field tests. Lastly, the ability of virus-mediated overexpression of subtype 2 of small-conductance, calciumactivated potassium (SK2) channel in BLA↛dmPFC PNs to negate the anxiety-related effects of CRS was assessed.RESULTS: BLA→dmPFC PNs were transiently activated after CRS, whereas BLA↛dmPFC showed sustained c-fos expression and augmented firing to external input. CRS led to a loss of SK2 channel-mediated currents in BLA KdmPFC PNs, which correlated with heightened anxietylike behavior. Virus-mediated maintenance of SK2 channel currents in BLA↛dmPFC PNs prevented CRS-induced anxiety-like behavior. Finally, CRS produced persistent activation of BLA

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The role of δ subunit-containing GABA receptor (GABA(δ)R) in fear generalization is uncertain. Here, by using mice with or without genetic deletion of GABA(δ)R and using protocols in which the conditioned tone stimuli were cross presented with different nonconditioned stimuli, we observed that when the two tone stimuli were largely similar, both genotypes froze similarly to either of them. However, when they differed markedly, the knockout mice froze much more than their wild-type littermates to the nonconditioned but not conditioned stimuli. Thus, GABA(δ)R may prevent inappropriate fear generalization when the incoming stimuli differ clearly from the learned threat.