Abstract
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.
Highlights
Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders
CORT pellet-treated mice displayed stronger dorsal mPFC (dmPFC)-evoked excitatory postsynaptic current (EPSC), intact inhibitory postsynaptic current (IPSC), and lower I–E ratio in their basolateral amygdala (BLA)→dmPFC PNs relative to the placebo-treated ones. No such differences were observed in dmPFC↔BLA PNs (Supplementary Fig. 6). These results strongly suggest that chronic CORT administration is sufficient to recapitulate the effects of chronic restraint stress (CRS) on dmPFC-to-BLA pathways and the dysregulated dmPFC inputs to dmPFC→BLA PNs may represent a common pathology among mice experiencing prolonged exposure to different stressors
We here show that CRS dysregulates prefrontal control over BLA in a fashion heavily dependent on target cells’ connectivity with PFC
Summary
Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. 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). 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. Lowfrequency 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. We observe that CRS selectively shifts the dmPFC-driven excitatory–inhibitory (E–I) balance toward excitation in dmPFC→BLA but not in dmPFC↔BLA PNs as a consequence of selective increase of presynaptic glutamate release onto the former population. Targeting the altered communication in this pathway may be of translational value for treatment of stress-related psychiatric disorders
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