Chemicogenetic Restoration of the Prefrontal Cortex to Amygdala Pathway Ameliorates Stress-Induced Deficits

Corticosteroid stress hormones exert a profound impact on cognitive and emotional processes. Understanding the neuronal circuits that are altered by chronic stress is important for counteracting the detrimental effects of stress in a brain region-and cell type-specific manner. Using the chemogenetic tool, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), which enables the remote, noninvasive and long-lasting modulation of cellular activity and signal transduction in discrete neuronal populations in vivo, we sought to identify the specific pathways that play an essential role in stress responses. We found that prolonged severe stress induced the diminished glutamatergic projection from pyramidal neurons in prefrontal cortex (PFC) to GABAergic interneurons in basolateral amygdala (BLA), leading to the loss of feedforward inhibition and ensuing hyperexcitability of BLA principal neurons, which caused a variety of behavioral abnormalities. Activating PFC pyramidal neurons with hM3D(Gq) DREADD restored the functional connection between PFC and BLA in stressed animals, resulting in the rescue of recognition memory, normalization of locomotor activity and reduction of aggressive behaviors. Inhibiting BLA principal neurons directly with hM4D(Gi) DREADD also blocked BLA hyperactivity and aggressive behaviors in stressed animals. These results have offered an effective avenue to counteract the stress-induced disruption of circuitry homeostasis.