Patients with stress-related psychiatric disorders exhibit impairments in cognitive flexibility, a form of executive function mediated by the medial prefrontal cortex (mPFC). Chronic stress in rodents impairs cognitive flexibility performance [1]. Exposure therapy in humans can reverse cognitive deficits and improve several mPFC-mediated symptoms. In rats, extinction of a cued fear conditioning memory reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST). The set-shifting stage of the AST evaluates animals’ ability to shift attention between perceptual stimuli to successfully retrieve a food reward [2].

Our previous work demonstrated that the therapeutic effects of extinction are dependent on the activity of pyramidal neurons in the infralimbic cortex (IL), a subregion of the mPFC that is integral to extinction memory consolidation. Brain-derived neurotrophic factor (BDNF) signaling in the IL during extinction is also necessary to reverse stress-induced cognitive flexibility impairments [1]. However, the circuit mechanisms underlying BDNF-mediated plasticity in the IL during extinction are poorly understood. The ventral hippocampus (vHipp) is vital for extinction memory consolidation, and infusion of BDNF in the vHipp is sufficient to mimic extinction in fear-conditioned rats [3,4,5]. We investigated the role of vHipp input to the IL for the effects of extinction in reversing stress-induced cognitive deficits. Excitatory vHipp input to the IL was silenced using Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. 24 h later, stressed and control rats were tested for cognitive flexibility performance on the AST. Stressed rats exhibited impaired performance, and extinction reversed this effect. Inhibition of vHipp terminals in the IL prevented the beneficial effects of extinction. We previously reported that extinction induces the phosphorylation of the BDNF receptor TrkB at the Y515 site in the IL [1]. This same site is dephosphorylated when vHipp terminals in IL are chemogenetically inhibited during extinction, suggesting that vHipp input to the IL contributes to BDNF signaling during extinction. Therefore, we investigated whether activation of vHipp terminals in the IL (with Gq-DREADDs) is sufficient to reverse stress-induced deficits on cognitive flexibility. Stressed rats received a CNO microinjection in the IL in lieu of extinction, and were tested on the AST 24 h later. Indeed, chemogenetic activation of vHipp terminals in the IL was sufficient to reverse stress-induced cognitive deficits. Finally, we demonstrated that the beneficial effects of vHipp-IL activation were blocked with a local infusion of a neutralizing anti-BDNF antibody in the IL. Our studies suggest that extinction learning in the IL engages long-lasting plasticity processes that reverse the deleterious effects of stress, such as formation of de novo dendritic spines, translation of BDNF-associated proteins, and enhancement of neuronal connectivity. These data demonstrate that the vHipp is not only encoding contextual information during extinction but is modulating IL plasticity that counteracts the effects of chronic stress. Our work denotes the therapeutic potential of enhancing vHipp-IL plasticity for the treatment of stress-related psychiatric illnesses.

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