Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress.

Neuronal activity in the dorsal hippocampus (dHP) influences how mice cope with inescapable stress, acting through excitatory connections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly activates both dorsal and ventral hippocampi. Suppressing GABAergic transmission in the dHP produces molecular changes similar to ketamine's effects—including dephosphorylation of eEF2, elevation of BDNF, and phosphorylation of ERK—and reduces immobility in tail-suspension and forced swim tests without affecting anxiety. Conversely, enhancing inhibitory transmission in the dHP CA1 region induces passive coping. Chemogenetic activation of dHP-recipient mPFC neurons reverses this passive coping, suggesting the dHP-mPFC circuit modulates stress-coping strategies and contributes to ketamine's antidepressant action.

Study at a glance

Abstract

Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit.