Differential Role of GABAergic and Cholinergic Ventral Pallidal Neurons in Behavioral Despair, Conditioned Fear Memory and Active Coping

Abstract

The ventral pallidum (VP), a core structure of the reward circuit, is well-associated with appetitive behaviors. Recent evidence suggests that this basal forebrain nucleus may have an overarching role in affective processing, including behavioral responses to aversive stimuli. We investigated this possibility by utilizing selective immunotoxin lesions and a series of behavioral tests in adult male Wistar rats. We made bilateral GAT1-Saporin, 192-IgG-Saporin or PBS (vehicle) injections into the VP to respectively eliminate GABAergic and cholinergic neurons, and tested the animals in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), Morris water maze (MWM) and cued fear conditioning. Both GAT1-Saporin and 192-IgG-Saporin injections reduced behavioral despair without altering general locomotor activity. This antidepressant-like effect was accompanied by reduced freezing and increased darting in the acquisition phase of cued fear conditioning. In the test phase, cholinergic, but not GABAergic lesions, impaired context-dependent fear memory, while both groups showed diminished conditioned freezing in a novel context. In line with this, selective cholinergic lesions impaired spatial memory in the MWM as compared to GAT1-Saporin or vehicle-injected animals. No differential effect was observed in anxiety-like behavior assessed in the OFT or EPM. These findings show that both the GABAergic and cholinergic cell groups of the VP contribute to behavioral despair and acquired fear responses by suppressing active coping. In conditioned learning, cholinergic ventral pallidal neurons contribute to the fear response in a context-independent manner, while the GABAergic population is required when the context information is missing. Significance StatementThe ventral pallidum (VP), associated with motivation and appetitive behaviors, is tested for its role in behavioral responses to aversive stimuli. Findings show that both the GABAergic and cholinergic neuronal groups of the VP contribute to behavioral despair and acquired fear response by suppressing active coping. In conditioned learning, the cholinergic neurons are required for the acquired fear response, while the VP GABAergic population becomes necessary only when the context information is missing. These results suggest that ventral pallidal GABAergic and cholinergic projections to the amygdaloid complex may constitute therapeutic targets for affective disorders.