Forebrain glucocorticoid receptor overexpression alters behavioral encoding of hippocampal CA1 pyramidal cells in mice

Abstract

Glucocorticoid signaling influences hippocampal-dependent behavior and vulnerability to stress-related neuropsychiatric disorders. In mice, lifelong overexpression of glucocorticoid receptor (GR) in forebrain excitatory neurons altered exploratory behavior, cognition, and dorsal hippocampal gene expression in adulthood, but whether GR overexpression alters the information encoded by hippocampal neurons is not known. We performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female WT and GR-overexpressing (GRov) mice during exploration of a novel open field, where most CA1 neurons are expected to respond to center location and mobility. Most neurons showed sensitivity to center location and/or mobility based on single-neuron calcium amplitude and event rate, but these sensitivity patterns differed between genotypes. GRov neurons were more likely than WT neurons to display center sensitivity and less likely to display mobility sensitivity. More than one-third of these responsive GRov neurons were sensitive only to center location and not mobility, while uniquely center-sensitive neurons were rare in WT. Most center-sensitive neurons exhibited anticipatory activity, suggesting they could drive behavior. We conclude that, compared to wild type, dorsal CA1 pyramidal cells in GRov mice preferentially respond to center location rather than mobility in a novel open field. Such changes in the information encoded by individual hippocampal neurons in an aversive environment could underlie changes in stress vulnerability due to genetic or epigenetic variations in glucocorticoid receptor signaling.

Significance Statement

Glucocorticoids alter hippocampal-dependent behaviors and vulnerability to stress-related disorders. Here, we find that increased sensitivity to glucocorticoid via lifelong overexpression of glucocorticoid receptor in forebrain neurons (GRov) changes the information encoded by individual hippocampal neurons in a mildly aversive environment, the novel open field. GRov neurons showed heightened sensitivity to center location and lower sensitivity to mobility. These changes in hippocampal neuronal sensitivity could underlie the differences in stress vulnerability in humans with genetic and epigenetic differences in glucocorticoid receptor signaling or excess glucocorticoid exposure during development.