Investigating steroid hormones, neurosteroids, and perineuronal nets in early life adversity-induced changes in hippocampal function

PROJECT DESCRIPTION Early life adversity predisposes individuals to develop anxiety and mood disorders. More women than men have these diagnoses, and times of hormonal change, including puberty, postpartum, and menopause, are associated with increased risk of emotional dysfunction. Neuronal oscillations in the anterior hippocampus of humans are associated with anxiety and memory consolidation. In rodents, neuronal oscillations in the ventral hippocampus (vHIP), considered analogous to the anterior hippocampus, have been linked to avoidance behavior and memory function. The early life adversity paradigm of maternal separation with early weaning (MSEW) alters vHIP neuronal oscillations and behavior in male mice. MSEW also increases expression of vHIP perineuronal nets, extracellular matrix structures that surround inhibitory interneurons and are known to restrict plasticity. Females show similar changes in vHIP function after MSEW, but only in the diestrus stage of the estrous cycle, a time characterized by a relatively high ratio of progesterone to estradiol. In the vHIP, progesterone is converted to the neurosteroid allopregnanolone, which binds to inhibitory GABAA  subunit extrasynaptic receptors, and increases tonic inhibition. During diestrus, MSEW females have higher progesterone to allopregnanolone ratios in the vHIP than control-reared females and blocking progesterone receptors restores MSEW behavior to control levels. The masking of MSEW effects during other stages of the estrous cycle raises questions about protective mechanisms, with estradiol being a potential candidate. The broad, long-term objectives of this proposal are to investigate potential roles for progesterone, allopregnanolone, and estradiol in early life adversity effects on vHIP neuronal oscillations and behavior in both sexes. More specifically, we will use RT-qPCR, in situ hybridization, ELISA, and mass spectrometry to better understand the influence of MSEW on vHIP gene expression and steroid content, as well as pharmacological and viral manipulations of steroids and PNN components in wildtype and transgenic mice. These approaches will be used to assess the underpinnings of MSEW-induced changes in vHIP function using high-resolution confocal imaging of immunolabeled perineuronal nets and GABAA  subunit receptors, in vivo electrophysiology, and behavioral analyses. Taken together, the findings of the proposed experiments will advance our understanding of how steroid hormones and neurosteroids confer vulnerability or protection after early life adversity in female and male mice.