Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice

Abstract

The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period. Here we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN. Mice lacking KCC2 specifically in corticosterone-releasing hormone (CRH) neurons, which govern the activity of the HPA axis (KCC2/Crh mice), exhibit dysregulation of the HPA axis and abnormal postpartum behaviors. Loss of KCC2 specifically in CRH neurons in the PVN is sufficient to reproduce the depression-like phenotype and deficits in maternal behaviors during the postpartum period. Similarly, chemogenetic activation of CRH neurons in the PVN is sufficient to induce abnormal postpartum behaviors and chemogenetic silencing of CRH neurons in the PVN can ameliorate abnormal postpartum behaviors observed in KCC2/Crh mice. This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression.

Hippocampal corticotropin-releasing hormone neurons support recognition memory and modulate hippocampal excitability

“…The CRH-ires-Cre mice are knock-in mice generated in which Cre recombinase expression is driven by endogenous promoter/enhancer elements [ 31 ]. The fidelity of Cre recombinase expression in the BAC CRH-Cre line has recently been questioned [ 28 ], although the reported expression pattern does not match our findings [ 16 , 32 ]. In order to determine whether the BAC CRH-Cre line faithfully targets Cre expression to bona fide hippocampal CRH neurons, we assessed CRH reporter (tdTomato) expression and its colocalization with CRH peptide immunoreactivity in BAC CRH-Cre/Ai9 and CRH-ires-Cre/Ai9 hippocampal sections.…”

Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression

“…We also find psychosocial stressors contribute to the emergence of PPD by interfering with basal and stress-induced peripartum HPA axis adaptations. A recent study found chemogenetic stimulation of PVN CRH neurons to be sufficient to generate deficits in maternal care as well as depressive-like behaviors 89 . Consistent with these findings, our results implicate increased PVN CRH signaling with the emergence of abnormal postpartum behaviors and neuroendocrine function, and further suggest downregulation in PVN nuclear steroid receptors could in part be mediating these effects.…”

Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

“…KCC2 FL mice ( Slc12a5 lox/lox ) were have been described previous and have been backcrossed on the C57BL/6 J mice for 10 generations [ 26 ]. PCR was with an expected product size of 426 bp for wild-type and 543 bp for KCC2 FL mice.…”