Early-life stress alters affective behaviors in adult mice through persistent activation of CRH-BDNF signaling in the oval bed nucleus of the stria terminalis

Abstract

Early-life stress (ELS) leads to stress-related psychopathology in adulthood. Although dysfunction of corticotropin-releasing hormone (CRH) signaling in the bed nucleus of the stria terminalis (BNST) mediates chronic stress-induced maladaptive affective behaviors that are historically associated with mood disorders such as anxiety and depression, it remains unknown whether ELS affects CRH function in the adult BNST. Here we applied a well-established ELS paradigm (24 h maternal separation (MS) at postnatal day 3) and assessed the effects on CRH signaling and electrophysiology in the oval nucleus of BNST (ovBNST) of adult male mouse offspring. ELS increased maladaptive affective behaviors, and amplified mEPSCs and decreased M-currents (a voltage-gated K+ current critical for stabilizing membrane potential) in ovBNST CRH neurons, suggesting enhanced cellular excitability. Furthermore, ELS increased the numbers of CRH+ and PACAP+ (the pituitary adenylate cyclase-activating polypeptide, an upstream CRH regulator) cells and decreased STEP+ (striatal-enriched protein tyrosine phosphatase, a CRH inhibitor) cells in BNST. Interestingly, ELS also increased BNST brain-derived neurotrophic factor (BDNF) expression, indicating enhanced neuronal plasticity. These electrophysiological and behavioral effects of ELS were reversed by chronic application of the CRHR1-selective antagonist R121919 into ovBNST, but not when BDNF was co-administered. In addition, the neurophysiological effects of BDNF on M-currents and mEPSCs in BNST CRH neurons mimic effects and were abolished by PKC antagonism. Together, our findings indicate that ELS results in a long-lasting activation of CRH signaling in the mouse ovBNST. These data highlight a regulatory role of CRHR1 in the BNST and for BDNF signaling in mediating ELS-induced long-term behavioral changes.

FKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior

“…FKBP51 and the ovBNST play a pivotal role in stress-induced anxiety disorders ( Ising et al, 2008 ; Kang et al, 2012 ; Kim et al, 2013 ; Klengel et al, 2013 ; Scheuer et al, 2016 ; Hu et al, 2020a , b ). However, the precise function of FKBP51 in the ovBNST and its role in anxiety remained unknown.…”

“…Likewise, chronic stress and acute optogenetic activation of the ovBNST increased anxiogenic behaviors ( Hu et al, 2020a ). Moreover, early life stress resulted in a long-lasting activation of CRH signaling in the mouse ovBNST, leading to potential maladaptive changes in ovBNST function in adulthood ( Hu et al, 2020b ). The ovBNST is therefore a promising region with regard to anxiety disorders, since it is strongly involved in mediating anxiety-like behavior.…”

Chronic stress-induced synaptic changes to corticotropin-releasing factor-signaling in the bed nucleus of the stria terminalis

“…Chronic RS leads to neuroplastic changes, including increased BNST volume and dendritic arborization, that facilitate avoidance behavior in male rats ( Vyas et al, 2003 ). Different chronic stress paradigms can also cause upregulation of glutamate ( Dabrowska et al, 2013 ; Hu et al, 2020b ), GABA ( Ventura-Silva et al, 2012 ), and NMDA ( Ventura-Silva et al, 2012 ; Dabrowska et al, 2013 ) receptors in the BNST, altering responses to both excitatory and inhibitory inputs ( Ventura-Silva et al, 2012 ). Both chronic social isolation and chronic corticosterone administration induce long term depression (LTD) in glutamatergic anterolateral BNST neurons and blunt long term potentiation (LTP) in anterodorsolateral BNST neurons ( Conrad et al, 2011 ).…”

“…Neuroplastic changes in the BNST are necessary for fear learning, wherein exposure to sustained or unpredictable aversive stimuli causes changes at the synaptic level ( Conrad et al, 2011 ; Haufler et al, 2013 ; Goode and Maren, 2017 ; Goode et al, 2019 ). Several recent studies have demonstrated synaptic and electrophysiological changes after exposure to chronic stress ( Makino et al, 1994 ; Vyas et al, 2003 ; Forray and Gysling, 2004 ; Hammack et al, 2009 ; McElligott et al, 2010 ; Conrad et al, 2011 ; Ventura-Silva et al, 2012 ; Dabrowska et al, 2013 , 2016 ; Partridge et al, 2016 ; Snyder et al, 2019 ; Hu et al, 2020a , b ). Much of these changes occur within corticotropin-releasing factor (CRF)-expressing neurons.…”

“…The CRF signaling pathway is modulated by upstream regulator pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor PAC1, which regulates avoidant behavior ( Hammack et al, 2009 ; Kocho-Schellenberg et al, 2014 ). Striatal-enriched protein tyrosine phosphatase (STEP) is a known upstream inhibitor of CRF, and is also implicated in the stress-response ( Hammack et al, 2009 ; Hu et al, 2020a , b ).…”