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.
Highlights
Early-life stress (ELS) exposure is a major risk factor for developing psychopathologies in adulthood[1,2,3]
We previously reported that chronic variable mild stress (CVMS) in adult male mice induces maladaptive avoidance behaviors by increasing ovBNST Corticotropin-releasing hormone (CRH) expression[21]; we hypothesized that ELS activates bed nucleus of stria terminalis (BNST) CRH signaling and alters levels of the upstream activator pituitary adenylyl cyclase (AC)-activating peptide (PACAP) (Fig. 2b) and the CRH inhibitor striatalenriched protein tyrosine phosphatase (STEP) (Fig. 2c)
When firing activity of ovBNST CRH neurons was monitored in current-clamp mode, we found KCNQ/Kv7-selective channel blocker XE991 induces robust action potential burst firing after 5–6 min (Fig. 3v), demonstrating a tonic inhibitory role of
Summary
Early-life stress (ELS) exposure is a major risk factor for developing psychopathologies in adulthood[1,2,3]. The bed nucleus of stria terminalis (BNST) connects limbic inputs (amygdala and hippocampus) to the hypothalamus and brain stem, and mediates avoidance behaviors. Corticotropin-releasing hormone (CRH) coordinates the behavioral stress response and is regulated by early-life experiences[6,9,10]. In BNST, the highest concentration of CRH neurons is found in the oval nucleus (ovBNST)[12,13,14], which connects directly to several limbic nuclei and plays an important role in regulating outflow of information from BNST15. BNST CRH neurons, likely through indirect innervation of hypothalamic PVN neurons[16], are thought to modulate stress responses[17,18,19]. ELS affects CRH and induces persistent developmental alterations in the hypothalamus and other areas[22,23,24,25], remarkably little is known about how ELS modulates CRH signaling in BNST
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