Neuropeptide Y mediates the initial hypothalamic–pituitary–adrenal response to maternal separation in the neonatal mouse

Abstract

The function of the hypothalamic-pituitary-adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPYdeficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.

The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder

“…Additionally, treatment with high-dose corticosterone 1 h after stressful exposure reduces the prevalence rate of extreme behavioral disruption 30 days later (Cohen et al, 2008a). These results confirm the bulk of evidence indicating that NPY stimulates the activity of the central branch of the HPA axis, thereby enhancing glucocorticoid secretion from the adrenal cortex during prolonged maternal absence (Schmidt et al, 2008). Furthermore, a recent study in a rat model of depression has evidenced increased BDNF levels in the hypothalamus together with increased systemic levels of adrenocorticotropin hormone and corticotropin-releasing hormone, suggesting a possible role of BDNF in HPA-axis hyper-activation (Naert et al, 2011).…”

Infant maternal separation impairs adult cognitive performance in BALB/cJ mice

“…While postnatal handling dampens HPA responsivity to stress, IMS produces the opposite effect. Rats and mice exposed to IMS show increased levels of adrenocorticotropic hormone (ACTH) and corticosterone in response to an acute stressor (Aisa et al 2007;Schmidt et al 2008), and elevated CRF mRNA levels in the paraventricular nucleus of the hypothalamus in adulthood (Plotsky et al 2005;Aisa et al 2007). IMS also reduces glucocorticoid receptor expression in the hippocampus in rats and mice (Aisa et al 2007;Navailles et al 2010), resulting in less negative feedback onto the HPA axis and increased HPA responsivity to stress.…”

The three-hit concept of vulnerability and resilience: Toward understanding adaptation to early-life adversity outcome

“…For the neonate’s hypo-responsiveness to stressors a lot of factors have been implicated like: adrenal inhibition/insensitivity (Stanton et al, 1988; Chatelain et al, 1989; Walker, 1995; Okimoto et al, 2002), enhanced glucocorticoid receptor (GR) mediated negative feedback (Walker et al, 1986; van Oers et al, 1998a; Schmidt et al, 2005), inhibition of the brain renin-angiotensin system (Muret et al, 1992; Liebl et al, 2009), CRHR1 and CRHR2 receptors functions (Eghbal-Ahmadi et al, 1998; Schmidt et al, 2003b; Fenoglio et al, 2005; Schmidt et al, 2006a), central α 2 adrenoreceptor control of pituitary adrenocorticotropic hormone (ACTH) release (Grino et al, 1994) and central action of metabolic factors (Proulx et al, 2001; Salzmann et al, 2004; Schmidt et al, 2006b; Schmidt et al, 2008) as well as immaturity of the hypothalamus-pituitary connection (Suchecki et al, 1993) Yet, the most proximal cause for the transient hypo-responsiveness to stress is a strongly reduced responsiveness of the adrenals to ACTH (Rosenfeld et al, 1991; Okimoto et al, 2002). In fact, during the SHRP, the central stress response after a challenge does not translate into adrenal corticosterone secretion.…”