Dexamethasone induces apoptosis in the developing rat amygdala in an age-, region-, and sex-specific manner

Abstract

Exposure to glucocorticoids (GCs) in early development can lead to long-term changes in brain function and behavior although little is known about the underlying neural mechanisms. Perinatal exposure to GCs alters adult anxiety and neuroendocrine responses to stress. Therefore, we investigated the effects of either late gestational or neonatal exposure to the GC receptor agonist dexamethasone (DEX), on apoptosis within the amygdala, a region critical for emotional regulation. DEX was administered to timed-pregnant rat dams from gestational day 18 until parturition, or postnatal day 4-6. Offspring were sacrificed the day following the last DEX treatment and tissue was processed for immunohistochemical detection of cleaved caspase-3, a marker for apoptotic cells. Prenatal DEX treatment significantly increased the number of cleaved caspase-3 positive cells in the amygdala of both sexes, largely due to increases within the medial and basomedial sub-regions. Postnatal DEX treatment also increased cleaved caspase-3 immunoreactivity within the amygdala, although effects reached significance only in the central nucleus of females. Overall, DEX induction of cleaved caspase-3 in the amygdala was greater following prenatal compared to postnatal treatment, yet in both instances elevations in cleaved caspase-3 correlated with an increase in pro-apoptotic Bax mRNA expression. Dual-label immunohistochemistry of cleaved caspase-3 and the neuronal marker NeuN confirmed that virtually all cleaved caspase-3 positive cells in the amygdala were neurons and a subset of these cells (primarily following postnatal treatment) expressed a GABAergic calcium binding protein phenotype (calbindin or calretinin). Together these results indicate that early developmental GC exposure induces neuronal apoptosis within the amygdala in an age, sex, and region dependent manner.

RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats

“…While the precise mechanism remains unknown, strong evidence has been obtained for glucocorticoid-induced changes in the brain [15]. Several studies have been undertaken to understand impaired glucocorticoid signaling and glucocorticoid associated neurotoxicity [16, 17].…”

Human milk cortisol is associated with infant temperament

“…Additionally, there is some evidence that male and female fetuses are differentially affected by prenatal cortisol exposures (DiPietro et al, 2009; Clifton, 2010; Glynn & Sandman, in press), and that these differential sensitivities may extend into the postnatal period (Zuloaga et al, in press). It also is possible that enhanced sensitivity to GC exposures in females during early life may help illuminate underlying causes of the increased vulnerability to and prevalence of certain psychiatric disorders among females later in life (Jacobi et al, 2004; Hyde et al, 2008; McLean & Anderson, 2009).…”

Sex-dependent programming effects of prenatal glucocorticoid treatment on the developing serotonin system and stress-related behaviors in adulthood

“…Adult females develop anxiety- and depressive- like behaviors following maternal stress (Fride and Weinstock, 1988, Alonso et al, 1991, Keshet and Weinstock, 1995, Vallee et al, 1997, Frye and Wawrzycki, 2003, Richardson et al, 2006, Zagron and Weinstock, 2006) or overexposure to glucocorticoids (GC) (Welberg et al, 2001, Oliveira et al, 2006, Zagron and Weinstock, 2006, Nagano et al, 2008). Prenatal stress and overexposure to GC also have been shown to have a variety of sex-specific impacts on brain regions thought to be involved in stress regulation, such as the hypothalamus, amygdala, and frontal cortex (Tobe et al, 2005, Murmu et al, 2006, Zuloaga et al, 2011, Carbone et al, 2012, Zuloaga et al, 2012). These data, if applicable to the human condition, imply that developmental overexposure to GC alters brain programming in a sex selective manner, resulting in increased risk in females for developing anxiety or depressive disorder in adulthood.…”