Gender and Puberty Interact on the Stress-Induced Activation of Parvocellular Neurosecretory Neurons and Corticotropin-Releasing Hormone Messenger Ribonucleic Acid Expression in the Rat

“Androgens and estrogen modulate cortisol synthesis in the adrenal cortex and CRH and AVP synthesis in the hypothalamus; the latter effect is mediated by sex hormone receptors in the amygdala (Viau, 2002; Viau et al., 2005).”

“In the PVN, neuronal activation following numerous stressors, as measured by the expression of immediate early genes such as c-Fos, is greater in females [6, 40, 45].”

“Similarly, the stressinduced activity of CRH neurons in the prepubertal PVN is greater than that of adults, demonstrating that the prolonged prepubertal pattern of corticosterone and ACTH may be driven by increased hypothalamic CRH synthesis (Romeo et al., 2004b; Viau et al., 2005) and altered by the onset of male pub…”

“Activation of the stress response and of PVN neurons is reported to be higher in females than males (Larkin et al., 2010; Seale et al., 2004; Viau et al., 2005), and this could be due to variations in estradiol levels that occur across the estrous cycle of females (Iwasaki-Sekino et al.”

“Hypothalamic CRF expression is greater in female humans and rodents, and certain stressors increase hypothalamic CRF exclusively in females (42-45).”

“in total corticosterone is paralleled by greater levels of ACTH in females following stress, as seen in numerous studies using psychological and physiological stressors (167, 199, 307, 309, 334, 381).”

“brain regions, including the paraventricular hypothalamic nucleus, but also the CE and BNST [105, 176, 347, 365].”

“In response to acute stress, we found the prepubertal PVN has a greater number of FOS-ir cells immediately after the 30-min session of restraint stress compared with adults, replicating a recent observation by Viau and colleagues (21).”

“…after a stressor is limited primarily to the PVN in adolescents and is more widespread in adults (Kellogg, Awatramani, & Piekut, 1998), and Fos and AVP expression is increased more rapidly in the PVN of pre-pubertal adolescents compared to adults (Romeo, Bellani et al., 2006; Viau et al., 2005).”

“Moreover, although basal CRH mRNA in the PVN is higher in prepubertal compared to adult rats [107], stress results in elevated CRH expression at both ages [64,107,138].”

“…RNA in the PVN is higher prepubertally in males (Romeo et al., 007; Viau et al., 2005); lower baseline corticosterone and CRH RNA in prepubertal females (Viau et al., 2005); greater expresion of adrenal melanocortin 2 receptor accessory protein mRNA n prepubertal males (Romeo et al., 2014)).”

“It is tempting to suggest that these differences may reflect sex differences in HPA axis regulation (Handa et al., 1994; Toufexis & Wilson, 2012; Viau et al., 2005), and in how HPA axis responses are modified by dietary environment.”

“Adolescent males have greater CRF mRNA expression in the PVN, while the opposite was reported in adolescent females (Romeo et al. 2007; Viau et al. 2005).”

“Prior to puberty, when testosterone levels are low, the corticosterone response to acute and chronic stress is high relative to the response seen after puberty (Viau et al. 2005, Romeo et al. 2006) which corresponds to elevations in testosterone that occur during the pubertal transition of males.”

“These findings are in agreement with the previously reported enhancement of acute restraint stress-induced CORT response in adult females relative to their younger counterparts [78], although such age differences among females are not ubiquitous [15].”

“some to be elevated in the central nucleus of the amygdala in female relative to male rats [95], although this sex difference is not always observed [96].”

“…adolescent male and female rats show prolonged corticosterone release in response to a stressor compared to adult rats (Romeo et al., 2004a,b; Viau et al., 2005; Romeo and McEwen, 2006) and adolescent male rats do not habituate to chronic stressors unlike adult rats who eventually show a…”

“Specifically, basal (i.e., unstressed) levels of the glucocorticoid, corticosterone, are elevated in female compared to male rats (Kitay 1961; Viau et al. 2005; Weinstock et al. 1998).”

“…than that on the adult (Goldman et al. 1973), while others have shown greater post-stress activation of the paraventricular nucleus of the hypothalamus, the brain region integral in initiating this hormonal cascade, and in prepubertal compared to adult rats (Viau et al. 2005, Romeo et al. 2006a).”

“For example, compared with males, female rodents have greater HPA axis activation and subsequent higher levels of glucocorticoids (Bangasser, 2013; Kitay, 1961; Viau et al., 2005; Weinstock et al., 1998), a state that is thought to cause anxiety.”

“logical stressors, and females show a higher average concentration of glucocorticoids than males (Viau et al., 2005).”

“At baseline, female rodents display a more active HPA axis than their male counterparts, as well as higher circulating levels of corticosterone (Kitay, 1961; Viau et al., 2005; Weinstock et al., 1998).”

“Higher levels of ACTH were also observed at the peak (not basal levels) in cycling rat females in proestrus compared to estrous and di-estrus (Viau and Meaney, 1991).”

“In female rats, higher levels of CRF mRNA in the paraventricular nucleus are reported that associate with the estrous cycle (276, 277) and are reviewed elsewhere (274).”

“…in this study, the region of interest we analyzed in the mpdPVN here is where all CRH neurosecretory cells are amassed (Viau and Sawchenko, 2002; Viau et al, 2005) suggesting that a suppression of stress-induced activation of CRH neurosecretory cells is likely mediating the effect of…”

“One such mechanism is greater CRF expression in the hypothalamus of female compared to male rodents, which can translate into greater HPA axis activation [91-94,197].”

“Moreover, although basal CRH mRNA in the PVN is slightly higher in pre-adolescent versus adult rats (Romeo et al., 2007b), stress results in elevated CRH expression at both ages (McCormick et al., 2007; Romeo et al., 2007b; Viau et al., 2005).”

“In the PVN, there are several reports that female rats had greater CRF expression than males (Duncko, Kiss, Skultetyova, Rusnak, & Jezova, 2001; Viau et al., 2005), although this difference was not found in every rat study or with the Crh‐IRES‐Cre::Ai14 (tdTomato) reporter mouse (Sterrenburg et al.”

“Our findings also complement preclinical studies revealing the emergence over adolescence/puberty of increases in female basal corticosterone levels, with corresponding decreases observed among males, as well as of increases in adrenal weight and adrenal corticosterone content among females alone (Critchlow et al., 19…”

“The differential activation of the HPA axis in male and female rodents is primarily a consequence of differential exposure to testosterone and estradiol (37).”

“…and baseline corticotropin-releasing factor expression, have been associated with the rapid change in stress responsivity, suggesting that puberty stimulates a wholesale change in the regulation of the HPA axis (Goldman et al., 1973; Lui et al., 2012; Romeo et al., 2005; 2007; Viau et al., 2005).”

“For example, stress enhances corticotropin-releasing factor (CRF), ACTH, and corticosterone more in female than male rats [41, 47, 48], but when surgical adrenalectomy is performed in female rats, and corticosterone is substituted, resulting in stable corticosterone levels, females continue to…”

“Moreover, basal expression of CRH in the PVN appears to be higher in male rats prior to puberty (Romeo et al., 2007b), though the opposite trend has been noted in females (Viau et al., 2005).”

“21 Stress-induced CORT responses then decrease again in adulthood in rodents (Romeo, 2010b), 22 although not all results are consistent with this pattern across ages (e.g., Viau et al., 2005).”

“Puberty is accompanied by dynamic changes in circulating adrenal and gonadal steroids in males and females, which contribute to the organisation and maturation of the HPA axis (Viau et al., 2005).”

“The PVN was analyzed because previous reports indicated that the parv portion of the PVN displays differential neural activation in prepubertal and adult male rats following acute or homotypic stress paradigms [24,27].”

“…is thought to mediate anxiety in the EPM (Koob et al., 1993; Shepard et al., 2000), whereas CRF release in the hypothalamus stimulates the HPA axis cascade, leading to peripheral corticosterone release in a process affected by interindividual variation in testosterone levels (Viau et al., 2005).”

“being said, there are several maturational changes that occur during puberty due to changes in gonadal hormones, such as changes in HPA axis function (Viau et al., 2005; Evuarherhe et al., 2009), that could in turn impact the regulation of CB1 receptor densities by stress during these different developmental periods.”

“stress-induced HPA axis hormone release following a variety of stressors compared to males (Aloisi et al., 1994, 1998; Babb et al., 2013a; Drossopoulou et al., 2004; Handa et al., 1994; Heinsbroek et al., 1991; Larkin et al., 2010; Le Mevel et al., 1978; Livezey et al., 1985; Ogilvie & Rivier, 1997; Seale et al., 2004…”

“…there are reports of greater corticosterone release in response to 30 min of restraint in prepubertal than in adult females (Romeo et al., 2004b; Viau et al., 2005), and a report of reduced corticosterone release at 15 and 30 min into a 90 min restraint session compared with adult females…”

“We and others find a greater number of FOS-positive cells in the PVN of stressed pre-adolescent animals compared to adults in response to either a single (Viau et al., 2005; Romeo et al., 2006a; Lui et al., 2012) or repeated exposure to restraint stress (Romeo et al.”

“…response, the simplest explanation is that in these studies, LHPA activity is modulated by hormonal status, as has been seen in rodents (Viau, 2002; Viau et al., 2001, 2005), monkeys (Stavisky et al., 2003; Wilson et al., 2005; Wood et al., 2004), and women (Burleson et al., 1998; Gudmundsson et…”

“Our results showed that females produce greater basal levels of ACTH and both basal and stress-induced levels of CORT compared to males, as previously observed (Goel and Bale, 2008; Handa et al., 1994; Viau et al., 2005).”

“Estrogenic regulation of the HPA axis has also been consistently associated with alterations in medial parvocellular recruitment and anterior pituitary output (Dayas et al., 2000; Lund et al., 2004; Viau et al., 2005; but see Figueiredo et al., 2002).”

“Sex-dependent effects of corticotropinreleasing factor Preclinical studies have also shown that female rodents have higher basal levels of the glucocorticoid, corticosterone, than males (Weinstock et al., 1998; Viau et al., 2005).”

“The precise molecular mechanisms of gonadal hormone action on the HPA axis are yet to be identified, but female rats have a higher basal level of CRF mRNA in the PVN than do males (Duncko et al., 2001; Viau et al., 2005).”

“It has been shown previously that circulating glucocorticoid levels are higher in females than males under resting conditions [29].”

“Under non-BPA conditions, stress typically generates greater CORT release for a longer time period in female rather than male rodents (Handa et al., 1994a; Iwasaki-Sekino et al., 2009; Kitay, 1961; Viau et al., 2005).”

“…gene and its protein counterpart, Fos, within the PVN and several putative central regula- tors of the HPA axis (Da Costa et al., 1996; Kerr et al., 1996; Cheung et al., 1997; Nappi et al., 1997; Rachman et al., 1998; Figueiredo et al., 2002; Ceccarelli et al., 2003, 2006; Viau et al., 2003, 2005).”

“…adrenal GC secretion is greater in females than in males (Kitay 1963, Critchlow et al, 1963, Handa et al, 1994a) and stimulation of the hypophysiotrophic stress response and PVN neuron activation are correspondingly higher in females (Larkin et al, 2010, Seale et al, 2004, Viau et al, 2005).”

“Prior to puberty, when T levels are low, the CORT response to acute and chronic stress is high relative to the response seen after puberty (Viau et al., 2005; Romeo and McEwen, 2006; Follib et al., 2011).”

“Along similar lines, female rodents display larger increases in corticosterone secretion (Goel et al., 2014; Viau et al., 2005), and use different behavioral strategies than males in response to a variety of challenges (Goel et al.”

“…including foot- or tail-shock (Bland et al., 2005; Heinsbroek et al., 1991; Rivier, 1991), neonatal handling (Panagiotaropoulous et al., 2004), restraint (Aloisi et al., 1994; 1998; Babb et al., 2013; Le Mevel et al., 1979; Viau et al., 2005), and immune challenge (Seale et al., 2004a, b).”

“T has also been shown to reduce activation of the hypothalamic–pituitary– adrenal (HPA) axis in rats, providing yet another possible mechanism whereby T reduces indices of anxiety (Meaney et al., 1993; Viau and Meaney, 1996; Viau et al., 2001, 2005; Viau, 2002).”