Sex differences in the hypothalamic–pituitary–adrenal axis’ response to stress: an important role for gonadal hormones

Heck, Ashley L; Handa, Robert J.

doi:10.1038/s41386-018-0167-9

Cited by 318 publications

(229 citation statements)

References 178 publications

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“…The mechanism(s) underlying the relationship observed in the current study between symptom burden and inflammation following SRC are unknown. However, given the strong influence of the neuroendocrine system on inflammation [44][45][46], its role in both brain injury [9,17,[47][48][49] and related symptomology [50][51][52][53] along with the differences in neuroendocrine biology between males and females [54][55][56], it is plausible that the stress-immune axis mediates the relationship between symptoms and inflammation following concussion. The two major arms of the body's stress system, the sympathetic nervous system (SNS) and the hypothalamic pituitary adrenal (HPA) axis can augment the immune system in numerous ways.…”

Section: Discussionmentioning

confidence: 99%

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion

et al. 2020

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Background: Inflammation appears to be an important component of concussion pathophysiology. However, its relationship to symptom burden is unclear. Therefore, the purpose of this study was to evaluate the relationship between symptoms and inflammatory biomarkers measured in the blood of male and female athletes following a sport-related concussion (SRC). Results: Forty athletes (n = 20 male, n = 20 female) from nine interuniversity sport teams at a single institution provided blood samples within one week of an SRC. Twenty inflammatory biomarkers were quantitated by immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms. Partial least squares (PLS) analyses were used to evaluate the relationship(s) between biomarkers and symptoms. In males, a positive correlation between interferon (IFN)-γ and symptom severity was observed following SRC. The relationship between IFN-γ and symptoms was significant among all symptom clusters, with cognitive symptoms displaying the largest effect. In females, a significant negative relationship was observed between symptom severity and cytokines IFN-γ, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO); a positive relationship was observed between symptom severity and MCP-4. Inflammatory mediators were significantly associated with all symptom clusters in females; the somatic symptom cluster displayed the largest effect. Conclusion: These results provide supportive evidence of a divergent relationship between inflammation and symptom burden in male and female athletes following SRC. Future investigations should be cognizant of the potentially sexspecific pathophysiology underlying symptom presentation.

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Section: Discussionmentioning

confidence: 99%

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion

et al. 2020

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“…Glucocorticoids (the "stress hormone"; cortisol in humans and corticosterone in rodents) may also play a role in PV-mediated over-inhibition. Glucocorticoid receptors (GRs) in the PFC help turn down activity in the hypothalamic-pituitary-adrenal (HPA) axis, the stress response that mediates the release of glucocorticoids (Hill et al, 2011;Heck and Handa, 2019;McKlveen et al, 2019). This negative feedback action of glucocorticoids in the PFC may be mediated by inhibitory neurons, according to studies conducted in male rodents.…”

Section: Structural Changes That May Influence Functionmentioning

confidence: 99%

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

Page

Coutellier

2019

Neuroscience & Biobehavioral Reviews

131

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Chronic stress-related emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory γaminobutyric acid (GABA) system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. In this dissertation, I propose and discuss the hypothesis that chronic stress-induced anxiety involves hypoactivity of the PFC due to increased inhibition, mediated in part through increased activity of prefrontal parvalbumin (PV)-expressing inhibitory interneurons. Differing sensitivity of the prefrontal GABAergic system and PV neurons to chronic stress may also underlie sex differences in the prevalence of anxiety disorders, with women presenting with anxiety at higher rates than men. I first present evidence that chronic stress increases the activity of prefrontal PV neurons, and that increased activity of this cell population induces hypoactivity of the PFC. Furthermore, increasing prefrontal PV cell activity using DREADDs (designer receptors exclusively activated by designer drugs) induces anxietylike behaviors specifically in females (Chapter 2). However, acute inhibition of prefrontal PV cells using DREADDs is insufficient to rescue stress-induced anxiety-like behavior, though it does modulate activity and synaptic plasticity in the PFC in a sex

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“…Clear sex- and age-dependent differences in both how the HPA axis responds to stress, and how stress leads to psychiatric disorders have been documented (Bale and Epperson 2015). A consistent trend in animals demonstrates higher and longer-lasting CORT secretion after various stressors in adult females compared to males (Heck and Handa 2018). Sex differences at multiple sites in the HPA axis have been implicated, including pituitary response to ACTH, CRF expression, and glucocorticoid feedback (Bale and Epperson 2015; Heck and Handa 2018).…”

Section: Introductionmentioning

confidence: 84%

“…A consistent trend in animals demonstrates higher and longer-lasting CORT secretion after various stressors in adult females compared to males (Heck and Handa 2018). Sex differences at multiple sites in the HPA axis have been implicated, including pituitary response to ACTH, CRF expression, and glucocorticoid feedback (Bale and Epperson 2015; Heck and Handa 2018). Moreover, women are roughly twice as likely as men to suffer from stress associated disorders such as anxiety, PTSD, and depression (Bangasser and Valentino 2014).…”

Section: Introductionmentioning

confidence: 84%

Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress

Jin

Dickson

Maguire

et al. 2020

Preprint

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ABSTRACTRas-GRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates Ras and Rac GTPases. In hippocampal neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed that GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after exposure to 7-days of restraint-stress (7DRS) (30 min/day) elevation of serum CORT levels are suppressed in early adolescent (EA) female, but not EA male or adult female GRF1 knockdown mice. Here, we show that this phenotype is due, at least in part, to the loss of GRF1 expression in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockdown specifically in these cells also reduces serum CORT response to 7DRS in EA females, but not EA males or adult females. Moreover, it reduces females CORT levels to those to found in comparably stressed control male mice. GRF1 knockdown in CRF cells also blocks the anxiolytic phenotype normally found in EA females 24 hrs after 7DRS. Interestingly, loss of GRF1 in these cells has no effect after only 3 exposures to restraint stress, revealing a role for GRF1 in repeated stress-induced CRF cell plasticity that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response early-adolescent female display to repeated stress.

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Sex differences in the hypothalamic–pituitary–adrenal axis’ response to stress: an important role for gonadal hormones

Cited by 318 publications

References 178 publications

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress

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