Gonadal steroid hormone receptors in the medial amygdala contribute to experience-dependent changes in stress vulnerability

Cooper, Matthew A.; Clinard, Catherine T.; Dulka, Brooke N.; Grizzell, J. Alex; Loewen, Annie L.; Campbell, Ashley; Adler, Samuel G.

doi:10.1016/j.psyneuen.2021.105249

Cited by 15 publications

(5 citation statements)

References 78 publications

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“…In adult hamsters, dominant males have more androgen receptor expression in the medial amygdala (MEA) than subordinates, and pharmacological inhibition of AR in the MEA of dominant males increases sensitivity to social stress ( 93 ). Similarly, testosterone can exert acute anxiolytic effects in a variety of behavioral assays ( 94 – 96 ).…”

Section: Discussionmentioning

confidence: 99%

Sexual differentiation of neural mechanisms of stress sensitivity during puberty

Wright,

Luo,

Zakharenkov

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice ( Peromyscus californicus ), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

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Section: Discussionmentioning

confidence: 99%

Sexual differentiation of neural mechanisms of stress sensitivity during puberty

Wright,

Luo,

Zakharenkov

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…To understand the underlying mechanisms, preclinical studies are relevant. In animals, task demands can modify the expression of androgen receptors in the amygdala, which further seems to be associated with social behavior [106]. We can only speculate on the sex-sensitive expression of androgen receptors due to environmental demands, although it might be that social and cognitive challenges differently impact the expression of androgen receptors in the central nervous system.…”

Section: Future Directions and Limitationsmentioning

confidence: 94%

“…These sex differences might further be affected by confounding variables such as gender stereotypes [96,101] or time limits [102]. The functional organization of the brain seems to be dynamic, associated with endogenous and exogenous sex hormones (e.g., [103][104][105]), and related to further confounding variables such as stress, social behavior, environment, or genotype [106,107]. Testosterone seems to affect variables such as risk-taking behavior, aggression, and sexuality (e.g., [10,108]), which might further be associated with confounding variables such as socio-economic background.…”

Section: Future Directions and Limitationsmentioning

confidence: 99%

Testosterone and the Amygdala’s Functional Connectivity in Women and Men

Kogler,

Müller,

Moser

et al. 2023

JCM

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The amygdala contains androgen receptors and is involved in various affective and social functions. An interaction between testosterone and the amygdala’s functioning is likely. We investigated the amygdala’s resting-state functional connectivity (rsFC) network in association with testosterone in 94 healthy young adult women and men (final data available for analysis from 42 women and 39 men). Across the whole sample, testosterone was positively associated with the rsFC between the right amygdala and the right middle occipital gyrus, and it further predicted lower agreeableness scores. Significant sex differences appeared for testosterone and the functional connectivity between the right amygdala and the right superior frontal gyrus (SFG), showing higher testosterone levels with lower connectivity in women. Sex further predicted the openness and agreeableness scores. Our results show that testosterone modulates the rsFC between brain areas involved in affective processing and executive functions. The data indicate that the cognitive control of the amygdala via the frontal cortex is dependent on the testosterone levels in a sex-specific manner. Testosterone seems to express sex-specific patterns (1) in networks processing affect and cognition, and (2) in the frontal down-regulation of the amygdala. The sex-specific coupling between the amygdala and the frontal cortex in interaction with the hormone levels may drive sex-specific differences in a variety of behavioral phenomena that are further associated with psychiatric illnesses that show sex-specific prevalence rates.

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“…All of this suggests that mood stands under strong influence of sexual hormones, presumably under the influence of E2. Indeed, there are ERs in the amygdala [236,237] and hippocampus, parts of the limbic system that are well-known for their regulatory roles in emotions. However, the hippocampus is important for spatial memory formation, while the amygdala is also important in social behavior regulating, e.g., pair bonding and dominance through ERα [236,237].…”

Section: Mood Swingsmentioning

confidence: 99%

“…Indeed, there are ERs in the amygdala [236,237] and hippocampus, parts of the limbic system that are well-known for their regulatory roles in emotions. However, the hippocampus is important for spatial memory formation, while the amygdala is also important in social behavior regulating, e.g., pair bonding and dominance through ERα [236,237]. The amygdala was also shown to have non-classical, CREB-related E2 signaling [238].…”

Section: Mood Swingsmentioning

confidence: 99%

Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions

et al. 2022

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Estrogen is one of the most important female sex hormones, and is indispensable for reproduction. However, its role is much wider. Among others, due to its neuroprotective effects, estrogen protects the brain against dementia and complications of traumatic injury. Previously, it was used mainly as a therapeutic option for influencing the menstrual cycle and treating menopausal symptoms. Unfortunately, hormone replacement therapy might be associated with detrimental side effects, such as increased risk of stroke and breast cancer, raising concerns about its safety. Thus, tissue-selective and non-classical estrogen analogues have become the focus of interest. Here, we review the current knowledge about estrogen effects in a broader sense, and the possibility of using selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), phytoestrogens, and activators of non-genomic estrogen-like signaling (ANGELS) molecules as treatment.

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Gonadal steroid hormone receptors in the medial amygdala contribute to experience-dependent changes in stress vulnerability

Cited by 15 publications

References 78 publications

Sexual differentiation of neural mechanisms of stress sensitivity during puberty

Sexual differentiation of neural mechanisms of stress sensitivity during puberty

Testosterone and the Amygdala’s Functional Connectivity in Women and Men

Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions

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