GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

Gilfarb, Rachel A.; Leuner, Benedetta

doi:10.3389/fnbeh.2022.802530

Cited by 17 publications

(8 citation statements)

References 188 publications

(380 reference statements)

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“…Potential biological mechanisms underlying hormonalassociated fluctuations in anxiety that have been examined in female rats and humans include oestradiol and the oestrogen receptors [78,79], the progesterone metabolite allopregnanolone and its actions on the GABAergic system [80,81] and the neurotransmitter serotonin [82]. However, the mechanisms remain understudied, and the mechanisms contributing to individual variance in menstrual fluctuations in anxiety are unknown and are difficult, time-intensive and costly to examine in humans.…”

Section: Oestrous Fluctuations In Anxiety-like Behaviour In Female Ratsmentioning

confidence: 99%

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Pestana

Islam

Eyk

et al. 2022

Curr Psychiatry Rep

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Purpose of Review Anxiety symptoms increase during the peri-menstrual phase of the menstrual cycle in people with anxiety disorders. Whether this reflects a heightened variant of normal menstrual-related changes in psychological states experienced by healthy (i.e. non-anxious) people is unknown. Moreover, menstrual-related change in anxiety symptoms is a poorly understood phenomenon, highlighting a need for pre-clinical models to aid mechanistic discovery. Here, we review recent evidence for menstrual effects on anxiety-like features in healthy humans as a counterpart to recent reviews that have focused on clinically anxious populations. We appraise the utility of rodent models to identify mechanisms of menstrual effects on anxiety and offer suggestions to harmonise methodological practices across species to advance knowledge in this field. Recent Findings Consistent with reports in clinical populations, some evidence indicates anxiety symptoms increase during the peri-menstrual period in healthy people, although null results have been reported, and these effects are heterogeneous across studies and individuals. Studies in rats show robust increases in anxiety during analogous phases of the oestrous cycle. Summary Studies in female rats are useful to identify the evolutionarily conserved biological mechanisms of menstrual-related changes in anxiety. Future experimental approaches in rats should model the heterogeneity observed in human studies to increase alignment across species and advance understanding of the individual factors that increase the propensity to experience menstrual-related changes in anxiety.

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Section: Oestrous Fluctuations In Anxiety-like Behaviour In Female Ratsmentioning

confidence: 99%

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Pestana

Islam

Eyk

et al. 2022

Curr Psychiatry Rep

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“…Also, GABA is negatively correlated with human neural activity in functional MRI (Kiemes et al, 2021; Gao et al, 2013) which is consistent with our findings of increased GABA abundance with increased age. We also observed decreased estrogen signaling with age, which has been associated with cognitive decline (reviewed in Friedman and Robbins 2022) and modulates dopamine (Shanmugan and Epperson 2014) and GABA (Gilfarb and Leuner 2022) function. Proteins and metabolites in these pathways were of particular interest, providing multi-level molecular data on key signaling steps and pathway read outs, respectively.…”

Section: Discussionmentioning

confidence: 69%

Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders

Cox

Puppala

Chan

et al. 2022

Preprint

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The prefrontal cortex (PFC) is central to working memory, temporal processing, decision making, flexibility, and goal-oriented behavior, and has been implicated as a key brain region responsible for age-related cognitive decline. Although studies in humans and multiple nonhuman primate (NHP) species have shown reduction of PFC activity associated with cognitive decline, little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods and integrated analyses to determine PFC molecular changes across the adult age span in healthy primates. The goal of this study was to quantify PFC molecular changes associated with healthy aging in female baboons (Papio), a NHP model of aging, by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data, revealed 2 modules containing 587 transcripts and 13 proteins negatively correlated with age. In addition, we identified an additional 57 proteins and 20 metabolites associated with age using regression analyses. Pathway enrichment analysis revealed 25 overlapping, coordinated pathways negatively correlated with age. We identified pathways previously associated with PFC aging such as dopamine-DARPP32 feedback in cAMP signaling, and additional pathways not previously associated with aging-related PFC changes such as nitric oxide signaling. In addition, we found GABA associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.

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“…Women have a higher prevalence of stress-related disorders, including major depressive disorder and anxiety, and hormonal fluctuations associated with reproductive function may account for this increased vulnerability to stress-related disorders, beginning with a heightened risk of developing a depressive episode during adolescence [ 62 ]. Indeed, an increased prevalence of these disorders is observed during hormonal variations occurring at puberty, the premenstrual period, pregnancy, postpartum and perimenopause [ 1 , 63 , 64 ]. In addition, the hormonal milieu in women is further influenced by administration of exogenous steroids such as those in the hormonal contraceptive formulations [ 22 , 65 ].…”

Section: Allopregnanolone Levels Following Acute Stress In Womenmentioning

confidence: 99%

The Allopregnanolone Response to Acute Stress in Females: Preclinical and Clinical Studies

et al. 2022

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The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women.

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GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

Cited by 17 publications

References 188 publications

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders

The Allopregnanolone Response to Acute Stress in Females: Preclinical and Clinical Studies

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