Sex and Estrous Cycle Effects on Anxiety- and Depression-Related Phenotypes in a Two-Hit Developmental Stress Model

Abstract

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c , that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.

CACNA1C Gene rs11832738 Polymorphism Influences Depression Severity by Modulating Spontaneous Activity in the Right Middle Frontal Gyrus in Patients With Major Depressive Disorder

“…This channel is found in many types of cells, regulating the activity-dependent influx of calcium and is important for the normal functioning of the heart and brain cells (12). Evidence from animal studies, clinical studies, and genome-wide association studies supports the findings that CACNA1C is closely associated with depression (3,13).…”

“…Major depressive disorder (MDD) is a highly prevalent psychological condition characterized by a persistent low mood and anhedonia (1). The lifetime prevalence of MDD is approximately 17% (2), affecting approximately 350 million people worldwide (3,4). According to recent data from 2019, the lifetime prevalence of MDD in China is as high as 3.4%, and it is estimated that approximately 44 million people suffer from this disease (5).…”

Epigenetic Mechanisms in the Neurodevelopmental Theory of Depression

“…Early childhood experiences associated with severe stressors (considered a risk factor for depression in adult life) are linked with modifications in gene expression [14,15]. Changes in the scope of gene expression affect genes involved in response to stress (hypothalamic-pituitaryadrenal axis, HPA), related to autonomic nervous system hyperactivity and cortical and subcortical processes of neuroplasticity and neurodegeneration [3], including among other genes encoding the glucocorticoid receptor, FK506binding protein 5 (FKBP5) [16], arginine vasopressin and oestrogen receptor alpha, 5-hydroxytryptamine transporter gene (SLC6A4) [17], and brain-derived neurotrophic factors [18][19][20].…”

A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior

“…Isolation paradigms have also been utilized after postnatal development to elicit behavioral disruption later in life (see review : Fone & Porkess, 2008). While social isolation (SI) has often been employed to induce adversity throughout life after weaning (Lapiz et al, 2003;Liu et al, 2019;Möller et al, 2013a;Schiavone et al, 2009), few studies report SI during discrete developmental time points, such as juvenility (Bicks et al, 2020;Pietropaolo et al, 2008) or different periods of adolescence (Jaric et al, 2019;Li et al, 2018). Evidence regarding sex-dependent effects of SI is also sparse, with inconsistent effects on anxiety-like behavior in males and females (Pietropaolo et al, 2008;Rodgers & Cole, 1993).…”

“…Evidence regarding sex-dependent effects of SI is also sparse, with inconsistent effects on anxiety-like behavior in males and females (Pietropaolo et al, 2008;Rodgers & Cole, 1993). Notably, early life adversity paradigms are often combined to assess the additive effects of multiple adverse experiences throughout development (Castillo-Gómez et al, 2017;Deslauriers et al, 2013;Jaric et al, 2019;Monte et al, 2017;Rincel et al, 2019). Some evidence suggests that there are sex-specific effects of multiple hits of developmental stressors on later-life anxiety-like behavior, working memory, and social behavior (Hudson et al, 2014;Monte et al, 2017;Rincel et al, 2019); however, a dearth of information remains regarding the potential neuroplastic mediators underlying sex-specific effects of multiple behavioral stressors on anxiety-like behavior.…”