Long lasting anxiety following early life stress is dependent on glucocorticoid signaling in zebrafish

Abstract

Chronic adversity in early childhood is associated with increased anxiety and a propensity for substance abuse later in adulthood, yet the effects of early life stress (ELS) on brain development remain poorly understood. The zebrafish, Danio rerio, is a powerful model for studying neurodevelopment and stress. Here, we describe a zebrafish model of ELS and identify a role for glucocorticoid signaling during a critical window in development that leads to long-term changes in brain function. Larval fish subjected to chronic stress in early development exhibited increased anxiety-like behavior and elevated glucocorticoid levels later in life. Increased stress-like behavior was only observed when fish were subjected to ELS within a precise time window in early development, revealing a temporal critical window of sensitivity. Moreover, enhanced anxiety-like behavior only emerges after two months post-ELS, revealing a developmentally specified delay in the effects of ELS. ELS leads to increased levels of baseline cortisol, and resulted in a dysregulation of cortisol receptors’ mRNA expression, suggesting long-term effects on cortisol signaling. Together, these findings reveal a ‘critical window’ for ELS to affect developmental reprogramming of the glucocorticoid receptor pathway, resulting in chronic elevated stress.

Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut

“…In addition to its role in regulating the hypothalamic-pituitary-adrenal axis, glucocorticoid also plays an important role in gut development ( Majumdar and Nielsen, 1985 ). Together, the data presented in this study is concordant with existing literature highlighting the importance of ELS-associated glucocorticoid signaling in the CNS ( Chin et al, 2022 ) and suggests that nr3c1 modulation may also play an important role in the developmental programming of the ‘stress-informed’ gut.…”

“…Though zebrafish are a validated model to study the physiological effects of ELS, most studies have been limited to the embryonic or early larval period, or prolonged stressors are only applied for a relatively short duration of time (2–7 days in duration) ( Golla et al, 2020 ; Chin et al, 2022 ; Marcon et al, 2018 ). To determine the impact of chronic ELS throughout larval development we introduced environmental stressors to wild-type AB zebrafish beginning at 6 dpf and terminating after either 1 week, at 30 dpf, or at 30dpf and followed by a 7d washout ( Fig.…”

“…In contrast, nr3c1 expression was significantly downregulated in the gut following 1 week of ELS that was only moderately increased after ELS until 30dpf. Numerous studies indicate that aberrant modulation of glucocorticoid receptor gene nr3c1 is involved in the pathophysiological processes associated with ELS ( Palma-Gudiel et al, 2015 ; Holmes et al, 2019 ; McGowan et al, 2009 ) and recent work in a different zebrafish ELS model highlights the conservation of this important stress-response pathway ( Chin et al, 2022 ). In addition to its role in regulating the hypothalamic-pituitary-adrenal axis, glucocorticoid also plays an important role in gut development ( Majumdar and Nielsen, 1985 ).…”

The anti-platelet drug cilostazol enhances heart rate and interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

“…Early life stress in the form of childhood adversity is linked to epigenetic regulation of glucocorticoid receptor in the brain, as well as altered neuronal gene expressions due to sustained DNA hypomethylation [ 83 , 84 ]. In the zebrafish, long lasting anxiety following early life stress is mediated by cortisol and glucocorticoid signaling [ 85 ]. The studies above suggest that the hyperactivated glucocorticoid signaling during early life causes persistent effects on the neuronal as well as immune functions lasting to adulthood.…”

The anti-platelet drug cilostazol enhances interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

“…Early life stress in the form of childhood adversity is linked to epigenetic regulation of glucocorticoid receptor in the brain, as well as altered neuronal gene expressions due to sustained DNA hypomethylation [71, 72]. In the zebrafish, long lasting anxiety following early life stress is mediated by cortisol and glucocorticoid signaling [73]. The studies above suggest that the hyperactivated glucocorticoid signaling during early life causes persistent effects on the neuronal as well as immune functions lasting to adulthood.…”