Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis

Eachus, Helen; Choi, Min K; Tochwin, Anna; Kaspareit, Johanna; Ho, May; Ryu, Soojin

doi:10.1101/2023.01.27.525966

Cited by 3 publications

(10 citation statements)

References 81 publications

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“…Table 2). Indeed, we confirmed alteration of neurogenesis in larval bPAC+ fish 18 . Together these results indicate dysregulation of normal developmental processes in bPAC+ brains in early life coupled with potential genomic instability, replication stress 27 , and delayed or immature differentiation of neuronal cells.…”

Section: Distinct Transcriptional Alterations In Bpac+ Fish Across Th...supporting

confidence: 75%

“…Brain-wide analyses using qPCR and immunohistochemistry confirmed alteration of neurogenesis in larval bPAC+ fish. These results are reported in detail in a separate report 39 . During larval stages, downregulated DEGs were also enriched in anatomical structure formation, muscle structure development, vasculature development, external encapsulating structure organization, and more.…”

Section: Developmental Gc Exposure Leads To Downregulation Of Transcr...mentioning

confidence: 67%

“…1a). Firstly, we used our previously reported optogenetic transgenic model Tg(star:bPAC-2A-tdTomato) where the elevation of endogenous cortisol (GC in fish) is induced by blue light which activates beggiatoa Photoactivated Adenylyl Cyclase (bPAC), expressed specifically in steroidogenic interrenal cells [16][17][18] (Fig. 1b).…”

Section: Double-hit Zebrafish Stress Model Exhibit Altered Adulthood ...mentioning

confidence: 99%

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Lifelong molecular consequences of high Glucocorticoids exposure during development

Choi

Cook

Eachus

et al. 2023

Preprint

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Chronic or severe stress exposure during development primes an individual for altered stress sensitivity in adulthood and increases psychiatric disease susceptibility. However, the identity and function of genes affected by developmental stress exposure are poorly understood. Here, we used an optogenetic zebrafish model to identify brain-wide molecular alterations caused by chronic Glucocorticoid (GC) exposure during development and following subsequent exposure to an acute stressor in adulthood. We show that developmental GC-exposed fish display wide-ranging behavioral changes affecting social behavior, food consumption, and associative learning. The brain transcriptome of GC-exposed fish showed alteration of genes associated with DNA metabolism, axon development, and social behavior-related genes such as oxytocin across the life course. Strikingly, when GC-exposed fish were subjected to a stress challenge in adulthood, they showed exaggerated endocrine responses and a great number of brain-wide transcriptional changes, including gene sets associated with axon development, neuronal signaling, and epigenetic modulators. These altered gene sets showed an overrepresentation of genes linked to human psychiatric disorders. In short, our study provides a unique resource of long-term, time-dependent gene expression changes induced by developmental GC-exposure and identifies novel GC-primed genes which may shape adult responses of early life stress-exposed individuals.

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Section: Distinct Transcriptional Alterations In Bpac+ Fish Across Th...supporting

confidence: 75%

Section: Developmental Gc Exposure Leads To Downregulation Of Transcr...mentioning

confidence: 67%

Section: Double-hit Zebrafish Stress Model Exhibit Altered Adulthood ...mentioning

confidence: 99%

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Lifelong molecular consequences of high Glucocorticoids exposure during development

Choi

Cook

Eachus

et al. 2023

Preprint

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“…Our recent work analysed the effects of developmental GC exposure on neurogenesis in an optogenetic zebrafish model ( Eachus et al, 2023a preprint). We observed a striking brain-region-specific effect of GC on cell proliferation that was restricted to the developing hypothalamus.…”

Section: Where Is the Tipping Point?mentioning

confidence: 99%

“…Allostatic overload may manifest via accelerated aging, reduced longevity and behavioural disorders in later life. Figure adapted from Eachus et al (2023a preprint) .…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload

Eachus,

Ryu

2024

Journal of Experimental Biology

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Exposure to stress during early life may alter the developmental trajectory of an animal by a mechanism known as adaptive plasticity. For example, to enhance reproductive success in an adverse environment, it is known that animals accelerate their growth during development. However, these short-term fitness benefits are often associated with reduced longevity, a phenomenon known as the growth rate–lifespan trade-off. In humans, early life stress exposure compromises health later in life and increases disease susceptibility. Glucocorticoids (GCs) are major stress hormones implicated in these processes. This Review discusses the evidence for GC-mediated adaptive plasticity in development, leading to allostatic overload in later life. We focus on GC-induced effects on brain structure and function, including neurogenesis; highlight the need for longitudinal studies; and discuss approaches to identify molecular mechanisms mediating GC-induced alteration of the brain developmental trajectory leading to adult dysfunctions. Further understanding of how stress and GC exposure can alter developmental trajectories at the molecular and cellular level is of critical importance to reduce the burden of mental and physical ill health across the life course.

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Optogenetic induction of chronic glucocorticoid exposure in early‐life leads to blunted stress‐response in larval zebrafish

Nagpal,

Eachus,

Lityagina

et al. 2024

Eur J of Neuroscience

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Early life stress (ELS) exposure alters stress susceptibility in later life and affects vulnerability to stress‐related disorders, but how ELS changes the long‐lasting responsiveness of the stress system is not well understood. Zebrafish provides an opportunity to study conserved mechanisms underlying the development and function of the stress response that is regulated largely by the neuroendocrine hypothalamus–pituitary–adrenal/interrenal (HPA/I) axis, with glucocorticoids (GC) as the final effector. In this study, we established a method to chronically elevate endogenous GC levels during early life in larval zebrafish. To this end, we employed an optogenetic actuator, beggiatoa photoactivated adenylyl cyclase, specifically expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute‐stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress–response was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (pomc)‐expression in the pituitary as well as upregulation of fkbp5 gene expression. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of the HPA/I axis by early‐life GC exposure and its implications for vulnerability and resilience to stress in adulthood.

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Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis

Cited by 3 publications

References 81 publications

Lifelong molecular consequences of high Glucocorticoids exposure during development

Lifelong molecular consequences of high Glucocorticoids exposure during development

Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload

Optogenetic induction of chronic glucocorticoid exposure in early‐life leads to blunted stress‐response in larval zebrafish

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