Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks

Abstract

The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments.

Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway

“…GR is a potential drug target for AD, but it is ubiquitous, and its effect on large scale neuronal networks remains poorly understood [ 26 ]. For instance, the response to cortisol enhanced the excitability of memory allocated cells compared to the non-responders with respect to encoding and recall [ 35 ].…”

“…Disruption of the BDNF-dependent p-GR sites in mice preserved cortisol-induced phosphorylation, and impaired synaptic plasticity in task-activated neurons [ 2 ]. Deletion of the activity-dependent GR pathway is distinct from a complete loss-of-function [ 26 ]. Importantly, the impact of disrupting neurotrophin-dependent p-GR on age-related cognitive decline and in relevant animal models of AD remains unknown.…”

Possibilities of therapeutic action of cannabinoids in neurodegenerative diseases

“…These diseases also include pathological protein accumulation (e.g. tau proteins), impairment of the lysosomal system, excitotoxicity, oxidative stress (Huzard et al, 2021), and inflammatory features of the nervous system.…”

Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial

“…Moreover, ultradian rhythmicity differentially regulates steroid-sensitive gene expression patterns in the hippocampus ( Conway-Campbell et al, 2010 ), prefrontal cortex and pituitary ( George et al, 2017 ). It also modulates synaptic plasticity ( Sarabdjitsingh et al, 2014 ), dynamically defines periods of high and low neuroendocrine responsivity to stress ( Sarabdjitsingh et al, 2010 ), influences the electrical activity patterns in the amygdala, modifying the efficacy of cognitive processes like fear learning ( den Boon et al, 2019 ), and defines the context in which other neural stimuli with shared molecular downstream pathways (like the brain-derived neurotrophic factor) exert their effect upon brain cells ( Huzard et al, 2020 ). The molecular basis for these rhythm-related biological effects lies on the different binding affinities of the two types of corticosteroid receptors with glucocorticoids, resulting in a differential activation during the oscillatory activity of the hormone, leading consequently to changes of genomic, epigenomic and postgenomic cellular events ( de Kloet et al, 2018 , Kalafatakis et al, 2019 ).…”