Stress-Induced Sleep Dysregulation: The Roles of Astrocytes and Microglia in Neurodegenerative and Psychiatric Disorders

Abstract

Stress and sleep share a reciprocal relationship, where chronic stress often leads to sleep disturbances that worsen neurodegenerative and psychiatric conditions. Non-neuronal cells, particularly astrocytes and microglia, play critical roles in the brain's response to stress and the regulation of sleep. Astrocytes influence sleep architecture by regulating adenosine signaling and glymphatic clearance, both of which can be disrupted by chronic stress, leading to reduced restorative sleep. Microglia, activated under stress conditions, drive neuroinflammatory processes that further impair sleep and exacerbate brain dysfunction. Additionally, the gut-brain axis mediates interactions between stress, sleep, and inflammation, with microbial metabolites influencing neural pathways. Many of these effects converge on the disruption of synaptic processes, such as neurotransmitter balance, synaptic plasticity, and pruning, which in turn contribute to the pathophysiology of neurodegenerative and psychiatric disorders. This review explores how these cellular and systemic mechanisms contribute to stress-induced sleep disturbances and their implications for neurodegenerative and psychiatric disorders, offering insights into potential therapeutic strategies targeting non-neuronal cells and the gut-brain axis.

Keywords: astrocytes; microglia; neurodegenerative diseases; neuroinflammation; sleep homeostasis.

Figure 1

The reciprocal relationship between stress and sleep dysregulation. On the left, the stress response is shown, beginning with the activation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to glucocorticoid release from the adrenal cortex. Chronic activation of this system affects sleep-related brain regions and disrupts normal sleep processes. On the right, chronic stress-induced sleep dysregulation is detailed. Prolonged glucocorticoid exposure alters the function of sleep-regulating nuclei by increasing noradrenaline levels, suppressing melatonin production, and modifying circadian gene expression in the suprachiasmatic nucleus (SCN). Inflammatory processes further disrupt sleep by promoting hyperexcitability in the corticothalamic glutamatergic circuits and suppressing cholinergic signaling. Additionally, glial cells, including microglia and astrocytes, play a key role in mediating the effects of stress on sleep. Chronic stress promotes a pro-inflammatory microglial state and impairs astrocytic functions, leading to the dysregulation of adenosine metabolism, glymphatic clearance failure, and abnormal synaptic pruning. These changes contribute to fragmented, poor-quality sleep, which in turn exacerbates stress, creating a vicious cycle.

Figure 2

Chronic stress, glial dysfunction, and sleep dysregulation: a pathway to neurodegeneration and psychiatric disorders. This figure illustrates the pathological cycle through which chronic stress disrupts sleep homeostasis, leading to glial dysfunction, neuroinflammation, and neuronal damage, which in turn contribute to the development of neurodegenerative and psychiatric disorders.