SUMMARY Aging brains undergo cognitive decline, associated with decreased neuronal synapse number and function and altered metabolism. Astrocytes regulate neuronal synapse formation and function in development and adulthood, but whether these properties change during aging, contributing to neuronal dysfunction, is unknown. We addressed this by generating aged and adult astrocyte transcriptomes from multiple mouse brain regions. These data provide a comprehensive RNA-seq database of adult and aged astrocyte gene expression, available online as a resource. We identify astrocyte genes altered by aging across brain regions and regionally unique aging changes. Aging astrocytes show minimal alteration of homeostatic and neurotransmission-regulating genes. However, aging astrocytes upregulate genes that eliminate synapses and partially resemble reactive astrocytes. We further identified heterogeneous expression of synapse-regulating genes between astrocytes from different cortical regions. We find that alterations to astrocytes in aging create an environment permissive to synapse elimination and neuronal damage, potentially contributing to aging-associated cognitive decline.

Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.

Substance abuse and sleep deprivation are major problems in our society. Clinical studies suggest that measures of poor sleep quality effectively predict relapse to substance abuse. Previously, our laboratory has shown that acute sleep deprivation increases the rate and efficiency (i.e., the goal-directed nature of responding) of cocaine self-administration using a progressive ratio (PR) schedule of reinforcement. However, the problem of sleep deprivation in our nation is largely one of chronicity. Therefore, the current study used a rodent model of chronic sleep restriction more akin to that experienced by humans (approximately 40% reduction in baseline sleep over the course of 8 days) to assess the impact of chronic sleep deprivation on cocaine-seeking and cocaine-taking behaviors in rats early during acquisition of self-administration. While low drug-taking rats were unaffected by chronic sleep restriction, high drug-takers in the chronic sleep restriction (CSR) group exhibited enhanced fixed ratio (FR) responding by the fourth day of FR training and significantly higher PR breakpoints than their non-sleep restriction (NSR) counterparts. This study is the first to directly assess the impact of chronic sleep deprivation on drug self-administration. These results show that chronic sleep deprivation early during acquisition of self-administration has a significant effect on the perceived incentive reward value of cocaine in high drug-takers, as indicated by both increased FR responding and an increased willingness to work for drug. Thus, it is important to be mindful of such factors in clinical settings designed for treatment of addiction and relapse prevention.