Astrocyte CCN1 stabilizes neural circuits in the adult brain.

Neural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods - times of circuit refinement and maturation - and limit plasticity in adulthood for circuit stability. The mechanisms underlying these differing plasticity levels and how they serve to maintain and stabilize the properties of sensory circuits remain largely unclear. By combining a transcriptomic approach with ex vivo electrophysiology and in vivo imaging techniques, we identify that astrocytes release cellular communication network factor 1 (CCN1) to maintain synapse and circuit stability in the visual cortex. By overexpressing CCN1 in critical period astrocytes, we find that it promotes the maturation of inhibitory circuits and limits ocular dominance plasticity. Conversely, by knocking out astrocyte CCN1 in adults, binocular circuits are destabilized. These studies establish CCN1 as a novel astrocyte-secreted factor that stabilizes neuronal circuits. Moreover, they demonstrate that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.

Activity-dependent modulation of synapse-regulating genes in astrocytes.

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 is 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.

The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain.

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.

Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking.

Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the 'reward pathway' that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that the RPEC graft provides beneficial effects to prevent drug seeking in drug addiction via its effects directly on the NAc and its neural network with the VTA.

The role of neuronal versus astrocyte-derived heparan sulfate proteoglycans in brain development and injury.

Astrocytes modulate many aspects of neuronal function, including synapse formation and the response to injury. Heparan sulfate proteoglycans (HSPGs) mediate some of the effects of astrocytes on synaptic function, and participate in the astrocyte-mediated brain injury response. HSPGs are a highly conserved class of proteoglycans, with variable heparan sulfate (HS) chains that play a major role in determining the function of these proteins, such as binding to growth factors and receptors. Expression of both the core proteins and their HS chains can vary depending on cellular origin, thus the functional impact of HSPGs may be determined by the cell type in which they are expressed. In the brain, HSPGs are expressed by both neurons and astrocytes; however, the specific contribution of neuronal HSPGs compared with astrocyte-derived HSPGs to development and the injury response is largely unknown. The present review examines the current evidence regarding the roles of HSPGs in the brain, describes the cellular origins of HSPGs, and interrogates the roles of HSPGs from astrocytes and neurons in synaptogenesis and injury. The importance of considering cell-type-specific expression of HSPGs when studying brain function is discussed.

A novel model of chronic sleep restriction reveals an increase in the perceived incentive reward value of cocaine in high drug-taking rats.

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 25% 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.