Lasting effects of early resource scarcity on cortical astrocyte structure and function

Georgia State University, Atlanta GA

Investigators

Abstract

ABSTRACT Early life experiences can have lasting effects on the brain, influencing later resilience or susceptibility to substance use disorders (SUDs). The field has focused on how neurons mediate plasticity in response to early- life experiences. However, astrocytes, key regulators of glutamate function, develop during the postnatal period which is particularly sensitive to the environment. Yet the role of astrocytes in mediating the effects of the early environment on later addiction-related endpoints has rarely been explored. This proposal addresses this gap and determines how astrocyte morphology and function are affected by a postnatal environmental manipulation that leads to later resilience. Although traumatic events early in life often increase the risk of drug abuse, mild adversity can foster stress resilience via the development of adaptations and stress-coping skills, a phenomenon termed stress inoculation. We use a rat model of early resource scarcity, the limited bedding and nesting (LBN) manipulation, where rat dams and pups are put in low resources only for the pups’ first week of life, then are transferred to normal housing conditions through adulthood. Compared to control dams with ample resources, LBN dams provide increased maternal care (nursing and grooming) at the expense of self-care (self-grooming, resting outside the nest). Adult LBN offspring have a resilient phenotype to addiction-related behaviors with reduced impulsivity, risk-taking, and morphine self-administration. These behaviors are mediated by the medial prefrontal cortex (mPFC), a target of altered glutamatergic function following changes in neonatal parental care. These lines of research led to our preliminary studies that revealed that LBN exposure increases astrocyte surface area and volume in the adult mPFC relative to controls. This proposal extends this work to test the mechanistic hypothesis that LBN-induced astrocyte enlargement is linked to an enhanced astrocyte glutamate uptake and consequently a reduction in extrasynaptic neuronal glutamate signaling in the mPFC of adult LBN rats. The grant will also address a gap in our understanding of the developmental trajectory of LBN-induced astrocyte effects by determining if alterations in astrocyte morphology and function following LBN occur early in development (postnatal day, PND 10) or emerge with later brain maturation (adulthood, PND90). This multidisciplinary proposal integrates the MPIs expertise in development, structural plasticity, and astrocyte physiology. By delineating the impact of LBN on astrocyte morphology and function, the proposed studies will reveal novel mechanisms by which alterations in the early environment promote resilience to addiction-related behaviors. Moreover, this grant will lay the groundwork for developing novel therapeutics targeting astrocytes to improve SUD outcomes.