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

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.

Grant Number: 1R21DA062844-01
NIH Institute/Center: NIH
Principal Investigator: Debra Bangasser