Determining the effect of early resource scarcity on adolescent addiction-related behavior and cell-type specific transcription

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PROJECT SUMMARY Early life experiences can have long-lasting consequences on risk and resilience for developing substance use disorder (SUD). While trauma early in life increases risk for SUD, brief early stressor exposure can promote stress inoculation or later resilience. Much of the preclinical work studying how the early environment affects addiction-related behaviors has focused on outcomes in adult animals. However, this approach misses how early experiences alter the trajectory of the development of brain regions implicated in SUD and limits our ability to know if interventions for SUD would be effective earlier, such as in adolescence, when first exposure to drugs of abuse often occurs. This proposal addresses this gap and tests how a rat model of brief early resource scarcity alters adolescent impulsivity, opioid taking, and cell-type specific transcription in the medial prefrontal cortex (mPFC), a key part of the reward circuitry that is developing in adolescence. This proposal builds on our labs extensive work characterizing the effects of the limited bedding/nesting (LBN) manipulation on adult addiction- related outcomes. In LBN, dams and pups are in a low resource environment during pups first week of life and effects are compared to rats raised with adequate resources throughout development. We previously found that LBN causes sex-specific resilience to addiction-related behaviors, reducing impulsive choice and morphine taking, in adult male but not in adult female rats. We also found alterations in glutamatergic signaling in reward circuitry in adult LBN males that can contribute to resilience. This proposal will extend this work to determine, for the first time, whether LBN causes similar behavioral and molecular changes in adolescent rats. Aim 1 will used innovative new behavioral procedures that allow for testing impulsive choice with delayed discounting and morphine self-administration in adolescent rats. We expect that, like in adulthood, LBN will promote male-specific resilience to adolescent impulsivity and drug taking. Aim 2 will build on new unpublished single nucleus RNA sequencing (scRNAseq) assessing how LBN alters cell-type specific transcription in the adult mPFC. This approach overcomes limitations of past work using bulk tissue where transcriptomic alterations cannot be assigned to any particular cell type. In adults, we found that LBN alters genes in one subtype of excitatory glutamatergic neurons in the mPFC of only adult males and several of these genes are involved in vesicular transport, which could lead to altered presynaptic glutamate release. Here we will test the prediction that LBN causes similar male-specific transcriptional alterations in glutamatergic neurons in adolescents, while also discovering novel gene expression changes within genetically defined subtypes of cells in the mPFC. By combining this novel adolescent phenotyping with prior adult work, we can determine how LBN affects the developmental trajectory of addiction-related behaviors and the transcriptional dynamics of the mPFC. The data generated here will also serve as a valuable resource for the fields of SUD and developmental neuroscience.