Dopamine Receptor Expression In The Nucleus Accumbens Of Adult Rhesus Macaques And Resilience To Early Life Adversity
Open Access DepositedAcross species, adaptive behaviors are acquired in early life through reward-associated learning, a process that is facilitated by mothers and other parental figures who provide social stimuli, security, and guidance. As early life experiences shape the cellular and molecular organization of developing neural circuits, their disruption can increase vulnerability to behavioral deficits and poor mental health outcomes. The mesolimbic pathway, which transmits dopamine from the ventral tegmental area to the nucleus accumbens, is a central component of the broader reward circuit that drives reward-associated learning and is affected in neuropsychiatric disorders associated with adverse experiences in early life. Accordingly, altered dopamine signaling in the nucleus accumbens may be a key mechanistic link through which early life adversity influences long-term behavioral deficits and mental health outcomes. To assess whether early life adversity exerts long-term effects on dopamine signaling in the mesolimbic pathway, we measured spiny projection neuron abundance and regional distribution, as well as dopamine receptor expression in the nucleus accumbens of adult male rhesus macaques who experienced maternal separation during infancy. To this end, brains from five mother-reared and six nursery-reared individuals were collected and formalin-fixed for histological analyses. Using RNAscope in situ hybridization, we labeled dopamine receptor transcripts and quantified the densities of D1, D2, and D1-D2 co-expressing spiny projection neurons, as well as densities of DRD1 and DRD2 transcripts. We evaluated these data with linear mixed-effects models and analysis of variance tests. Our results indicate that across all individuals, D1 spiny projection neurons occurred at a significantly higher density relative to D2 spiny projection neurons. In contrast, D2 spiny projection neurons expressed DRD2 at significantly higher densities than D1 spiny projection neurons expressed DRD1, and both receptor types were expressed at higher levels in the medial nucleus accumbens compared to the central nucleus accumbens. Notably, measures of spiny projection neuron abundance and dopamine receptor expression exhibited substantial heterogeneity within individuals whereas inter-individual variation was relatively marginal. Contrary to our original hypothesis, rearing condition did not have a significant effect on densities of any of the three spiny projection neuron types or either dopamine receptor type. Collectively, these findings provide foundational characterizations of the cytoarchitecture and receptor expression patterns in the primate NAcc while adding to our understanding of the long-term effects of early life adversity on brain structure. The enrichment of D1 spiny projection neurons along with elevated DRD2 expression levels raises questions regarding species-specific variation and functional specializations while highlighting cellular and molecular heterogeneity as a core feature of the primate nucleus accumbens.
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