Yifeng Cheng, Xuehua Wang, Xiaoyan Wei, Xueyi Xie, Sebastian Melo, Rajesh C Miranda, Jun Wang
BACKGROUND: Prenatal alcohol exposure (PAE) is a leading cause of hyperactivity in children. Excitation of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the dorsomedial striatum (DMS), a brain region that controls voluntary behavior, is known to induce hyperactivity in mice. We therefore hypothesized that PAE-linked hyperactivity was due to persistently altered glutamatergic activity in DMS D1-MSNs.
METHODS: Female Ai14 tdTomato reporter mice were given access to alcohol in an intermittent access, 2-bottle choice paradigm before pregnancy, and following mating with male D1-Cre mice, through the pregnancy period, and until postnatal day (P) 10. Locomotor activity was tested in juvenile (P21) and adult (P133) offspring, and alcohol-conditioned place preference (CPP) was measured in adult offspring. Glutamatergic activity in DMS D1-MSNs of adult PAE and control mice was measured by slice electrophysiology, followed by measurements of dendritic morphology.
RESULTS: Our voluntary maternal alcohol consumption model resulted in increased locomotor activity in juvenile PAE mice, and this hyperactivity was maintained into adulthood. Furthermore, PAE resulted in a higher alcohol-induced CPP in adult offspring. Glutamatergic activity onto DMS D1-MSNs was also enhanced by PAE. Finally, PAE increased dendritic complexity in DMS D1-MSNs in adult offspring.
CONCLUSIONS: Our model of PAE does result in persistent hyperactivity in offspring. In adult PAE offspring, hyperactivity is accompanied by potentiated glutamatergic strength and afferent connectivity in DMS D1-MSNs, an outcome that is also consistent with the observed increase in alcohol preference in PAE offspring. Consequently, a PAE-sensitive circuit, centered within the D1-MSN, may be linked to behavioral outcomes of PAE.
