BackgroundThere has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI).MethodsThe moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task.ResultsT homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes.ConclusionsThis preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.
Background The prefrontal cortex (PFC) plays a critical role in regulating emotional behaviors, and dysfunction of PFC-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder (MDD). Methods Here we acquire multi-circuit in vivo activity from eight cortical and limbic brain regions as mice are subjected to the tail suspension test (TST) and an open field test (OFT). We use a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and OFT. We then perform repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. Results The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex (IL) and medial dorsal thalamic (Thal), and an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using “closed-loop” optogenetic stimulation is sufficient to increase movement in the TST in stress-naïve mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in IL-Thal circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. Conclusion Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.
Highlights d Loss of Htt in striatal neurons recapitulates key features of Huntington's disease d Striatal neurons require Htt for survival during aging d Deletion of Htt from striatal neurons disrupts synaptic connectivity
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