Optoneurogenetic investigation of nucleus accumbens circuits mediating maternal behavior in the rat

母亲照顾的变化深刻地影响后代的表型发育。母子互动的质量与母亲的情感健康有关。然而，我们对女性生殖需求的神经生物学反应及其对母性护理的影响知之甚少。尽管面临着令人震惊的生理挑战和生殖需求，哺乳动物雌性仍保持着适度的应激反应水平，持续专注于照顾后代，并有能力应对自己的大量代谢需求。哺乳期的雌性哺乳动物因此提供了一种自然的应激恢复模型。

Variations in maternal care profoundly influence phenotypic development in the offspring. The quality of mother-offspring interactions is linked to maternal emotional well being. Nevertheless we have little understanding of the neurobiological responses to the demands of reproduction in females and their effects on maternal care. Despite an astounding physiological challenge and reproductive imperative, the mammalian female maintains a dampened level of stress reactivity, a sustained focus on the care of the offspring and the ability to respond to her own, considerable metabolic demands. The lactating female mammal thus provides a natural model of stress resilience. The quality of maternal care in the rat is dependent upon dopamine signaling in the nucleus accumbens (NAc), which directs appetitive, approach behaviors towards the offspring. Interestingly, virgin females avoid pups, reflecting the dramatic shift in motivational states associated with maternal care in the rat. The NAc is a highly heterogeneous structure that receives glutamatergic, -aminobutyric acidergic (GABAergic) and dopaminergic projections from multiple brain regions including the prefrontal cortex (PFC), the ventral hippocampus and the ventral tegmental area (VTA). Interestingly, some of these projections appear to have opposing effects on behavior. Optogenetic studies identify different populations of dopamine neurons in the VTA that project to different regions of the NAc and that are associated with either rewarding or aversive behaviors and which might underlie the varying maternal motivational states in the female rat. We do not know which circuits and/or gene expression changes in the NAc are important for regulating maternal behavior. Lesion and pharmacological methods identify the NAc as a mediator of maternal behavior, but lesion methods are not cell-type specific and pharmacological drugs lack temporal precision. In contrast, optogenetic tools allow us to manipulate deep brain neuronal activity rapidly and precisely in freely moving rats. The combination of optogenetics with next generation sequencing will allow us to study the changes in gene expression across the entire genome and circuit activity that regulate maternal behavior with an exquisite level of temporal and genetic specificity that was previously impossible. In this NSERC research program, we will examine optogenetic stimulation in the medial and lateral nucleus accumbens, regions that have previously been associated with aversion and reward in freely moving lactating rats in the presence of their pups. We will measure how activation of these circuits affects maternal behavior and gene transcription. This will allow us to target specific genes that mediate maternal behavior for further gain of function experiments.