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孕产妇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较低的应激反应水平，持续专注于照顾后代，并有能力应对自己相当大的代谢需求。因此，哺乳期雌性哺乳动物提供了压力恢复力的天然模型。* 大鼠的母体护理质量取决于丘脑核（NAc）中的多巴胺信号传导，其指导对后代的食欲、接近行为。有趣的是，处女雌性避开幼崽，反映了大鼠与母亲护理相关的动机状态的戏剧性转变。NAc是一种高度异质性的结构，其接收来自多个脑区域的多巴胺能、γ-氨基丁酸能（GABA能）和多巴胺能投射，所述多个脑区域包括前额叶皮质（PFC）、腹侧海马和腹侧被盖区（VTA）。有趣的是，其中一些预测似乎对行为产生了相反的影响。光遗传学研究确定了腹侧被盖区中不同的多巴胺神经元群体，这些多巴胺神经元投射到NAc的不同区域，并与奖励或厌恶行为相关，这可能是雌性大鼠不同的母性动机状态的基础。* 我们不知道NAc中的哪些回路和/或基因表达变化对调节母性行为很重要。损伤和药理学方法确定NAc作为母体行为的介质，但损伤方法不是细胞类型特异性的，药理学药物缺乏时间精确性。相比之下，光遗传学工具允许我们在自由移动的大鼠中快速精确地操纵深部脑神经元活动。* 光遗传学与下一代测序的结合将使我们能够研究整个基因组中基因表达的变化和电路活动，这些活动以精细的时间和遗传特异性水平调节母体行为，这在以前是不可能的。在这个NSERC研究计划中，我们将研究内侧和外侧核中的光遗传学刺激，这些区域以前与自由移动的哺乳期大鼠在其幼崽存在的情况下的厌恶和奖励相关。我们将测量这些回路的激活如何影响母性行为和基因转录。这将使我们能够靶向介导母性行为的特定基因，以进一步获得功能实验。

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.**