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

母亲护理的差异深刻地影响着后代的表型发育。母子互动的质量与母亲的情绪健康有关。然而，我们对女性生殖需求的神经生物学反应及其对产妇护理的影响知之甚少。尽管面临着惊人的生理挑战和生殖需求，雌性哺乳动物仍然保持着一种受抑制的应激反应水平，持续专注于照顾后代，以及对自己相当大的新陈代谢需求做出反应的能力。因此，哺乳期的雌性哺乳动物提供了一种自然的压力恢复能力模型。 大鼠母体护理的质量取决于伏隔核(NAC)中的多巴胺信号，NAC引导对后代的食欲和接近行为。有趣的是，处女雌性会避开幼崽，这反映了老鼠在与母爱相关的动机状态上的戏剧性转变。NAc是一个高度异质性的结构，接受来自多个脑区的谷氨酸、γ-氨基丁酸能(GABA能)和多巴胺能投射，包括前额叶皮质、腹侧海马和腹侧被盖区。有趣的是，其中一些预测似乎对行为产生了相反的影响。光遗传学研究发现，VTA中投射到NAC不同区域的不同数量的多巴胺神经元与奖赏或厌恶行为有关，可能是雌性大鼠不同母性动机状态的基础。 我们不知道NAC中的哪些回路和/或基因表达变化对于调节母亲的行为是重要的。损伤和药理学方法确定NAC是母体行为的中介，但损伤方法不是细胞类型特异性的，药理药物缺乏时间精确度。相比之下，光遗传工具允许我们快速而准确地操纵自由活动的大鼠的大脑深层神经元活动。 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，以及调节母体行为的电路活动，具有以前不可能实现的精细的时间和遗传特异性。在NSERC的这个研究项目中，我们将研究伏隔内侧核和外侧核的光遗传刺激，这两个区域以前被认为与自由活动的哺乳鼠在其幼崽在场时的厌恶和奖励有关。我们将测量这些回路的激活如何影响母体行为和基因转录。这将使我们能够针对调节母体行为的特定基因，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, γ­aminobutyric 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.