A Genetically Defined Lateral Septum Circuit for Contextual Calibration of Food Reward-Seeking

用于食物奖励寻求的情境校准的基因定义的横向隔膜电路

• 批准号: 10642435
• 负责人: Travis David Goode
• 金额: $ 13.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642435
• 关键词: Animals; Appetitive Behavior; Behavior; Behavioral Paradigm; Brain; Calcium; Calibration; Cells; Chronic; Consummatory Behavior; Consumption; Cues; Data; Dependence; Desire for food; Dissection; Dorsal; Eating; Eating Disorders; Electrophysiology (science); Environment; Exhibits; Familiarity; Fasting; Feeding behaviors; Female; Food; Frequencies; Future; Glutamates; Goals; Hippocampus; Home; Hunger; Hypothalamic structure; Image; Individual; Inhibitory Synapse; Laboratories; Lateral; Life; Link; Mediating; Modeling; Molecular; Motivation; Mus; Neurons; Neuropeptides; Outcome; Pathway interactions; Pattern; Phase; Population; Positioning Attribute; Process; Regulation; Research; Rewards; Role; Satiation; Signal Transduction; Slice; Specificity; Structure; Synapses; System; Techniques; Testing; Training; Work; approach behavior; base; cell type; experimental study; feeding; food avoidance; food consumption; improved; in vivo; inhibitory neuron; insight; male; motivated behavior; nerve supply; neural; neural circuit; new therapeutic target; novel; novel therapeutics; optogenetics; prevent; prodynorphin; proenkephalin; programs; recruit; single cell sequencing; transcriptomics; transmission process

For the millions of individuals living with eating disorders (EDs), food-avoidance and -seeking have become debilitating and potentially life-threatening behaviors. If we are to improve treatments and identify novel therapeutics for EDs, it is absolutely critical that we understand brain circuits that calibrate feeding and interpret food-related contextual cues. The hippocampus (HPC) is critically involved in the contextual regulation of motivated behaviors, including feeding, but how contextual signals of the HPC are integrated and relayed to subcortical systems to scale motivated behaviors isn't well known. Leveraging deep molecular and circuit analyses, including single-cell sequencing, optogenetics, and monosynaptic neural tracing, we have uncovered a dorsally restricted subpopulation of LS neurons, characterized by its unique expression pattern of the neuropeptide, prodynorphin (Pdyn). Critically, and in male and female mice, these LS(Pdyn) neurons receive robust monosynaptic input from the dorsal HPC (e.g., CA3/2) and project strongly to feeding-related regions of the lateral hypothalamus (LH). Our preliminary data suggest that LS(Pdyn) neurons exhibit an inhibitory role on feeding. These findings concord with a food-seeking model in which inhibitory LS(Pdyn) neurons reduce food approach and eating by inhibiting food-seeking GABAergic LH(Vgat) neurons. As such, the proposed work will test the central hypothesis that a top-down excitatory dorsal HPC->dorsal LS(Pdyn)->LH(Vgat) circuit mediates context-dependent-regulation of food reward-seeking behavior. Accordingly, and in Aim 1 (spanning the first year of training under the K99 phase), we will deploy longitudinal 1-p calcium imaging in freely behaving mice to test the hypothesis that LS(Pdyn) neural activity negatively correlates with food approach and consumption, and that this activity can be deciphered to discriminate food-associated contexts (that promote feeding) from those that do not. In Aim 2 (in the final phase of the K99 period), we will characterize functional synaptic connectivity between excitatory hippocampal inputs to LS(Pdyn) inhibitory neurons, and we will test for the dependence of context-dependent feeding on hippocampal inputs to the dorsolateral septum [the region in which LS(Pdyn) neurons are expressed] using circuit-specific optogenetics. In the final Aim 3, and in the establishment of my own independent research program (in years 3-5 of the R00 stage), I will implement the techniques established in Aims 1 and 2 to test whether LS(Pdyn) inhibitory neurons synapse onto inhibitory LH(Vgat) neurons and whether this circuit is critical for the context-dependent expression of food reward-seeking (circuit-specific optogenetics). Moreover, Aim 3 will test whether LH(Vgat) neurons are inhibited in vivo following LS(Pdyn) activation (combining cell-type-specific optogenetics of the LS and longitudinal calcium imaging in the LH), directly linking LS(Pdyn) neural activity to the LH for regulation of context-triggered feeding. In total, these studies will identify how dorsal LS(Pdyn) activity patterns encode and deploy environmental signals for the contextual calibration of motivated feeding behaviors.

对于数百万患有饮食失调 (ED) 的人来说，回避和寻求食物已成为使人衰弱并可能危及生命的行为。如果我们要改进治疗方法并确定治疗 ED 的新疗法，那么了解校准喂养和解释与食物相关的情境线索的大脑回路绝对至关重要。海马体 (HPC) 关键参与动机行为的情境调节，包括进食，但海马体的情境信号如何整合并传递到皮层下系统以调节动机行为尚不清楚。利用深入的分子和电路分析，包括单细胞测序、光遗传学和单突触神经追踪，我们发现了一个背侧限制的 LS 神经元亚群，其特征是神经肽强啡肽原 (Pdyn) 的独特表达模式。至关重要的是，在雄性和雌性小鼠中，这些 LS(Pdyn) 神经元从背侧 HPC（例如 CA3/2）接收强大的单突触输入，并强烈投射到外侧下丘脑 (LH) 的进食相关区域。我们的初步数据表明 LS(Pdyn) 神经元对摄食表现出抑制作用。这些发现与食物搜寻模型一致，其中抑制性 LS(Pdyn) 神经元通过抑制食物搜寻 GABA 能 LH(Vgat) 神经元来减少食物接近和进食。因此，拟议的工作将测试中心假设，即自上而下的兴奋性背侧 HPC->背侧 LS(Pdyn)->LH(Vgat) 回路介导食物奖励寻求行为的上下文相关调节。因此，在目标 1（跨越 K99 阶段训练的第一年）中，我们将在自由行为的小鼠中部署纵向 1-p 钙成像，以检验 LS(Pdyn) 神经活动与食物方式和消耗呈负相关的假设，并且可以破译此活动以区分与食物相关的环境（促进喂养）和那些不相关的环境。在目标 2（K99 期的最后阶段）中，我们将表征兴奋性海马输入与 LS(Pdyn) 抑制性神经元之间的功能性突触连接，并且我们将测试情境依赖性进食对海马背外侧输入的依赖性使用电路特异性光遗传学技术对隔膜[LS(Pdyn)神经元表达的区域]进行了研究。在最终的目标 3 中，以及在建立我自己的独立研究计划时（R00 阶段的第 3-5 年），我将实施目标 1 和 2 中建立的技术来测试 LS(Pdyn) 抑制性神经元是否突触到抑制性 LH(Vgat) 神经元以及该电路是否对于食物奖励寻求的上下文相关表达至关重要（电路特异性光遗传学）。此外，Aim 3将测试LS(Pdyn)激活后LH(Vgat)神经元是否在体内受到抑制（结合LS的细胞类型特异性光遗传学和LH中的纵向钙成像），直接关联LS(Pdyn)神经活动LH 用于调节情境触发的进食。总的来说，这些研究将确定背侧 LS(Pdyn) 活动模式如何编码和部署环境信号，以对动机性进食行为进行情境校准。