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症（ED）的人来说，避免和寻找食物已经成为使人衰弱和潜在威胁生命的行为。如果我们要改进治疗方法并确定ED的新疗法，那么我们了解校准进食和解释食物相关上下文线索的大脑回路绝对至关重要。海马体（HPC）在包括进食在内的动机行为的情境调节中起着关键作用，但HPC的情境信号如何被整合并中继到皮层下系统以缩放动机行为还不为人所知。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LS神经元的背侧限制亚群，其特征在于其独特的神经肽前强啡肽（Pdyn）表达模式。关键的是，在雄性和雌性小鼠中，这些LS（Pdyn）神经元从背侧HPC（例如，CA 3/2），并强烈投射到外侧下丘脑（LH）的摄食相关区域。我们的初步数据表明，LS（Pdyn）神经元表现出抑制进食的作用。这些发现与食物寻求模型一致，在该模型中，抑制性LS（Pdyn）神经元通过抑制食物寻求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依赖性调节。因此，在目标1（跨越K99阶段下的第一年训练）中，我们将在自由行为的小鼠中部署纵向1-p钙成像，以测试LS（Pdyn）神经活动与食物接近和消费呈负相关的假设，并且这种活动可以被破译以区分与食物相关的上下文（促进进食）与不相关的上下文。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，我们将使用电路特异性光遗传学测试上下文依赖性摄食对海马输入到背外侧隔[LS（Pdyn）神经元表达的区域]的依赖性。在最终的目标3中，以及在建立我自己的独立研究计划（R 00阶段的第3-5年）时，我将实施目标1和2中建立的技术，以测试LS（Pdyn）抑制性神经元是否与抑制性LH（Vgat）神经元突触，以及该电路是否对食物奖励寻求的上下文依赖性表达至关重要（电路特异性光遗传学）。此外，目标3将测试在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），将LS（Pdyn）神经活性与LH直接联系起来以调节上下文触发的进食。总之，这些研究将确定背LS（Pdyn）活动模式如何编码和部署环境信号的背景校准的动机喂养行为。