The role of presynaptic C1QL3 in a hypothalamic arousal circuit

点击翻译按钮获取中文摘要

PROJECT SUMMARY: Narcolepsy with cataplexy is a debilitating neurological disorder that results in sleep attacks during the day and fragmented sleep at night. This condition is associated with the loss of hypocretin/orexin (HCRT/OX) neurons in the lateral hypothalamic area (LHA), which are important regulators of sleep/wake behavior and arousal states. Despite a broad array of work investigating HCRT/OX neuron function in physiology and behavior, comparatively little is known about the molecular mechanisms underlying their synaptic structure and function. Based on the results of our lab’s recent single cell RNA sequencing (scRNA-seq) analysis of the LHA, we propose that C1ql3, encoding C1QL3, a previously described excitatory synapse organizing protein in other brain regions, may likewise be an important element in excitatory synaptic transmission in HCRT/OX neurons, and help us shed light on the molecular components of these important arousal-regulating synapses. To test this, I will confirm the expression of C1ql3 and its gene product C1QL3 in HCRT/OX neurons, at both the mRNA and protein levels (Aim 1). I will then conditionally knock out the C1ql3 gene in HCRT/OX neurons to determine the consequences of its deletion on HCRT/OX synaptic structure and function (Aim 2), as well as its potential importance for HCRT/OX neuron function in promoting arousal (Aim 3). This work will have several important outcomes, including 1) identifying the role of a novel genetic marker in HCRT/OX neurons, 2) informing us of the importance of C1QL3 in synaptic function and behavior relating to HCRT/OX neurons, and 3) provide me with training in neuroscience techniques ranging from cellular and molecular to behavioral to enable me to become a more well- rounded scientist and scientific communicator, as I pursue my goal of becoming an independent researcher.