Mechanisms and significance of programmed cell death in hypothalamic CRH neurons

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PROJECT SUMMARY/ABSTRACT Corticotropin-releasing hormone (CRH) expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response. CRH neurons integrate stress-related neural inputs and, as part of the hypothalamic-pituitary-adrenal (HPA) axis, induce the release of ACTH and, ultimately, glucocorticoids (cortisol). The development of CRH neurons is of great biomedical interest, as developmental vulnerabilities of CRH neurons contribute to stress-associated disorders such as anxiety and depression. It is, therefore, critical to identify the molecular and cellular mechanisms mediating the development of CRH neurons and determine how developmental changes affect stress response. Using zebrafish, which are genetically accessible and optically translucent, we found that DSCAML1 deficiency impaired the developmental cell death of CRH neurons and caused hyperactivation of the HPI axis (the zebrafish analog of the HPA axis). Given that DSCAML1 is known to mediate intercellular interactions, we hypothesize that proximity-based and synaptic interactions in CRH neurons trigger developmental cell death, which tunes the activity of the neuroendocrine stress response system. To test this, we propose the following aims. In Aim 1, we will test whether proximity-based interactions promote cell death in CRH neurons. Using the live imaging strength of the zebrafish model, we will examine whether interactions between adjacent CRH neurons promote cell death and determine how varying levels of DSCAML1 modulate the extent of cell loss. In Aim 2, we will test whether synaptic interactions affect CRH neuron cell death. Synaptic activity plays an instructive role in neuronal survival. Given DSCAML1’s known functions in synaptogenesis, we will investigate whether CRH neuron survival is dependent on neuronal activity and how DSCAML1-mediated synaptogenesis controls the excitability of CRH neurons. In Aim 3, we will test how DSCAML1 acts within CRH neurons to trigger cell death and establish HPI-axis activity. Using CRH neuron-specific mutants, we will determine how DSCAML1 functions within CRH neurons and whether DSCAML1’s function in other cell types also contributes to HPI-axis development. In Aim 4, we will test the hypothesis that CRH neuron number tunes HPI-axis activity. While the significance of cell death is widely recognized, the functional impact of CRH neuron cell death has not been explored. We will use genetic tools to increase or decrease CRH neuron number and determine the causal relationship between cell number and HPI-axis activity. Together, these aims will shed light on how intercellular interactions influence CRH neuron cell death and provide a molecular framework for future molecular studies.