2018 — 2021 |
Han, Sung |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Contribution of the Parabrachial Cgrp-Expressing Neurons to the Pathophysiology of Panic Disorder @ Salk Institute For Biological Studies
Project Summary/Abstract Panic disorder is a debilitating anxiety disorder that is characterized by sudden and recurrent attacks of intense, uncontrollable anxiety and fear. This psychiatric illness is unique among other anxiety-related disorders because individuals with panic disorder not only experience mental symptoms during an attack, but they also suffer acute physical symptoms, including cardiorespiratory, autonomic, and gastrointestinal symptoms. In addition, these panic attacks occur spontaneously, and are associated with innate unconditioned fear (i.e., fear that has not been learned through an aversive experience). To understand what causes these bouts of unconditioned fear and associated physiological symptoms in panic disorder, it is critical to characterize the neural circuitry underlying innate threat perception. The lateral parabrachial nucleus (PBN) within the brainstem regulates cardiorespiratory and autonomic functions, and also relays multimodal aversive sensory signals to the amygdala. Preliminary data show that factors that induce panic attack in panic disorder patients, such as caffeine, yohimbine or high CO2 levels, robustly activate neurons in the external lateral region of the PBN (PBel) that express a particular neuropeptide, Calcitonin gene-related peptide (CGRP), and activation of these neurons is necessary and sufficient for innate threat perception. However, little is known about the circuit mechanism of the PBel CGRP-expressing neurons in panic disorder pathogenesis. To address this problem, proposed experiments use state-of-the-art neural circuit dissection tools to MONITOR and MANIPULATE the activity of PBel CGRP neurons, as well as target neurons that express the CGRP receptor. The central objective of this proposal is to determine how PBel CGRP neurons respond to and encode innate sensory threats, and how these neurons contribute to the unique physical and emotional comorbidities in panic disorder. To achieve this objective, activity of PBel CGRP neurons will be monitored (via in vivo calcium imaging) as mice are exposed to multimodal sensory threats or panicogenic agents (Aim 1). PBel CGRP neurons will then be manipulated (inhibited or activated) using optogenetic and chemogenetic techniques to establish causal relationships between CGRP neuronal activity and physiological changes during innate threat perception (Aim 2). Lastly, activity of downstream neurons (those that express CGRP receptors in brain regions innervated by PBel CGRP neurons) will be monitored and manipulated to establish functional neural circuits involved in panic disorder pathogenesis (Aim 3). Contributions of the proposed research will be significant because it will advance the circuit-level understanding of panic disorder pathogenesis. The research plan is innovative because it investigates, for the first time, involvement of the PBel in panic disorder pathogenesis using cell type-specific circuit dissection tools. Successful completion of the proposed research will therefore provide neural circuit-based understanding of panic disorder symptoms, which may provide important insights toward developing therapeutic interventions for panic disorder.
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1 |
2020 |
Han, Sung Min |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Understanding the Role of Mitochondria in the Age-Related Decline in Axon Regeneration
Axon regeneration is one of the essential processes that restore the nervous system after nerve injury and neurodegeneration. Aging decreases axon-regeneration capacity while increasing the risk of axonal damages. Failure of axonal regeneration following nerve injury can lead to permanent body-movement impairment and various disabilities. Very little is known about the underlying mechanism of axon regeneration, and there is no efficient treatment to enhance the function of damage neurons. The goal of this proposal is to identify an intrinsic mechanism underlying the age-related decline of axon regeneration by investigating the responses of mitochondria to axonal damage and aging. Mitochondria dynamically change in their morphology, motility, number, and activity by communicating with the nucleus of the host cell to match local demand for energy and to maintain cellular and their own homeostasis. Our and others' recent studies have found a clear link between axon-regeneration capacity and mitochondrial behavioral changes in response to axonal damage. Our unpublished studies also suggest that axon regeneration is regulated by ATFS-1, a key factor in the retrograde signaling from mitochondria to nucleus that mediates mitochondrial unfolded protein response (mitoUPR). Adjusting mitochondrial response to axonal damage could therefore be a critical determinant of axon regeneration. We do not know, however, the underlying mechanisms of these mitochondrial responses to axonal damage and their roles in the age-related decline of axon regeneration. To delineate these unmet needs, we will combine our expertise in C. elegans genetics, mitochondrial biology, and in vivo laser axotomy at a single axon resolution. Specifically, we will use in vivo imaging approaches to monitor the axonal trafficking of mitochondria and the activity of mitoUPR after axonal damage and during aging on short-term and long-term scales. We will also use both in vivo and in vitro assays to quantitatively measure the physiological properties of mitochondria that are altered by axonal injury signals and mitoUPR (Aim 1). We will use a laser-based axotomy and genetic approaches experimentally to change the nature of mitochondria in aging animals to test the correlation with axon regeneration ability (Aim 2). Finally, we will perform visual-based genetic approaches to discover a genetic mechanism that mediates mitochondrial localization and traffic in neurons (Aim 3). We believe that these approaches will achieve a new understanding of the mechanisms that maintain optimal function of the nervous system during aging by regulating mitochondrial function in aging and injured neurons. Our findings will provide better insight into novel therapeutic approaches to restore neuronal function after nerve injury.
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0.922 |