Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Exacerbations (asthma attacks) account for nearly one-third of all asthma deaths. Despite psychiatric illness as a risk factor for death from asthma, and many connections between asthma exacerbations and anxiety, the brain region that initiates anxiety, the amygdala, has received limited attention as a driver of asthma exacerbations. This represents a considerable gap in the field, which, if addressed, may lead to new mechanism-based approaches to treat asthma exacerbations and reduce patient deaths. Exciting preliminary data from control mice suggest that acute optogenetic activation of the basolateral amygdala, a key input center essential for anxiety, reduces airway resistance. In asthmatic mice, which show anxiety, optogenetic activation of the basolateral amygdala fails to reduce airway resistance, suggesting amygdala dysfunction. Amygdala dysfunction is mechanistically linked to anxiety and characterized by heightened activity and spinogenesis (e.g., development of new dendritic spines). Asthmatic mice showed spinogenesis, heightened activity, and elevated expression of genes important for functional and structural remodeling in the basolateral amygdala. To investigate whether these changes were mechanistically linked to impaired regulation of airway resistance, we blocked NMDA glutamate receptors with MK-801, an anxiolytic drug that prevents anxiety-associated basolateral amygdala spinogenesis and in a class of drugs that reduce airway resistance in asthma. We found that MK-801 mitigated bronchoconstriction and diminished elevated gene expression in asthmatic mice. Broadly disrupting the cAMP- responsive element-binding protein (CREB), a transcription factor downstream of NMDA receptor signaling necessary for maintenance of amygdala neuroplasticity, also attenuated bronchoconstriction in asthmatic mice. These data guide our central hypothesis that the basolateral amygdala undergoes NMDA-CREB-dependent plasticity that disrupts airway regulation and promotes pathologic bronchoconstriction. To test this hypothesis, we propose 3 Specific Aims. In Aim 1, we will use optogenetic approaches to activate or inhibit excitatory neurons of the murine basolateral amygdala to test the hypothesis that the basolateral amygdala regulates airway resistance. In Aim 2, we use pharmacologic approaches, magnetic resonance imaging, RNAscope, and Golgi staining to test the hypothesis that experimental asthma structurally and functionally remodels the basolateral amygdala through NMDA receptor signaling. Finally, in Aim 3, we use CRE-lox technology and transgenic mice to test the hypothesis that ablation or overexpression of CREB in the basolateral amygdala alleviates or promotes, respectively, bronchoconstriction. Completion of this proposal will establish NMDA-CREB signaling in the basolateral amygdala as a key driver of asthma exacerbations and highlight NMDA receptor antagonists as a stand-alone or adjunct relief medications for asthma.
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