Doctor of Philosophy
Miwa, Julie M.
Stress is a well-known factor in the development of anxiety disorders. Anxiety, in response to stressors, is thought to be advantageous but both erroneous or overgeneralized stress assessment and the continuation of anxiety past the stressor can lead to negative consequences. Not all stress-exposed individuals experience negative outcomes, but some do develop disorders, suggesting underlying factors can influence the ability to navigate stressors. Individual differences in biological factors such as genetics and functional connectivity of circuits can act to modulate responses and predispose some to anxiety disorder development. It is of critical importance to define how such factors affect stress responses as 18% of adults suffer from anxiety disorders and current treatments are inadequate, leading to high medical costs and lower life quality. How can neural systems and genetics interact with stressors to modify behavior? What underlies the ability to successfully navigate stressors?My central hypothesis is that the cholinergic system, a widespread modulatory neurotransmitter system that regulates neural excitability and drives attention to salient stimuli, acts as a transducer to integrate experiences into circuitry to modify behavior. Regulation of cholinergic signaling can be influenced by genetic factors. The lynx2 gene, which encodes a negative cholinergic protein modulator, affects anxiety circuits. The overall objective of my research was to define the role of lynx2 in human anxiety and to characterize mice lacking lynx2 in behavioral models of anxiety disorder development and identify underlying mechanisms. I found that lynx2 knockout (KO) mice demonstrate a robust inability to update behavior during a fear extinction paradigm, which could be restored by focal replacement of lynx2 in anxiety circuits. Mechanistically, I show that activity of the α7 nicotinic receptor and downstream calcium-based regulation are implicated in this deficit. In models of social stress, lynx2KO mice demonstrate unexpected changes in social behavior after stress. Furthermore, novel behavioral patterns between social interaction and fear extinction following social stress were documented. I found that regulation of neurotrophic factors in the mesolimbic dopamine pathway are implicated in the response to social stress. To investigate the translational potential of lynx2 for human anxiety, a subpopulation of human participants harboring a lynx2 mutation was found to be associated with heightened anxiety. Insights from lynx2KO studies can address the root cause of anxiety in this genetically defined population, providing a potential pharmacogenetic treatment option for anxiety amelioration.
Anderson, Kristin Rae, "Genetics, Circuits, & Environmental Adversity: Behavioral Adaptation Optimized By The Nicotinic Receptor Modulator lynx2" (2019). Theses and Dissertations. 5583.