Neurochemical modulation of high level cognition

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The ability to change behavior in response to a new environmental condition is critical for survival. This course-correction ability depends on our capacity to inhibit a given behavior and to establish a new behavioral strategy to respond to the change in contingency. Behavioral flexibility can be studied in a variety of ways in animal models, including by sophisticated higher-order cognitive tasks using touchscreens. This approach allows for different tests to be used to probe specific components underlying behavioural flexibility. Acetylcholine (ACh) and dopamine (DA) have an intricated relationship in the striatum and both neuromodulators have been implicated in behavioral flexibility. However, how the dynamic relationship between ACh and dopamine contribute to behavioral flexibility is not understood. One of the reasons for this gap of knowledge is the fact that up to now it has been extremally difficult to observe changes in these neurochemicals during behavioral processes. Fibre photometry can be combined with a new generation of GPCR-based neurotransmitter sensors that can be used to measure neurochemical activity with millisecond resolution. My overarching research program aims to elucidate how neurotransmitters and neuromodulators regulate high-level cognition. The short-term objective of my program is to understand acetylcholine/dopamine dynamics in the dorsal striatum and how these neuromodulators contribute to behavioral flexibility. To measure cognitive domains involved in behavioral flexibility we will use touchscreen tests. Based on published and preliminary data, we hypothesized that cholinergic signaling in the dorsal striatum regulates behavioral flexibility by providing spatially restricted regulation of dopamine release. To test this hypothesis, we will pursue the following short-term objectives: 1-Map the dynamics of ACh/DA release in the DMS and DLS in mice performing touchscreen behavioral flexibility tests. 2-Determine the extent by which decreased cholinergic activity affects the dynamics of DMS and DLS dopaminergic signaling during behavioral flexibility tests. 3-Determine whether increasing dopaminergic signaling can reverse behavioral and neurochemical deficits in the striatum in VAChT-KO mice. This research program will use unique genetic models, recording of neurochemical activity in behaving animals during touchscreen tests measuring behavioral flexibility. Causal manipulations will test whether specific changes in neurochemical tone regulate behavioral flexibility. These experiments will allow a deeper understanding of how changes in neurochemical tone relate to behavioral flexibility and their causal relationships. Development of this program will also allow for training of HQP in mouse genetics, neurochemistry, immunocytochemistry and high-level cognitive testing.