PROJECT SUMMARY A key problem in neuroscience is understanding how internal and external information are integrated in the brain to produce sensory experiences, cognition, and behavioral responses. This integration relies on flexible modulation of sensory processing in response to behavioral states like motivation, attention, and arousal. Neurons in the basal forebrain are key mediators of these behavioral states. At the same time, basal forebrain neurodegeneration in Alzheimer’s and Parkinson’s disease is associated with deficits in both cognitive and sensory processing. Olfactory deficits are especially common across neurodegenerative and neuropsychiatric diseases, particularly those associated with dementia. While it has been hypothesized that olfaction and cognitive processing are linked by common upstream regulatory systems, the circuit mechanisms mediating this control remain unknown. Therefore, the goal of this proposal is to develop a mechanistic understanding of how neural circuits in the basal forebrain impact sensory processing. The proposed Aims test the hypothesis that effects of attention, arousal, and reward prediction on olfactory processing rely on precisely timed, cholinergic signaling within the basal forebrain controlling projection output to the olfactory bulb. In the mentored K99 phase (Aim 1), I will investigate the impact of behavioral state on odor coding in the olfactory bulb using meso-scale, in vivo two-photon imaging. Under the mentorship of Drs. Ben Arenkiel and Paul Pfaffinger, and with the collaboration of Drs. Jacob Reimer and Ankit Patel, I will be trained in the technical aspects of meso-scale two-photon microscopy and computational methods. As I transition to independence in the R00 phase, I will look upstream to processing in the basal forebrain where I will use a combination of electrophysiology, optogenetics, fiber photometry, and targeted genetic manipulations to determine how cell type specific, state-dependent signaling within the basal forebrain influences olfactory learning (Aim 2). Finally, in Aim 3 I will test the hypothesis that basal forebrain cholinergic and GABAergic neurons play distinct roles in olfactory learning, via impacts on odor processing in the olfactory bulb. To test this, I will use a combination of targeted genetic manipulations, olfactory-based behavioral platforms, meso-scale two-photon imaging, and fiber photometry. Together the proposed research will reveal cellular and circuit mechanisms underlying basal forebrain control of olfactory sensory processing in the healthy brain. Ultimately, this addresses the question of how basal forebrain dysfunction impacts sensation and cognition in disease, and it will provide the conceptual framework for a future independent research program.

PROJECT NARRATIVE Neurodegeneration, particularly of the basal forebrain, is strongly associated with both cognitive and sensory deficits. Through this research we will develop a mechanistic understanding of how basal forebrain circuits mediate downstream effects on sensory processing, potentially revealing common mechanisms that underlie sensory and cognitive deficits in disease. Revealing these mechanisms will improve our understanding of circuit defects in neurodegenerative disease and may lead to novel, targeted therapies for treating dementia and sensory deficits.