Controlling oscillations to treat Alzheimers disease targeting the basal forebrain parvalbuminsystem

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Alzheimer's disease (AD) is a neurogenerative disorder characterized by early deposition of amyloid-beta protein (Aβ) followed by tauopathy and impaired cognition. Innovative treatment strategies are needed. Recent studies in amyloidosis and tauopathy model mice have shown that chronic 40Hz gamma entrainment using sensory stimuli (GENUS) improves pathological and behavioral outcomes. However, these exciting studies have not been independently replicated and optimal methods to reduce pathology by gamma entrainment are unknown. Thus, here, we test whether optogenetic excitation of non-cholinergic basal forebrain parvalbumin neurons (BF PV) enables widespread control of gamma oscillations throughout cortex and hippocampus to treat amyloidosis/tauopathy and restore hippocampal-cortical oscillatory functions that support memory. The mentored (K99) phase of this proposal will use 5XFAD mice to test benefits of 40Hz optogenetic BF PV excitation in preventing amyloidosis. All experiments record ipsilateral local field potentials (LFP) in medial prefrontal cortex (mPFC) and hippocampus (HPC). The first experiment directly compares the efficacy of 40Hz BF PV excitation treatment against GENUS in reducing plaque pathology. The second experiment uses chemogenetics to model pharmacologically targeting of BF PV and tests whether chemogenetic BF PV excitation and GENUS synergize to improve outcome. The third experiment assesses the hypothesis that chronic 40Hz BF PV excitation repairs gamma generating mechanisms in hippocampus and cortex to restore oscillatory communication and rescue working memory. The fourth experiment will use a closed-loop stimulation method to deliver two brief (10ms) laser pulses at the peak or trough of hippocampal theta phase to assess whether theta-phase specific timing of BF PV excitation matters. The independent (R00) phase studies will apply methods learned during the K99 phase to 3xTg amyloidosis/tauopathy model mice to strengthen the case for BF PV targeted treatments of moderate to severe AD. The same four experiments as above are proposed for these studies in 3xTg mice. Further, important preclinical behavioral experiments will assess the hypothesis that BF PV excitation can be used to enhance cognition in 3xTg mice without affecting motivation (a potential side effect) or reinforcement (abuse potential). The training plan for this award includes mentorship from an expert team of Harvard Medical School professors specializing in BF regulation of cortical oscillations and cognition. AD-directed training will be provided by additional members of the mentorship team from Boston University and through the candidate's participation in the Massachusetts AD Research Center Research Education Component program. The proposed AD research and didactic activities and training on the study of neural oscillations will facilitate the applicant's goal of becoming an independent investigator studying preclinical treatments for AD.