Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2017.
Cataloged from PDF version of thesis. "January 2016."
Includes bibliographical references (pages 101-107).
Gamma oscillations (20-50 Hz), a common local field potential signature in many brain regions, are generated by a resonant circuit between fast-spiking (FS)-parvalbumin (PV)-interneurons and pyramidal cells. Changes in gamma oscillations have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies of these disorders is unclear. Here, we investigated this relationship using the 5XFAD mouse model of Alzheimer's disease (AD) and found reduced behaviorally driven gamma activity before the onset of plaque formation or evidence of cognitive decline. Because of the early onset of gamma deficits, we aimed to determine if exogenous gamma manipulations could influence disease pathology progression. We discovered that optogenetically driving FS-PV-interneurons at gamma frequency (40 Hz) reduced levels of amyloid-[beta] (A[beta])₁-₄₀ and A[beta] ₁-₄₂ isoforms in the hippocampus of 5XFAD mice. Neither driving FS-PV-interneurons at other frequencies, nor driving excitatory neurons, reduced A[beta] levels. Furthermore, driving FS-PV-interneurons at 40 Hz reduced enlarged endosomes and amyloid precursor protein (APP) cleavage intermediates in hippocampus. Gene expression profiling revealed an induction of microglia specific genes associated with morphological transformation of microglia and increased A[beta] phagocytosis by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that induced 40 Hz activity in visual cortex. The light-flickering paradigm profoundly reduced A[beta]₁-₄₀ and A[beta]₁-₄₂ levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. A GABAA antagonist completely blocked this effect; further evidence that GABAergic signaling is essential for this neuroprotective gamma activity. Finally, we showed that 40 Hz activity reduced tau phosphorylation in the TauP301S mouse model. Overall, our findings uncover a previously unappreciated function of the brain's gamma rhythms in neuroprotection by recruiting both neuronal and glial responses to mitigate AD-associated pathology.
by Hannah Frances Iaccarino.
Ph. D.