Circuits and Systems

Systems level analysis of neurodegeneration

Rhythmic synchronous neural activity gives rise to brain oscillations at different frequencies. Cognitive deficits that occur in neurodegeneration may arise from an accumulation of altered cellular processes that lead to disruptions in neural circuits and network connectivity. In particular, oscillations in the gamma frequency range (between 30-80 Hz) are associated with higher order brain functions, and has been shown to be disrupted in the early stages of AD in human patients as well as in mouse models. We are thus interested in applying circuit manipulations to ameliorate cognitive deficits in AD. We previously showed that we could induce population-wide gamma oscillations in mice using optogenetics to entrain large groups of neurons to synchronize their firing patterns. Most recently, we developed non-invasive methods of inducing gamma oscillations by presenting sensory stimulation using light and sound at specific frequencies to the mice, which we have named Gamma ENtrainment Using Sensory stimuli (GENUS). In collaboration with Ed Boyden’s lab at MIT, we used GENUS to enhance gamma oscillations, and surprisingly found a marked reduction in amyloid and phospho-tau levels in several AD and neurodegeneration mouse models. The therapeutic effects of gamma oscillations appear to involve the concerted actions of neurons and microglia to reduce the production and enhance clearance of amyloid, respectively. Multi-site electrophysiological recordings in vivo reveal that GENUS can impact neural activity across broad brain regions and, significantly, improves cognitive performance in multiple mouse models. We are currently investigating the mechanisms that underlie the beneficial effects of GENUS. We are also exploring the interneuron network and involvement of neuromodulatory systems in mediating GENUS.

Through collaboration with MIT’s Clinical Research Center and faculty members across multiple disciplines at MIT, we are gearing up to apply GENUS to human subjects. State-of-the-art technology, such as magnetoencephalography (MEG), electroencephalography (EEG), functional magnetic resonance, imaging (fMRI), amyloid PET imaging, and cognitive tests will be used to investigate if this non-invasive approach using GENUS is neuroprotective in human subjects.

Through the targeted application of optogenetic and chemogenetic tools, we also aim to manipulate the activity of specific neural populations and circuits to gain insights at the intersection of pathology, network activity, and behavior. Additionally, we are mapping out the sequential temporal and spatial disruptions of neural circuits by the deposition of amyloid and aggregated tau protein in AD, to identify nodes of vulnerability and to understand how these pathologies propagate throughout the brain. Current work involves mapping various AD-related pathology in a 3-D manner in mouse and human brains. We are collaborating with Kwanghun Chung at the Picower Institute at MIT to apply enhanced CLARITY techniques to interrogate the relationship of amyloid plaques, tau tangles, neural inflammation, and vasculature pathology in different mouse models of AD and in postmortem human brain samples of AD subjects.