Research Projects

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, with a significant socioeconomic impact. Brain stimulation has shown promising therapeutic outcomes to provide symptomatic relief in AD individuals. However, studies related to the cell-type-specific neuronal activation and its mechanistic effects in AD are lacking. A core pathological hallmark of AD is the accumulation of hyperphosphorylated tau, which severely affects neuronal structure and function. Somatostatin-expressing (SST) interneurons, vulnerable to tau pathology, are a key regulator of cortical inhibition and network synchrony. Studies are required to understand the specific role of SST interneurons in disease progression and therapeutics. This lacuna is addressed through this proposal, which aims to investigate the dysfunction of SST interneurons in tauopathy and evaluate whether their activity can be modulated through non-invasive transcranial electrical stimulation (tES). We specifically hypothesize that tES administered with specific paradigms (8 Hz and 40 Hz) will regulate SST interneurons, improve their activity, mitigate tau pathology, and improve cognitive outcomes. Utilizing the SST-Cre x P301S transgenic mouse model, which allows selective monitoring of SST neuron activity in a tauopathy background, we will characterize SST interneuron activity patterns and use brain stimulation to improve learning and memory. To address this, experiments such as calcium signaling (jGCaMP), immunohistochemistry (e.g., cFos expression), and in vivo electrophysiology (neuronal action potentials) will be conducted. This will shed light on SST neuronal activity in a model of neurodegeneration. Further, chronic tES followed by behavioral analysis, such as novel object recognition and location and Y-Maze, will provide insight into the impact of specific frequencies of tES stimulation on spatial memory and cognition. After chronic tES, we will also measure synaptic and neurodegenerative markers. Overall, this work will provide novel mechanistic insights into SST-specific circuit dysfunction in AD and establish a foundation for developing targeted, circuit-based brain stimulation strategies for AD intervention.