Mala Ananth

Our brains are constantly changing. This lifelong process is a dynamic interaction between the brain, intrinsic gene programs, and experience. These interactions lay the foundation for neural circuit formation, refinement, and recovery, which fundamentally influence cognitive functions. As we age, our cognitive functions decline with the potential for significant cognitive impairment such as Alzheimer’s Disease (AD). But, remarkably, not all aspects of cognition, and thus not all brain regions, are equivalently affected by age. Our goal is to identify factors that underlie the differential resilience and vulnerability of brain circuits across the lifespan. We utilize cross-species, multimodal approaches, combining genetics, physiology, in-vivo imaging and behavior in preclinical and clinical studies. We use these approaches to address fundamental questions about brain susceptibility and resilience with age.

Our studies focus on the entorhinal cortex (EC), a region where the deterioration or long-term maintenance of circuits can have a dramatic effect on cognition. For example, structural, functional, and histopathological deficits to the EC precede and even predict age-related cognitive impairment. Conversely, resilience of these factors in the EC leads to intact cognition 20-30 years longer than the normal aging process (known as super-agers)! What features of the EC determine its resilience or vulnerability across lifespan? When do perturbations to the EC begin? How do these changes affect cognition?

The EC is uniquely poised to affect cognition. As the primary input-output structure to the hippocampus and a critical mediator of cortico-hippocampal communication, disruption to the EC likely leads to long-lasting consequences brain-wide. We propose that EC vulnerability is a critical, yet understudied, component underlying pathological circuit dysfunction not just with advanced age, but across lifespan.

With these studies we aim to advance understanding of neural circuit vulnerability and resilience. Using factors identified in resilient circuits, our goal is to identify testable avenues to support vulnerable neural circuits and cognition long-term.