Re-engineering memory circuits to restore cognition in brain disorders

Adaptively responding to the environment is critical to optimal navigation of our world. The hippocampus plays a critical role in this process by generating memories of our experiences, transferring these memories for storage or consolidation to the prefrontal cortex and recalling and routing memories to subcortical circuits to calibrate defensive and motivated behaviors (e.g., approach, cadence, avoidance, reward seeking). It is intuitive to think how aberrations in hippocampal circuit mechanisms underlying memory processing or storage or linkage of mnemonic information with subcortical circuits are the basis for cognitive impairments in neurodevelopmental disorders, aging and Alzheimer’s Disease. The mission of the Sahay lab is to generate insights to reverse these aberrations through investigation of molecular, circuit and network plasticity mechanisms supporting hippocampal dependent memory processing in cognition.

Our projects are governed by the intuitive logic that elemental features of wiring diagrams are prescribed by proteins, whose functions have been fine-tuned by evolution and experience. By identifying molecular determinants of elemental features of circuit wiring diagrams, we strive to ascribe causal relationships between circuit motifs and function. Towards this goal, we have undertaken a multifaceted bottom-up approach that integrates inducible mouse- and viral-genetics, pharmaco- and optogenetics, synaptic tracing, in vivo awake behaving optical imaging, ex vivo electrophysiology, in vivo electrophysiological recordings and behavioral analysis. In published and ongoing studies, we have identified mechanisms to rejuvenate hippocampal circuitry with new adult-born neurons, re-engineer connectivity of hippocampal inhibitory microcircuits and restore inhibitory circuit plasticity to reverse cognitive impairments in aging, AD and in models of neurodevelopmental disorder risk genes.