My lab is interested in better understanding how individual neural ensembles are activated upon learning and/or memory. We previously generated an indelible activity-dependent tagging line based off the gene Arc - the ArcCreERT2 mice. We have utilized these mice to better understand how various diseases alter memory traces. Current work is focused on developing combinatorial models to label multiple ensembles in a single mouse.
WHOLE-BRAIN MEMORY TRACE LABELING
Much of our memory trace work was initially focused on the hippocampus. However, we focused on developing an immunostaining, imaging, and quantification pipeline that allowed for unbiased, automatic counting of neural ensembles throughout the brain. This pipeline is now being applied to all areas of research in the lab.
AGE-RELATED COGNITIVE DECLINE AND ALZHEIMER'S DISEASE
Using the ArcCreERT2 x eYFP mice bred with a mouse model of Alzheimer's disease (AD) - the APP/PS1 mice, we have found that memory traces are significantly altered in the dentate gyrus (DG) of the hippocampus. Optogenetic stimulation of these ensembles rescued memory decline. Current work is focusing on sex-specific differences in AD, how age-related cognitive decline (ARCD) influences memory loss, and most recently, how sundowning is represented in neural ensembles following AD progression.
STRESS AND FEAR GENERALIZATION
Much of our work tries to understand how stress influences memory and/or how stressful, fearful exper is generalized from aversive to neutral contexts. Current work is investing fear generalization across the lifespan and in a mouse model of traumatic brain injury (TBI).
We have reported that a single injection of (R,S)-ketamine 1 week before stress attenuates learned fear, decreases behavioral despair, and decreases fear generalization. More recent work has shown that specific metabolites of (R,S)-ketamine differentially impact stress. Current work is focusing on the mechanisms underling this increased stress resilience.
TARGETED DRUG DEVELOPMENT FOR PSYCHIATRIC DISEASE
Although we have found (R,S)-ketamine is an effective prophylactic, there are numerous side effects associated with (R,S)-ketamine. Our recent work has identified three separate 5-HT4R agonists and a novel NMDAR antagonist fluoroethylnormemantine (FENM) as effective prophylactics. We are currently developing other novel compounds with the goal of clinical development.