Victor Luna, PhD 
Assistant Professor of Clinical Neurobiology (Research)
Department of Psychiatry, Columbia University Irving Medical Center
and Research Scientist IV, New York Psychiatric Institute

Harnessing Neurogenesis to Rejuvenate Cognitive Function in Aged Mice
Dementia is the loss of cognitive functioning across multiple domains (e.g. memory, attention, language). Age is the major risk factor for dementia, yet the neuronal mechanisms underlying age-related cognitive decline remain unclear. In this talk, I will discuss our studies on the dentate gyrus (DG) of the hippocampus, one of the most vulnerable structures to the aging process. The DG is one of only two brain regions capable of generating new neurons throughout adulthood, a process known as ‘adult hippocampal neurogenesis’ (AHN). This is a powerful form of brain plasticity that promotes ‘cognitive discrimination’: the ability to distinguish similar memories from each other, deficits of which manifest as a tendency to lump experiences together and confuse memories. AHN levels sharply decrease with advancing age and even more significantly with dementia. This has led to the hypothesis that low levels of AHN could be a major driver of age-related cognitive decline. However, previous studies have merely speculated on this possibility but were unable to directly manipulate AHN in aged animals without affecting other physiological mechanisms that could, on their own, also improve cognitive performance. To circumvent this problem, we developed a genetic gain-of-function strategy that allowed us to specifically increase AHN in aged mice (referred to as ‘aged iBax’ mice). We determined that increasing AHN can be sufficient to rescue cognitive discrimination deficits due to aging, as evidenced by the improved performance of aged iBax mice compared to aged controls in a contextual fear discrimination task. In fact, aged iBax mice performed nearly as well as young mice. We then identified the mechanisms that could underlie this behavioral rescue using a combination of electrophysiology and optogenetics. We found that increasing AHN in aged iBax mice resulted in enhanced inhibition of mature granule cell (mGCs)—the main cell type of the DG—through upregulation of metabotropic glutamate receptor 2 (mGluR2). Additionally, we found that increasing AHN attenuated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitation of mGCs. These mechanisms effectively dampen DG excitability and ensure that network activity is sparse, a key DG feature believed to promote cognitive discrimination. To determine the precise role of mGluR2 and AMPARs on cognitive discrimination, I will discuss future experiments employing virus-based overexpression and RNA interference strategies to control these glutamate receptors in the DG of aged mice. Finally, I will discuss collaborative opportunities I hope to establish with UW faculty to understand the adaptive (and maladaptive) effects of targeting AHN on cognitive functions of aged animals. These studies will be essential for developing AHN-based therapies that could mitigate cognitive impairments that arise due to advancing age.

This lecture is part of the candidate review process for the Molecular Mechanisms of the Mind faculty position in the Department of Psychology.  Faculty host: Joe Sisneros, sisneros@uw.edu.

Accommodation requests related to a disability should be made by 1/18/21 to chairpsy@uw.edu.