Project Summary
The hippocampus plays a critical role in the formation of episodic memories by generating
distinct, conjunctive representations of (spatial and social) experiences and transferring these
representations to prefrontal cortical sites for memory storage or consolidation. Age-related
cognitive decline and mild-cognitive impairment (MCI) are characterized by increased memory
interference, decreased stability of memory representations and inefficient memory
consolidation. Evidence from humans, non-human primates and rodents demonstrate reduced
hippocampal neurogenesis, hippocampal hyperactivity and inflexible remapping during age-
related cognitive decline and MCI. Parvalbumin inhibitory interneurons (PV INs) play a pivotal
role in memory discrimination and consolidation by regulating neuronal excitability and
synchronizing neuronal firing underlying neuronal ensembles and sharp-wave ripples (SWRs).
Thus, reduced PV IN recruitment in hippocampal CA2, a hub for social memory processing, may
contribute to age-associated social memory impairments. Here, we propose a role for
neurogenesis-inhibition coupling in the dentate gyrus-CA2 as a candidate circuit mechanism by
which adult-born neurons promote social memory consolidation in adulthood and aging. In
response to the FOA, we will develop and validate an in vivo gain-of-function platform for iterative
testing of pro-cognitive potential of novel candidate regulators of neurogenesis-inhibition
coupling during aging. Towards this goal, we will build on extensive preliminary and published
data and integrate a genetic approach to enhance neurogenesis, input-specific manipulation of
PV INs, activity-dependent molecular profiling of PV INs, PV IN targeted viral expression,
optogenetics, ex vivo and in vivo local field potential recordings and an aging-sensitive social
memory behavioral paradigm. Together, these Aims will establish proof-of-concept for a novel
platform for targeting a neurogenesis-inhibition coupling mechanism to improve social memory
in aging and MCI.