Date of Award

Fall 2021

Document Type

Open Access Dissertation


Biomedical Science

First Advisor

Michy P. Kelly


People tend to be social by nature. Being socially connected not only helps people live longer and healthier lives, but being an engaged and contributing member of society strengthens our communities overall. Maintaining intact social behaviors is key to maintaining this wellbeing, with disruptions negatively affecting both mental and physical health. Indeed, social isolation and feelings of loneliness can significantly increase a person’s risk of premature death, heart disease, and stroke as well as depression, anxiety, suicide, and dementia. Maintaining the ability to create and store social memory with age is, therefore, key to maintaining proper social behaviors. Unfortunately, individuals experience age-related cognitive decline, including memory deficits. Despite the prevalence of deficits in social behaviors in neuropsychiatric and age-related diseases, there is a lack of therapeutics to treat them. In particular, the underlying mechanisms that control social behaviors, how social experiences feedback to regulate these pathways, and how these pathways change with age are not well understood. Therefore, studies here aim to determine how modulating expression and subcellular compartmentalization of PDE11A across the lifespan drives social behaviors. Specifically, these studies investigated how region- (e.g., CA1 versus subiculum) and compartment-specific manipulations (e.g., cytosol versus membrane) of PDE11A4 change social memory and social interaction behavior. Modulation of PDE11A was accomplished through environmental changes, such as social isolation, genetic deletion, or virally increasing/decreasing expression. Overall, we determined that membrane-associated PDE11A4 expression in the ventral hippocampus is a key driver of social behaviors. First, we investigated the role of PDE11A4 in short-term and long-term social memory and found that deletion of Pde11a produces transient amnesia for social memories in adolescent, young adult, and old adult mice. Further, we could reverse this transient amnesia phenotype by acutely restoring recombinant PDE11A4 in young adult Pde11a KO mice. Since we find that PDE11A4 increase with age, we sought to investigate the effects of modulating PDE11A4 across the lifespan. To do this, we mimicked/reduced age-related increases to cause/reverse age-related cognitive decline for social memories. Next, we resolved that even brief social experiences during adulthood (e.g., acute social isolation)—but not adolescence--regulates PDE11A4 subcellular compartmentalization and selectively decreases membrane pools of PDE11A in the VHIPP, Further, isolation induced-decreases in PDE11A4 in adults are sufficient to drive increases in neuroinflammation. Lastly, selectively reducing the membrane-pool of PDE11A4 alone alters both social preference behaviors and social memory formation. Altogether, these studies resolve the temporal and sub-regional function of PDE11A4 signaling in modulating social behavior.


© 2021, Kaitlyn Pilarzyk

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