Investigating perineuronal nets and hippocampal plasticity in early life adversity-induced anxiety

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PROJECT SUMMARY Early life adversity is associated with an increased incidence of anxiety disorders in adulthood. Understanding the cellular processes that connect early life stress with excessive anxiety may provide clues for the development of new therapies to treat anxiety disorders. Studies in humans and rodents have identified subregions of the hippocampus as important for anxiety regulation. Neuronal oscillations in both theta and gamma frequency ranges in the hippocampus have been linked to anxious behavior and these oscillations are driven by coordinated activity among a specific class of inhibitory interneurons, the parvalbumin positive (PV+) basket cells. Perineuronal nets (PNNs), extracellular matrix structures that modulate plasticity and have been linked to psychopathology, surround many PV+ basket cells. In mice, early life adversity increases PNN formation around PV+ cells in the ventral hippocampus, raising the possibility that this change leads to early life adversity-induced enhancement of neuronal oscillations and anxiety. Adult neurogenesis in the ventral hippocampus is also impacted by early adverse experience and adult-generated granule cells are known to synapse with PV+ basket cells. The possibility that connections between adult-generated neurons and inhibitory interneurons are altered by postnatal stress, potentially through alterations in PNNs, and thus produce enhanced neuronal oscillations and anxiety remains unknown. This proposal is designed to address the gaps in our understanding about how early life stress alters hippocampal PNNs, adult-generated granule cell connections with inhibitory interneurons, neuronal oscillations and anxiety and to explore the connections among these effects. The proposed experiments will use a mouse model of early life stress, manipulations of PNNs in the hippocampus, retroviral labeling of new granule cells in the hippocampus, immunolabeling combined with confocal microscopy and electron microscopy, transgenic and retroviral-mediated manipulation of adult-generated neuron number, in vivo electrophysiology during behavior and anxiety test analyses in adult male and female mice. The studies in this proposal are designed to achieve three significant and related, but not interdependent, aims regarding the influence of early life stress on hippocampal plasticity in adulthood with the long-term goal of understanding the cellular changes that lead to increased neuronal oscillations and anxiety.