Dissertations, Theses, and Capstone Projects

Date of Degree

6-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

Ekaterina Likhtik

Committee Members

Carmen Melendez

Nesha Burghardt

Patrizia Casaccia

Susan Sangha

Subject Categories

Behavioral Neurobiology | Biology | Molecular and Cellular Neuroscience | Neuroscience and Neurobiology | Systems Neuroscience

Keywords

parvalbumin, interneurons, oligodendrocytes, infralimbic cortex, satellite oligodendrocyte lineage cells perineuronal nets, post traumatic stress disorder (PTSD), anxiety, safety learning

Abstract

The ability to differentiate between threat and safety cues is essential for adaptive behavior, yet this process is disrupted in psychiatric disorders, such as post-traumatic stress disorder (PTSD), where safety cues fail to downregulate fear expression. To better understand the neurobiological mechanisms of safety learning, I investigate how safety conditioning vs contextual fear conditioning modify behavioral and cellular mechanisms in the infralimbic (IL) region of the medial prefrontal cortex (mPFC) at several time points after learning. Through this work, I identify a novel mechanism whereby safety learning promotes learning dependent neuro-glial interactions that promote conditions for plasticity in the mPFC. First, I show that safety conditioning (SC) promotes a long-term reduction in contextual fear, providing evidence for improved behavioral flexibility compared to the contextual fear conditioned (CFC ) group. Next, I highlight the role of IL parvalbumin (PV) interneurons, which show higher activity in the SC than CFC group at recent and remote memory retrieval. I demonstrate that these changes in PV activity coincide with an enduring low density of perineuronal nets (PNNs) around the PV cells, supporting the hypothesis that PNN and extracellular matrix (ECM) remodeling underlie plasticity. Next, I test the hypothesis that oligodendrocyte lineage cells (OLCs) modulate PNN dynamics through lineage-specific gene expression. I use data from open-source single-cell RNA sequencing repositories to reveal that oligodendrocyte precursor cells (OPCs) express PNN structural genes, newly-formed oligodendrocytes (NFOLs) express both structural and remodeling gene, and mature oligodendrocytes (MOLs) primarily express PNN-degrading genes. Accordingly, our bulk RNAseq data from the medial prefrontal cortex (mPFC) of SC animals shows reduced expression of OPC and PNN structural genes and increased expression of OL and PNN-degrading genes compared to fear-conditioned animals. I then show that recent safety retrieval induces oligodendrogenesis and recruits satellite oligodendrocyte lineage cells (i.e., satOlig2 cells) to IL PV interneurons, which remain present during subsequent remote safety retrieval sessions. I find that the accumulation of PNNs around PV- satOlig2 cell pairs is a time- and safety learning-dependent process. Thus, the CFC group exhibits an accumulation of PNNs around PV- satOlig2 cell pairs at remote retrieval, whereas most of these pairs are not covered by PNNs in SC animals. To understand the mechanism underlying this time-dependent process of PNN accumulation, I tested the maturation status of the satOlig2 population. I find that during remote safety retrieval, the satOlig2 population is predominantly composed of satOLs, which express more PNN degradation enzymes, suggesting that this recruitment has a safety-dependent purpose. Finally, to understand how satOLs are recruited to the PV INs in safety, I use optogenetics to inhibit PV activity during safety learning. I find that PV inhibition during learning restores contextual fear at the remote time point, prevents satOL pairing with PV, prevents satOL maturation, and prevents PNN degradation in the IL. Taken together, I propose that a heterogeneous satOlig2 population supports memory consolidation in SC animals. Immature satOPCs may stabilize synaptic inputs by expressing PNN-building genes early after learning, whereas mature satOLs likely express enzymes which degrade existing PNNs or keep new ones from forming later after learning. With less PNN accumulation, PV interneurons may be more open to new synaptic inputs, which help maintain balanced excitatory/inhibitory signaling in the cortex that is critical for fear inhibition and adaptive behavior. In contrast, the high-fear phenotype observed in CFC animals—characterized at remote retrieval by low infralimbic PV activity, high PNN density, and low satOlig2 cell recruitment—may underlie a system that induces rigid, inflexible memory, reminiscent of PTSD. This may be driven by the aggregated expression of prefrontal PNN structural genes, which we observe in fear conditioned animals. This study highlights a novel role for satellite oligodendroglia in supporting memory processes through modulation of PNN dynamics. These findings offer new insights into the mechanisms of safety learning and suggest potential OL- and ECM- based therapeutic targets for PTSD and related disorders.

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