THE ROLE OF HIPPOCAMPAL NEURAL IMMUNE SIGNALING IN STRESS-ENHANCED FEAR LEARNING: IMPLICATIONS FOR POST-TRAUMATIC STRESS DISORDER
Public Deposited- Last Modified
- March 20, 2019
- Creator
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Jones, Meghan
- Affiliation: College of Arts and Sciences, Department of Psychology and Neuroscience
- Abstract
- Psychopathology and disease states involving depression and anxiety, including post-traumatic stress disorder (PTSD), have been associated with immune dysregulation. Preliminary data from our laboratory has suggested that severe stress induces a time-dependent increase in hippocampal IL-1β immunoreactivity and that centrally blocking IL-1 signaling prevented the development of stress-enhanced fear learning, a rodent PTSD-like phenotype. In parallel, astrocyte-derived cytokines and astroglial signaling have been linked to the development of PTSD-like phenotypes following severe stress. The goal of the current dissertation was to use the stress-enhanced fear learning paradigm to explore the role of neural immune signaling in the development of a PTSD-like phenotype. The experiments described in the current dissertation tested the overarching hypothesis that (1) severe stress induces changes in hippocampal astrocyte-derived IL-1β expression and the morphometric properties of hippocampal astrocytes and (2) that both blocking hippocampal IL-1 signaling and activating hippocampal astroglial Gi signaling prevent the development of SEFL. Experiments described in Chapter 2 confirm the hypothesis that hippocampal IL-1 signaling is required for the development of SEFL and reveal astrocytes as the predominant cellular source of hippocampal IL-1β. Additional analyses in Chapter 2 revealed that severe stress induces a reduction in ionized calcium-binding adaptor molecule 1 (Iba-1) immunoreactivity, with no effect on glial fibrillary acidic protein (GFAP) immunoreactivity. Experiments described in Chapter 3 demonstrate that there is no change in hippocampal astrocyte volume, surface area, or colocalization with a synaptic marker, postsynaptic density 95 (PSD95), 48 hours post-stress. However, there was a significant stress-induced reduction in PSD95 immunoreactivity. Finally, experiments described in Chapter 4 show that astroglial Gi activation was sufficient to attenuate SEFL and provide the first direct evidence to support the validity of GFAP-hM4Di in that we detected a CNO-induced reduction in the colocalization between virus-positive cells and cyclic adenosine monophosphate (cAMP), a Gi-dependent second messenger. Collectively, these data suggest that hippocampal astrocytes are critically involved in SEFL and identify two signaling pathways that can be targeted to attenuate the development of a PTSD-like phenotype. This work suggests that neural immune signaling represents a promising target for the development of novel therapeutics to treat PTSD and provides insight to inform future endeavors to better understand the neurobiological mechanisms driving the acquisition and encoding of fear memories.
- Date of publication
- December 2017
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Lysle, Donald
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2017
- Language
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