Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Steven F. Maier

Second Advisor

Linda R. Watkins

Third Advisor

Robert Spencer

Fourth Advisor

Ryan Bachtell

Fifth Advisor

Monika Fleshner

Abstract

Neuroinflammatory processes are well known to regulate behavior, mood, and cognition and are considered a key factor in the development of psychiatric disorders. Exposure to acute or chronic stressors primes the neuroimmune microenvironment to produce exaggerated or enhanced neuroinflammatory responses to a subsequent immune challenge. This primed state persists for many days after stress exposure. However the mechanism(s) that lead stressors to prime neuroinflammation are largely unknown.

Advancement in our understanding of peripheral innate immune function led to the discovery that endogenous molecules are released in response to `danger' to assist immune/inflammatory processes. Recent evidence suggests similar processes are present in the CNS. Here, stress is explored as a process that can be conceptualized as `danger' in which the danger signal, high mobility group box 1 (HMGB-1) is released in the brain to prepare neuroinflammatory responses to subsequent pro-inflammatory stimuli.

The data presented in this dissertation established that signaling via toll-like receptor (TLR) 2 and/or TLR4 in the brain is required for stress-induced microglia priming and sensitization of neuroinflammatory responses to a peripheral immune challenge. Next, HMGB-1 was explored as the signal to TLR2/TLR4. Inescapable tailshock increased HMGB-1 protein in the hippocampus and HMGB-1 was actively released by hippocampal microglia. Central administration of an HMGB-1 antagonist during inescapable tailshock prevented stress-induced microglia priming.

HMGB-1 is susceptible to post-translational modifications that determine receptor interaction and inflammatory function. Disulfide HMGB-1 has been shown to bind TLRs and is likely the primary form that drives stress-induced priming. Central administration of dsHMGB-1 was sufficient to prime the overall neuroinflammatory response to a peripheral LPS injection as well as microglia response to LPS ex vivo. This is likely mediated, in part, by a direct effect on microglia as microglia treated with dsHMGB-1 were primed to a later LPS challenge.

Lastly, the intracellular mechanism by which HMGB-1 drives neuroinflammatory priming was explored. Stress-induced HMGB-1 likely primes neuroinflammatory responses via the NLRP3 inflammasome. Both inescapable tailshock and central administration of dsHMGB-1 increased hippocampal NLRP3 protein for at least 24 h. Furthermore, direct treatment of dsHMGB-1 on isolated microglia increased NLRP3 transcription. This effect was not accompanied by the synthesis of pro-inflammatory cytokines suggesting that the NLRP3 inflammasome is primed but not active.

The work presented in this dissertation implicates HMGB-1 as an endogenous danger signal that is released in the brain in response to stress to prime neuroinflammatory responses by acting on the NLRP3 inflammasome, in preparation for a later immune challenge.

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