Exposure to chronic stress can activate the neuroinflammatory system in the brain, including microglial cell that may then produce the proinflammatory cytokines interleukin-1? (IL-1?), IL-6 and tumor necrosis factor-alpha (TNF?). One possible regulator of this inflammatory response is Orphanin FQ/nociceptin (OFQ/N), a neuropeptide that contributes to a variety of physiological regulatory processes, including inhibition of anxiogenic and/or depressive-like behaviors. Indeed, OFQ/N has been implicated in the regulation of systemic immunological and inflammatory processes, and in preliminary data, it was found that 14 days of chronic unpredictable stress produced a significant and augmented elevation in hippocampal IL-1?, but not TNF?, in mice lacking the precursor polypeptide for OFQ/N (ppOFQ/N). We therefore hypothesize that OFQ/N is necessary to attenuate stressor-induced activation of the brain neuroinflammatory system, including microglial activation and the synthesis and release of proinflammatory cytokines, such as IL-1?.
Two Specific Aims will test this hypothesis.
In Specific Aim 1, chronic stress will be imposed on mice deficient for either ppOFQ/N or the OFQ/N receptor, NOP-1. Wildtype mice (stressed and non-stressed) will be used as controls. Measures of protein and mRNA for IL-1?, IL-6, and TNF?, as well as the anti-inflammatory cytokines IL-10 and TGF? will be obtained in the prefrontal cortex, hippocampus, amygdala and hypothalamus. In addition, immunohistochemistry will determine whether there is genotype-dependent activation and cytokine localization to microglial cells, as well as stress-dependent changes in NOP-1 expression. Finally, 2-photon ex vivo hippocampal slice imaging of microglial activity will be performed on OFQ/N and NOP-1 KO and WT mice expressing eGFP in microglia to assess genotype- and/or stress-dependent effects on microglial morphology and dynamics. These biochemical and cellular observations will be complemented by behavioral analysis in Specific Aim 2. The ppOFQ/N and NOP-1 KO and WT mice will be exposed to chronic stress and then subjected to behavioral testing to assess learning and memory, as well as anxiety-like behavior. A major focus is to use a working memory version of the hippocampal-dependent T-maze spatial learning task. Excessive deficits in these behaviors in stressed KO mice, but not WT mice exposed to stress, will suggest that OFQ/N limits the neuroinflammatory response during stress in order to maintain behavioral stability. If the data lead to this interpretation, the role of IL-1? will be tested using IL-1 receptor antagonist administration in stressed and non-stressed KO and WT mice. These experiments will establish the importance of the OFQ/N ligand-receptor system as an anti-inflammatory mechanism for maintaining behavioral resilience in the face of persistent stress. Further, this will create new developments in understanding the cause and treatment of stress-related mental health disorders, and indicate that the failure of correction systems (such as OFQ/N) may result in impaired adaptation to chronic stress.
Statement Psychological stress activates the cellular and molecular components of inflammation in the brain. This inflammatory response needs to be negatively regulated during stress to prevent pathology. Therefore, understanding these regulatory systems, may reveal therapies to treat and prevent psychiatric disorders.
| Ye, Xuan; Feng, Tuancheng; Tammineni, Prasad et al. (2017) Regulation of Synaptic Amyloid-? Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease. J Neurosci 37:2639-2655 |
