Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zenz, G.
Protective potential of neuropeptide Y to maintain brain function and behavior disturbed by viral or bacterial immune stimulation in the periphery
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 127
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Farzi Aitak
- Holzer Peter
- Reichmann Florian
- Altmetrics:
- Abstract:
- The peripheral immune system and the brain continuously interact with each other via several routes. Thus, visceral inflammation evokes an immune reaction within the periphery which also induces the expression of pro-inflammatory cytokines and other modulators within cerebral tissue. These effects are associated with a behavioral sickness response, reflected by reduced motivation to explore new environments and to interact with other individuals, as well as decreased ingestive behavior. While these sickness-evoked molecular and behavioral alterations are physiologic responses to an acute infection, under certain circumstances an overshooting or chronic stimulation of the immune-brain axis has detrimental effects. Thus, a subgroup of patients suffering from neuropsychiatric disorders, like major depressive disorder, present with elevated circulating inflammatory markers as well as an activated hypothalamus-pituitary-adrenal (HPA) axis and are often treatment-resistant. Therefore, strategies to interfere in the transmission of certain pro-inflammatory processes from the periphery to the brain are urgently needed. Many studies in this field thus far used peripheral toll-like receptor 4 (TLR4) activation by bacterial factors like lipopolysaccharide (LPS) to stimulate the immune-brain axis, however, little is known about the effects of virus-associated molecular patterns. The first aim of this study was therefore to systematically analyze the acute (neuro-) immune and behavioral effects of intraperitoneally applied polyinosinic:polycytidylic acid (Poly(I:C)) (12 mg/kg), a viral dsRNA mimic and TLR3 agonist, in mice. Additionally, the behavioral effects of the TLR3 agonist were compared to the effects evoked by a comparably lower dose of LPS (0.03 mg/kg). Furthermore, it was investigated whether Poly(I:C) might induce anxiety- and depression-related behavioral changes when the acute sickness response had already abated, effects that were previously reported in studies involving LPS. Another set of experiments aimed to elucidate whether a time-restricted feeding regimen, which is thought to beneficially influence some inflammation-related disorders, might impact the detrimental effects induced by Poly(I:C). Furthermore, it was analyzed whether intranasal pretreatment with the anti-inflammatory neuropeptide Y (NPY) (100 µg), a peptide with anti-inflammatory effects in the brain, could interfere with the behavioral and immunological effects in response to LPS at 3 h and 21 h post treatment. This report shows that Poly(I:C) evokes a clear acute behavioral sickness response, which peaks around 4 h after application in a homecage-like environment and is not followed by anxiety- or depression-related behavior. Furthermore, a comparably high dose of Poly(I:C) elicits a relative mild behavioral sickness response when compared to LPS as assessed within the LabMaster system. Surprisingly, preceding fasting aggravated Poly(I:C)-induced increase in circulating cytokine levels (IL-6, IFN-γ, TNF-α, IFN-α, MCP-1, IL-10) as well as the behavioral sickness response observed at 4 h following immune stimulation during the open field (OF) test. Intranasal pretreatment with NPY, on the other hand, potently abated the acute behavioral sickness response 3 h following LPS treatment, attenuated LPS-induced weight loss and reduced the HPA axis activation as reflected by reduced circulating corticosterone (CORT) levels at the later time-point under study. In summary, the findings of this study highlight an adverse influence of intermittent fasting on TLR3-mediated immune stimulation and sickness behavior associated with a boost in peripheral cytokine levels, and a favorable impact of NPY, infused to the nasal cavity, on the behavioral and HPA axis effects of peripheral LPS challenge.