title: Time-dependent sensitization of corticotropin-releasing hormone, arginine vasopressin and c-fos immunoreactivity within the mouse brain in response to tumor necrosis factor-alpha.
abstract: Stressor or cytokine treatments, such as interleukin-1beta, promote time-dependent alterations of hypothalamic-pituitary-adrenal functioning, including increased arginine vasopressin stores within corticotropin-releasing hormone (CRH) terminals in the external zone of the median eminence. Likewise, we have previously shown that the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), provoked a time-dependent sensitization of neuroendocrine and brain monoamine activity. To further explore the protracted consequences of TNF-alpha, the present investigation determined whether the cytokine sensitized activity of neuroendocrine regulatory brain regions, as assessed by c-fos expression, and had protracted consequences on amygdaloid CRH, as well as hypothalamic corticotropin secretagogues. Indeed, immunoreactivity for arginine vasopressin and corticotropin-releasing hormone, and their colocalization within cell terminals of the median eminence, varied over time following an initial 4.0-microg tumor necrosis factor-alpha treatment, peaking after 7 days and normalizing within 28 days. Within the central amygdala, a sensitization effect was evident as reflected by increased CRH immunoreactivity, but this effect required re-exposure to the cytokine, unlike the median eminence changes that simply evolved with the passage of time. As well, tumor necrosis factor-alpha provoked a marked sensitization of c-fos staining within the paraventricular nucleus of the hypothalamus, supraoptic nucleus and the central amygdala. From these data we suggest that tumor necrosis factor-alpha influences responsivity of stressor-reactive brain regions and has protracted effects on central neuropeptide expression within the hypothalamus and central amygdala, although the time course for the effects vary across brain regions. Evidently, exposure to tumor necrosis factor-alpha may promote neuroplasticity of brain circuits involved in mediating neuroendocrine, sickness or inflammatory responses. It is suggested that such a sensitization may influence the response to immunological and traumatic insults and may thus be relevant to behavioral pathology.
authors.affiliation: Institute of Neuroscience, Life Science Research Building, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S 5B6. shayley@ccs.carleton.ca
authors.forename: S
authors.initials: S
authors.lastname: Hayley
authors.forename: W
authors.initials: W
authors.lastname: Staines
authors.forename: Z
authors.initials: Z
authors.lastname: Merali
authors.forename: H
authors.initials: H
authors.lastname: Anisman
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008473:Median Eminence / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology; D013495:Supraoptic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone