Elsevier

Neuroscience

Volume 106, Issue 1, 3 September 2001, Pages 137-148
Neuroscience

Time-dependent sensitization of corticotropin-releasing hormone, arginine vasopressin and c-fos immunoreactivity within the mouse brain in response to tumor necrosis factor-α

https://doi.org/10.1016/S0306-4522(01)00276-7Get rights and content

Abstract

Stressor or cytokine treatments, such as interleukin-1β, 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-α (TNF-α), provoked a time-dependent sensitization of neuroendocrine and brain monoamine activity. To further explore the protracted consequences of TNF-α, 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-μg tumor necrosis factor-α 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-α 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-α 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-α 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.

Section snippets

Experimental procedures

Adult male CD-1 mice (3–4 months of age), obtained from Charles River Inc. (Laprairie, QC, Canada) were housed in groups of four in standard propylene cages. After arrival, mice were given at least 2 weeks to acclimate to the laboratory. Animals were maintained on a 12-h light–dark cycle (lights on 08.00–20.00 h), and all experimental procedures were conducted between 09.00 h and 12.00 h in order to avoid variations due to diurnal rhythms. An ad libitum diet of Ralston Purina (St. Louis, MO,

Results

At the time of killing, mice acutely treated with TNF-α showed few signs of illness. However, as we previously observed (Hayley et al., 1999), mice re-exposed to TNF-α 14 or 28 days following initial exposure to this cytokine generally displayed marked sickness, characterized by reduced motor activity and social exploration, curled body posture, piloerection, and ptosis. In addition, mice showed clear signs of cyanosis of the ears, nose and tail, and hypovolemia reflected by a pronounced

Median eminence colocalization of AVP and CRH

Over time following acute stressor or IL-1β treatment, phenotypic changes occur within CRH neurons terminating in the external zone of the median eminence, such that AVP and CRH expression increases (Schmidt et al., 1995). In the present investigation, a single dose of TNF-α likewise provoked a time-dependent shift towards increased AVP/CRH co-immunoreactive terminals within this site, largely attributable to increased AVP within CRH terminals. This effect peaked 7–14 days following cytokine

Acknowledgements

This research was supported by Grant MT-13124 from the Medical Research Council of Canada. H.A. is an Ontario Mental Health Senior Research Fellow and S.H. was supported by a scholarship from the Canadian Institutes of Health Research. The technical assistance of Babben Tinner, Amy Peaire and Dr. Jerzy Kulczyski is greatly appreciated.

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