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Although brain pathways activated by sepsis may respond acutely to endotoxin administration, the long-term central response to sepsis is not known. We prepared male rats for hormonal sampling at the circadian nadir (AM) and peak (PM) after cecal ligation and puncture (CLP) or sham surgery. Diurnal variation of corticosterone was present on postoperative day (D) 3 and D4 after sham surgery but not after CLP. CLP increased Fos immunostaining in the nucleus of tractus solitarius (NTS), ventrolateral medulla, medullary raphe, parabrachial nucleus, hypothalamus, amygdala, bed nucleus of stria terminalis, and preoptic region. Fos responses were generally greatest on D1 but persisted to the AM of D4. The number of Fos-positive cell nuclei in the NTS on D3 and D4 did not differ but had greater variance on D3 than on D4 (P<0.01) with a divergent response in the PM of D3 that was correlated with plasma ACTH (r=0.927, P<0.01) but not with corticosterone. CLP increased CRH-staining intensity in the hypothalamic paraventricular neurons uniformly from D1 through D4 (P<0.01). Similar to Fos in NTS, this response was correlated with plasma ACTH (r=0.738, P<0.05) and adrenal size (r=0.730, P<0.05) in the PM of D3. Neuronal CRH became detectable after CLP in specific medullary areas on D1 and in the preoptic region on D3 and D4. Thus, the suppression of circadian variation by CLP was associated with central neural responses that increased in relation to plasma ACTH without apparent influence on the release of corticosterone.