Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Abstract

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.

Sepsis-induced alterations in sleep of rats

“…In addition to direct actions of cytokines on neurons in the SCN, the disruption to the normal diurnal rhythms for the parameters of interest in this study may also be due to endocrine responses to sepsis. CLP-induced sepsis alters rhythms of the hypothalamic-pituitary-adrenal axis (HPA) of rats (10), which is associated with increased immunoreactivity of corticotropin-releasing hormone in the hypothalamus (9). Cytokine actions in the brain are modulated via negativefeedback effects of corticosterone (56).…”

Messenger RNA for neuropeptide Y in the arcuate nucleus increases in parallel with plasma adrenocorticotropin during sepsis in the rat

“…These metabolic effects result in part from the response of central stress pathways [21]. We recently mapped the central expression of the immediate gene product, Fos, in the cecal ligation and puncture (CLP) model of polymicrobial sepsis [9]. The most intense expression of Fos occurred during the first 28 h, but some responses were sustained for three or more days.…”

Neuroanatomy of Sepsis-Associated Encephalopathy

“…Sepsis is associated with multiple neuroendocrine disorders [23,25,[31][32][33][34][35]. While the initial stage of sepsis is marked by increased secretion of pituitary hormones notably in response to a decreased sensitivity in peripheral hormonal receptors, prolonged sepsis is characterized by a decrease in pituitary hormone release [36].…”

“…1 Schematic representation of the interaction between sepsisassociated neurological syndromes, the affected structures and clinical outcomes. Modified from [15] with permission response [23]. Brainstem dysfunction might result in impaired alertness and impaired cardiovascular and immune controls, thereby leading to increased mortality.…”

“…Two distinct pathways transmit inflammatory signals to the brain in the absence of blood brain barrier disruption: (1) the vagal nerve senses local inflammation and transfers the information to the medullary autonomic nuclei [23,24]; and (2) circumventricular organs allow the trafficking of inflammatory mediators into the brain [25]. The vagal nerve is stimulated shortly after a lipopolysaccharide (LPS) challenge [24].…”