Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.
(9/3099)
The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function. (+info)
The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease.
(10/3099)
The neuroendocrine protein 7B2 has been implicated in activation of prohormone convertase 2 (PC2), an important neuroendocrine precursor processing endoprotease. To test this hypothesis, we created a null mutation in 7B2 employing a novel transposon-facilitated technique and compared the phenotypes of 7B2 and PC2 nulls. 7B2 null mice have no demonstrable PC2 activity, are deficient in processing islet hormones, and display hypoglycemia, hyperproinsulinemia, and hypoglucagonemia. In contrast to the PC2 null phenotype, these mice show markedly elevated circulating ACTH and corticosterone levels, with adrenocortical expansion. They die before 9 weeks of severe Cushing's syndrome arising from pituitary intermediate lobe ACTH hypersecretion. We conclude that 7B2 is indeed required for activation of PC2 in vivo but has additional important functions in regulating pituitary hormone secretion. (+info)
Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection.
(11/3099)
Certain cytokines activate the hypothalamic-pituitary-adrenal axis for glucocorticoid release, and these hormones can protect against cytokine-mediated pathologies. However, endogenous activation of such a pathway has not been established during infections. A prominent glucocorticoid response peaks 36 h following murine CMV (MCMV) infection, coincident with circulating levels of the cytokines IL-12, IFN-gamma, TNF, and IL-6, and dependent on IL-6 for maximal release. These studies examined functions of the hormone induction. Mice rendered glucocorticoid deficient by adrenalectomy were more susceptible than intact mice to MCMV-induced lethality, and the increased sensitivity was reversed by hormone replacement. Lack of endogenous glucocorticoids resulted in increases in IL-12, IFN-gamma, TNF, and IL-6 production, as well as in mRNA expression for a wider range of cytokines, also including IL-1 alpha and IL-1 beta. Viral burdens did not increase, and actually decreased, in the livers of glucocorticoid-deficient mice. TNF, but not IFN-gamma, was required for increased lethality in the absence of endogenous hormone. These results conclusively demonstrate the importance of induced endogenous glucocorticoids in protection against life-threatening effects resulting from infection-elicited cytokine responses. Taken together with the dependence on induced IL-6, they document existence of an immune system-hypothalamic-pituitary-adrenal axis pathway for regulating endogenous responses to viral infections. (+info)
No effect of pinealectomy on the parallel shift in circadain rhythms of adrenocortical activity and food intake in blinded rats.
(12/3099)
Twenty-four-hr patterns of plasma corticosterone levels were determined at 4-hr intervals every 3-4 weeks in sighted and blinded pinealectomized rats of adult age. Through the whole period of the experiment, 24-hr patterns of food intake were also measured weekly. The sighted rats manifested the same 24-hr patterns of plasma corticosterone levels and food intake for 15 weeks after pinealectomy as those observed in the intact control rats. The magnitude of peak levels of plasma corticosterone and the amount of food intake did not differ between the two groups. A phase shift in circadian rhythms of plasma corticosterone levels and food intake was observed in both groups of blinded rats, with and without pinealectomy. Between the two groups, the patterns of phase shift were essentially similar for 10 weeks examined after optic enucleation. The peak elevation of plasma levels took place at 11 p.m. at the end of the 4th week after optic enucleation. Thereafter, 4- to 8-hr delay of peak appearance was observed every 3 weeks. No significant differences were found in peak values between the two groups of blinded rats. Furthermore, the circadian rhythm of food intake shifted in parallel with that of plasma corticosterone levels. A phase reversal of these two activities was observed between the 8th and 10th week after the operation. These results indicate that the pineal gland does not play any important role either in the maintenance of normal circadian periodicities of adrenocortical activity and food intake or in the shift in circadian rhythms of the two activities in the blinded rats. (+info)
Regulation of protein synthesis after acute resistance exercise in diabetic rats.
(13/3099)
These studies determined whether insulin-like growth factor-I (IGF-I) involvement in exercise-stimulated anabolic processes becomes more evident during hypoinsulinemia. Male Sprague-Dawley rats (n = 6-12/group) were made diabetic (blood glucose congruent with 300 mg/dl) by partial pancreatectomy (PPX) or remained nondiabetic (glucose congruent with 144 mg/dl). Rats performed acute resistance exercise by repetitive standing on the hindlimbs with weighted backpacks (ex), or they remained sedentary (sed). Resistance exercise caused increases in rates of protein synthesis (nmol Phe incorporated. g muscle-1. h-1, measured for gastrocnemius muscle in vivo 16 h after exercise) for both nondiabetic [sed = 154 +/- 6 (SE) vs. ex = 189 +/- 7] and diabetic rats (PPXsed = 152 +/- 11 vs. PPXex = 202 +/- 14, P < 0.05). Arterial plasma insulin concentrations in diabetic rats, congruent with180 pM, were less than one-half those found in nondiabetic rats, congruent with444 pM, (P < 0.05). The activity of eukaryotic initiation factor 2B (eIF2B; pmol GDP exchanged/min) was higher (P < 0.05) in ex rats (sed = 0.028 +/- 0.006 vs. ex = 0.053 +/- 0.015; PPXsed = 0.033 +/- 0.013 vs. PPXex = 0.047 +/- 0.009) regardless of diabetic status. Plasma IGF-I concentrations were higher in ex compared with sed diabetic rats (P < 0.05). In contrast, plasma IGF-I was not different in nondiabetic ex or sed rats. Muscle IGF-I (ng/g wet wt) was similar in ex and sed nondiabetic rats, but in diabetic rats was 2- to 3-fold higher in ex (P < 0.05) than in sed rats. In conclusion, moderate hypoinsulinemia that is sufficient to alter glucose homeostasis does not inhibit an increase in rates of protein synthesis after acute moderate-intensity resistance exercise. This preserved response may be due to a compensatory increase in muscle IGF-I content and a maintained ability to activate eIF2B. (+info)
Induction of epithelial Na+ channel in rat ileum after proctocolectomy.
(14/3099)
In patients with colectomy, epithelial transport function in the remnant small intestine can be regulated in response to the increased fecal electrolyte and fluid loss. Using a rat colectomy model, we investigated the Na+ and K+ transport mechanisms underlying the intestinal response. Proctocolectomy with ileoanal anastomosis was performed on rats. The small intestinal mucosa was mounted in Ussing chambers; then short-circuit currents and 22Na+ fluxes were measured. mRNA expression of the epithelial Na+ channel (ENaC) was determined by Northern blotting. Amiloride-sensitive, electrogenic Na+ absorption appeared in the ileum after proctocolectomy. This functional change was accompanied by the chronological induction of mRNAs for alpha-, beta-, and gamma-subunits of the ENaC in the ileum. Tetraethylammonium-sensitive short-circuit current was also activated. We conclude that electrogenic Na+ absorption and probably K+ secretion are induced in the ileum after proctocolectomy. This induction of electrogenic Na+ absorption is probably mediated by the increase in the mRNA levels for all three types of subunits of the ENaC and may contribute to the recovery from the increased fecal Na+ loss. (+info)
Mechanisms underlying the anti-inflammatory actions of central corticotropin-releasing factor.
(15/3099)
Immune activation of hypothalamic corticotropin-releasing factor (CRF) provides a negative feedback mechanism to modulate peripheral inflammatory responses. We investigated whether central CRF attenuates endothelial expression of intercellular adhesion molecule 1 (ICAM-1) and leukocyte recruitment during endotoxemia in rats and determined its mechanisms of action. As measured by intravital microscopy, lipopolysaccharide (LPS) induced a dose-dependent increase in leukocyte rolling, adhesion, and emigration in mesenteric venules, which was associated with upregulation of endothelial ICAM-1 expression. Intracisternal injection of CRF abrogated both the increased expression of ICAM-1 and leukocyte recruitment. Intravenous injection of the specific CRF receptor antagonist astressin did not modify leukocyte-endothelial cell interactions induced by a high dose of LPS but enhanced leukocyte adhesion induced by a low dose. Blockade of endogenous glucocorticoids but not alpha-melanocyte-stimulating hormone (alpha-MSH) receptors reversed the inhibitory action of CRF on leukocyte-endothelial cell interactions during endotoxemia. In conclusion, cerebral CRF blunts endothelial upregulation of ICAM-1 and attenuates the recruitment of leukocytes during endotoxemia. The anti-inflammatory effects of CRF are mediated by adrenocortical activation and additional mechanisms independent of alpha-MSH. (+info)
Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF.
(16/3099)
We assessed the role of central corticotropin-releasing factor (CRF) in stress-induced worsening of colitis in inbred rat strains with hypo (Lewis/N) and hyper (Fischer344/N) CRF responses to stress. Intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (TNB) induced colitis of similar severity in both strains as assessed on day 7 by macroscopic scoring, histological evaluation, tissue myeloperoxidase (MPO) activity, and decrease in food intake and body weight. Colitis was inhibited by daily intracerebroventricular injections of CRF in both strains. Chronic stress (3 h/day, water avoidance or wrap restraint on alternate days for 6 days) aggravated colitis more in Lewis than Fischer rats (71 and 22% further increase in MPO activity, respectively). The CRF antagonist astressin injected intracerebroventricularly enhanced the colitis response to stress and caused mortality in both strains. Fischer rats had higher plasma corticosterone levels 20 min after stress alone on day 1 and after TNB plus stress on days 1 and 3 compared with Lewis. These data show that central CRF restrains the proinflammatory action of stress in experimental colitis. (+info)