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Traditional fermented millet gruel is frequently eaten by children in Burkina Faso as a complementary food or for breakfast. The effects of gruel energy density and feeding style on intakes (amounts and energy) were assessed in children in Ouagadougou. Twenty-three young children (11 infants and 12 toddlers) were given two meals of gruel per day for two periods of 11 consecutive days, first, the traditional fermented gruel (TFG), and second, an improved high energy density fermented gruel (IFG). On the first 10 days of each period, the children were fed as usual, while on the 11th day, the mothers were asked to use encouraging feeding. Intakes of TFG and IFG were also measured once a day for nine days in 25 preschoolers (2-5 years-old). After adjustment for the subject effect, IFG intakes did not significantly differ from TFG intakes in the groups of infants and toddlers, meaning there was a significant increase in energy intakes, which almost doubled. Encouraging feeding increased TFG intakes in both age groups, but IFG intakes only increased in toddlers, whose energy intake tripled compared to that from TFG with the usual feeding style. In preschoolers, mean IFG intakes were lower than TFG intakes and there were no increase in mean energy intakes. Improving fermented gruel and training the mothers to encourage their young children during feeding are two possible strategies to improve food intakes, and hence to better satisfy the children's nutritional needs., (Copyright © 2016. Published by Elsevier Ltd.)

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists., (Copyright © 2014. Published by Elsevier Inc.)

Ethanol stimulates hypothalamic-pituitary-adrenal axis activity in vivo. To determine the cellular and molecular mechanisms through which ethanol regulates corticotropin-releasing factor (CRF) gene expression, we compared the effect of ethanol and forskolin on CRF peptide secretion and messenger RNA levels in hypothalamic primary cell cultures, and on CRF promoter activity in the NG108-15 cell line. CRF secretion, mRNA levels, and gene transcription significantly increased in response to ethanol or forskolin. Mutation of the cAMP-response element (CRE) reduced luciferase activity under basal conditions as well as in response to forskolin or ethanol. On the other hand, plasmid with five CRE repeats yielded dramatically elevated basal luciferase activity and significantly increased upregulation by ethanol. Inclusion of adenosine deaminase reduced the promoter response to ethanol. Finally a PKA inhibitor and a cAMP antagonist both decreased ethanol-induced CRF peptide secretion, gene expression, and transcription. These results suggest that ethanol upregulates CRF expression through cAMP/PKA-dependent pathways.

Prenatal exposure to ethanol (E) enhances the offspring's ACTH and corticosterone responses to stressors. Here, we determined the role of increased pituitary responsiveness and/or PVN neuronal activity in this phenomenon. Pregnant rats were exposed to E vapors during days 7-18 of gestation, and we compared the responses of their 55- to 60-day-old offspring (E rats) to those of control (C) dams. PVN mRNA levels of the immediate early genes (IEGs) c-fos and NGFI-B, which were low under basal conditions in all groups, showed a peak response 15 min after shocks and 45 min after LPS treatment. These responses were significantly enhanced in E, compared to C offspring of both genders. CRF, but not VP hnRNA levels were also significantly higher in the PVN of shocked E offspring. Resting median eminence content of CRF and VP, and pituitary responsiveness to CRF, were unchanged, while responsiveness to VP was marginally increased in females. These results indicate that prenatal alcohol selectively augments the neuronal activity of hypothalamic CRF perikarya.

The immune system and the hypothalamic-pituitary (H-P) axis are functionally connected, so that exposure to antigens elicits a coordinated response which allows the organism to successfully withstand immunologic challenges. An important feature of this bilateral communication is the appearance of proteins released into the circulation by activated immune cells. These proteins, called cytokines or interleukins, stimulate the activity of the H-P axis, thus increasing circulating ACTH and corticosteroid levels. This in turn induces metabolic changes such as increases in energy substrates, restrains the activity of specific immune cells, and alters the release of secretagogues important for both the immune system and neuroendocrine organs. After acute increases in blood-borne levels of cytokines, nerve terminals in the median eminence, particularly those containing corticotropin-releasing factor (CRF), represent an important site of action of these immune signals. Subsequently, changes take place within the brain in general and the hypothalamus in particular. They include the synthesis/release of peptides such as CRF and vasopressin, of neurotransmitters such as catecholamines and prostaglandins, and of cytokines themselves. Upon prolonged exposure to blood-borne immune signals additional mechanisms come into play, including those taking place directly at the pituitary level. These observations indicate that cytokines released into the general circulation act on multiple sites within the H-P axis, a phenomenon that relies on the recruitment of a large number of pathways. This review discusses these pathways and the mechanisms through which they allow cytokines to convey the occurrence of immune activation to the brain.

We have observed that alcohol does not alter adrenocorticotropin (ACTH) released in response to the iv injection of interleukin-1 beta (IL-1 beta). In contrast, prior (-30 to -90 min) administration of moderate doses of alcohol (0.5-2.0 g/kg) significantly blunts ACTH secretion following the intracerebroventricular (icv) injection of the cytokine. We explored two possible mechanisms responsible for this phenomenon: Corticosteroid feedback and alcohol-induced inhibition of hypothalamic neuronal activation (measured through changes in c-fos and NGFI-B mRNA levels). Increasing plasma corticosterone levels by exposing rats to mild electroshocks or injecting them with corticosterone did not alter ACTH released by rats administered with IL-1 beta into the brain ventricles. Alcohol, which by itself did not stimulate c-fos or NGFI-B mRNA levels in the paraventricular nucleus of the hypothalamus, significantly blunted the ability of icv IL-1 beta to increase the expression of these immediate early genes. We conclude that the inhibitory influence exerted by prior alcohol treatment on ACTH released by icv administered IL-1 beta may reflect an interference with the stimulatory influence of the cytokine on hypothalamic neurons involved in the activation of the hypothalamic-pituitary-adrenal axis.

The administration of cocaine to rats causes the release of adrenocorticotropin hormone (ACTH). The observation that immunoneutralization of endogenous corticotropin-releasing factor (CRF) significantly blunts this response has suggested the importance of CRF-dependent pathways in this response. As the paraventricular nucleus (PVN) of the hypothalamus represents a major source of the CRF delivered to the pituitary, the present studies investigated the role of this hypothalamic nucleus in mediating cocaine-induced ACTH secretion. We first observed that one single iv injection of 5 mg cocaine/kg, or two sequential sc injections of 40 mg cocaine/kg, caused a measurable increase in steady-state levels of CRF mRNA. Bilateral lesions of the PVN significantly (P < 0.01) decreased the ability of cocaine to release ACTH measured 15 min later. Though we failed to measure any changes in the levels of the mRNA encoding for vasopressin (VP) following either regimen of drug administration, we noted that rats in which the magnocellular portion of the PVN (which contains VP perikarya) was spared, showed a normal ACTH response to cocaine. We therefore studied the possibility that VP might regulate the activity of the corticotrophs in response to cocaine. However, prior iv injection of polyclonal antibodies against VP did not measurably alter cocaine-induced ACTH secretion, while in the same experiment, immunoneutralization of endogenous CRF completely blocked the stimulatory action of cocaine. Taken together, these results show that CRF of PVN origin represents the major modulator of ACTH released in response to cocaine, while VP does not appear to play an important role.

Induction of the immediate early gene c-fos occurs in striatal nerve cells in response to psychotropic drugs affecting the dopaminergic system. Although this nuclear induction is mediated in part through D(1) receptors, the involvement of N-methyl-d-aspartate (NMDA)-sensitive receptors has been also demonstrated. In the experiments reported here, we examined the effects of the noncompetitive NMDA receptor antagonists ketamine (2 mg/kg; as an anesthetic mixture) and dizocilpine (MK-801; 1 mg/kg), as well as the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 5 mg/kg), on the expression of fos-like protein induced by dl-fenfluramine (20 mg/kg), in the rat caudate putamen. Systemic (IP) administration of the above receptor antagonists 30 min prior to fenfluramine exposure resulted in the blockade of c-fos immunoreactivity. Although the ketamine mixture totally abolished the expression of the immediate early gene, MK-801 and CPP only partially blocked such expression. In addition, pretreatment with the D(1) receptor antagonist SCH 23390 (0.5 mg/kg) also partially suppressed the induction of c-fos by fenfluramine. These findings suggest the participation of NMDA as well as dopamine-sensitive receptors for the induction of striatal c-fos by an indirect serotonergic (5-HT) agonist. The significance of these results is discussed in terms of a possible glutamatergic and dopaminergic mechanism.

The topographic ontogeny of nitric oxide synthase (NOS) within the paraventricular nucleus (PVN) of the rat hypothalamus was studied by nicotinamide adenine dinucleotide-diaphorase (NADPH-diaphorase) histochemistry. At Day 1 of postnatal life (P1), NOS-positive neurons were already present and achieved their maturity (in terms of perikarya number and dendritic arborization) about the time of weaning (P21). Across all ages studied (P1 to adulthood), intense NADPH-diaphorase staining was primarily confined within magnocellular cells of the PVN largely characterized by medium-sized (12-15 mum in diameter), ovoid bipolar neurons with prominent clear nuclei. To identify the neurosecretory cells of the adult PVN in which NOS was present, double-labeling studies were carried out via fluorescent immunocytochemistry. Magnocellular oxytocin (OT) and arginine vasopressin (AVP), as well as parvocellular corticotropin-releasing factor (CRF), were found to be colocalized with NOS. However, colocalization occurred significantly more frequently in OT-containing neurons, relative to AVP- or CRF-positive cells. Most of the colocalization occurring between NOS and OT was observed in the rostral constituent of the magnocellular subdivision of the PVN, as opposed to a more caudal defined PVN. To provide a distribution comparison of OT, AVP, and CRF to that of NOS in the adult PVN, in situ hybridization was carried out with (35)S-cRNA antisense probes for the aforementioned neuropeptides. The results obtained with this evaluation were correlated with NOS histochemistry in the same brain sections. As expected, specific labeling was observed for all three neuroactive substances over their topographically distinctive nuclei. Among these nuclei, labeling by the OT cRNA probe provided the closest topographical correlation of hybridized signal over NOS perikarya, thus reinforcing the tenet that a relatively small population of OT nerve cells are concurrently colocalized with the enzyme. Taken together, these results indicate that NOS is present in the PVN of the rat at all postnatal ages which we tested. They also indicate that among neurosecretory cells of the PVN, only OT prominently shared with NOS the same common nerve cell type. This suggests that NOS neurons may represent a distinct neuropil group among multiple neuroactive nuclei in the neuroendocrine hypothalamus. Finally, we demonstrate that NADPH-diaphorase histochemistry can be easily combined with immunocytochemical and in situ hybridization procedures to evaluate the colocalization and topographical distribution of NOS with other phenotypic neurons in the mammalian central nervous system.

We have previously suggested a possible role of increased maternal corticosterone (CORT) secretion in mediating the endocrine effects of prenatal alcohol administration. We tested this hypothesis by adrenalectomizing pregnant rats and exposing them to high levels of CORT that mimicked those previously measured in intact dams exposed to alcohol. CORT (28 mg/day) or placebo pellets were placed subcutaneously in adrenalectomized (ADX) dams during Days 8-14 of gestation. At 21 days of age, the offspring were either decapitated under nonstressed conditions or exposed to mild, inescapable electroshocks (1.5 mA; 1 s duration; 2.5/min) over a 10-min period and then sacrificed. Plasma ACTH and CORT levels were measured by radioimmunoassay. There were no measurable differences between basal or stress-induced ACTH secretion of pups born to ADXCORT or ADX-placebo dams. In contrast, the offspring of ADX-CORT dams demonstrated significantly (P 0.01; P 0.05) lower CORT secretion when exposed to the shocks despite unaltered basal levels. Measurement of CRF expression by in situ hybridization methodology indicated no difference between CRF biosynthesis of both groups of pups. These results do not support the hypothesis that the increased stress-induced ACTH release of rats born to intact dams exposed to alcohol is primarily mediated by increased maternal corticosterone levels.

The ability of immature (21-day-old) rats to release ACTH and corticosterone (CORT) in response to stress is known to be enhanced by in utero exposure to ethanol (EtOH). However, the precise time during which EtOH is effective, as well as the mechanisms mediating these effects, has not been elucidated. The first part of the present study was designed to evaluate the time course of action of EtOH during various times of gestation. The second part examined the possible role of maternal adrenal steroids, as well as changes in the pups' hypothalamic corticotropin-releasing factor (CRF) biosynthesis and/or expression, in mediating the deleterious action of EtOH. Pregnant intact or adrenalectomized (ADX) Sprague-Dawley rats were exposed to EtOH vapors. Control rats were kept in a normal atmosphere. At 21 days of age, the offspring were either decapitated under nonstressed conditions or exposed to mild, inescapable electroshocks (1.5 mA; 1 s duration) over a 10-min period, then sacrificed. ACTH and CORT levels were measured by radioimmunoassay. When exposed to the shocks, 21-day-old rats born to intact mothers exposed to EtOH during the second, but not the first or third week of gestation, demonstrated significantly enhanced ACTH secretion (P 0.05), but unaltered CORT secretion compared to controls. Measurement of CRF biosynthesis by Northern blot analysis and in situ hybridization indicated a significant (P 0.01) increase in CRF mRNA levels, and a marked accumulation of CRF mRNA in the parvocellular division of the paraventricular nucleus. Rats born to ADX control mothers had significantly (P 0.01) higher stress-induced ACTH, but lower CORT secretion, than the offspring of intact control dams. In contrast to what we observed in pups born to intact dams, the offspring of ADX mothers (whether control or exposed to EtOH) showed no measurable increase in ACTH secretion when exposed to electroshocks, nor did they exhibit any measurable difference in the levels of CRF mRNA levels. We conclude that (i) prenatal exposure to EtOH during the second, but not the first or third week of gestation, alters the hypothalamic-pituitary-adrenal response to stress at 3 weeks of age, and (ii) a significant increase in CRF biosynthesis and expression, which may be at least in part a consequence of past elevated circulating corticosterone levels in EtOH-exposed dams, may modulate this augmented ACTH secretion in response to stress.