Brain‐derived neurotrophic factor,corticotropin‐releasing factor,and hypothalamic neuronal histamine interact to regulate feeding behavior

Brain‐derived neurotrophic factor (BDNF), corticotropin‐releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α‐fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild‐type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1‐R) in BDNF neurons. BDNF‐induced feeding suppression was partially attenuated in rats pre‐treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1‐Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.     

Hypothalamic neuronal histamine signaling in the estrogen deficiency-induced obesity

Menopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, α-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with α-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mice but not in H1KO mice. Immunohistochemical analysis revealed ERs were expressed on histamine neurons and western blotting analysis and pre-absorption study confirmed the specificity of ER antiserum we used. These results indicate that CRH and hypothalamic neuronal histamine mediate the suppressive effects of E2 on feeding behavior and body weight.     

下丘脑Nesfatin-1抑食效应及机制研究

目的:探讨下丘脑nesfatin-1与组胺信号通路间的相互作用及对摄食的影响。方法:采用第三脑室置管、药物注射、免疫组化、ELISA等方法,观察氟甲基组氨酸(FMH)、α螺旋促肾上腺皮质激素释放激素(CRH)和促甲状腺激素释放激素(TRH)对Nesfatin-1诱导的抑制摄食的影响,以及Nesfatin-1与组胺信号通路相互影响调控摄食机制。结果:第三脑室注射nesfatin-1可显著减少大鼠摄食量,而第三脑室内预先注射FMH,nesfatin-1抑制摄食效应明显减弱,但FMH本身并不影响大鼠夜间摄食量。第三脑室注射nesfatin-1,可显著增加优降宁诱发的PVN、腹内侧核(VMH)、结节乳头核(TMN)内t-MH的积累;但腹腔注射nesfatin-1没有引起大鼠摄食改变,t-MH蓄积也无显著变化。第三脑室注射α螺旋CRH或抗TRH血清均可显著减弱nesfatin-1的抑食效应,而α螺旋CRH、抗TRH血清本身并不显著影响大鼠摄食量。第三脑室注射nesfatin-1可显著增加下丘脑PVN内CRH和TRH水平,且nesfatin-1可显著增加优降宁诱导的PVN、VMH和TMN内t-MH的表达,而α螺旋CRH或抗TRH血清可显著抑制nesfatin-1诱导的PVN、VMH和TMH内t-MH的蓄积。第三脑室注射组胺可显著增加大鼠下丘脑PVN内nesfatin-1含量,但LH、VMH、TMN以及血浆内nesfatin-1水平无显著改变。免疫组化研究显示,PVN内有nesfatin-1和H1-R免疫反应阳性神经元,且部分神经元共存。结论:Nesfatin-1的抑食效应可能与下丘脑组胺信号通路介导。     

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with alpha-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.     

Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.     

Hypothalamic neuronal histamine modulates febrile response but not anorexia induced by lipopolysaccharide

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats.To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.     

Histamine Receptor Expression, Hippocampal Plasticity and Ammonia in Histidine Decarboxylase Knockout Mice

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of “histaminergic” neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.     

Twenty-four hour rhythms of hypothalamic corticotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone-releasing hormone and somatostatin in rats injected with Freund's adjuvant

The effect of Freund's adjuvant injection on 24-hour variation of hypothalamic corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), GH-releasing hormone (GRH) and somatostatin levels was examined in adult rats kept under light between 0800 and 2000 h daily. Groups of rats receiving Freund's complete adjuvant or its vehicle 3 days before sacrifice were killed at six different time intervals throughout a 24-hour cycle. In the median eminence, adjuvant vehicle-injected rats exhibited significant 24-hour variations for the four hormones examined, with maxima at noon. These 24-hour rhythms were inhibited or suppressed by Freund's adjuvant injection. In the anterior hypothalamus of adjuvant vehicle-treated rats, CRH content peaked at 1600 h, while two peaks were found for TRH and GRH levels, i.e., at 2400-0400 h and 1600 h. Freund's adjuvant injection suppressed 24-hour rhythm of anterior hypothalamic CRH, TRH and GRH content and uncovered a peak in anterior hypothalamic somatostatin levels at 0400 h. In the medial hypothalamus of adjuvant vehicle-treated rats, significant 24-hour variations were detectable for TRH (peaks at 1600 and 2400 h) and somatostatin (peak at 2400 h) which disappeared after Freund's adjuvant injection. In the posterior hypothalamus of adjuvant vehicle-treated rats, two peaks were apparent for CRH, TRH and somatostatin levels, i.e. at 1600 h and 2400-0400 h, this hormonal profile remaining unmodified after Freund's adjuvant administration. The administration of the immunosuppressant drug cyclosporine (5 mg/kg, 5 days) impaired the depressing effect of Freund's adjuvant injection on CRH, TRH and somatostatin content in median eminence, but not that on GRH. In the anterior hypothalamus, cyclosporine generally prevented the effect of immunization on hormone levels an revealed a second maximum in TRH at 0400 h. Cyclosporine also restored 24-hour variations in TRH and somatostatin levels of medial hypothalamus of Freund's adjuvant-injected rats but was unable to modify them in the posterior hypothalamus. The results further support the existence of a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on hypothalamic levels which was partially sensitive to immunosuppression by cyclosporine.     

Anti‐aging drugs reduce hypothalamic inflammation in a sex‐specific manner

Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF‐1 signals. Early‐life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM‐HET3 mice in a sex‐specific way: acarbose (ACA), 17‐α‐estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti‐aging drugs on neuro‐inflammation in hypothalamus and hippocampus. We found that age‐associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA‐treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba‐1‐positive microglia and GFAP‐positive astrocytes, as well as age‐associated overproduction of TNF‐α. This effect was not observed in drug‐treated female mice or in the hippocampus of the drug‐treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF‐α in both sexes at 12 months of age. Together, these results suggest that the extent of drug‐induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long‐lived nutrient restricted or mutant mice.     

Histamine H1 receptors mediate the anorectic action of the pancreatic hormone amylin

We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.     

Effects of α-fluoromethylhistidine (FMH), an irreversible inhibitor of histidine decarboxylase,on development of brain histamine and catecholamine systems in the neonatal rat

Daily administration of FMH to neonatal rats produced long-lasting inhibition of histidine decarboxylase in hypothalamus and cerebral cortex and led to depletion of histamine in both brain regions. The onset of depletion was more rapid in cerebral cortex, a region in which non-neurotransmitter pools of histamine predominate in early postnatal life, appearing as early as postnatal day 3; depletion in the hypothalamus, a region rich in histaminergic neuronal projections, appeared later. No effects were seen on body or brain growth, nor was development of other biogenic amine systems affected. FMH thus provides a selective probe for examining the role of histamine in brain development.     

Dynamics of appetite-mediated gene expression in daidzein-fed female rats in the meal-feeding method

We previously found that daidzein decreased food intake in female rats. The present study aimed to elucidate the relationship between dynamics of appetite-mediated neuropeptides and the anorectic effect of daidzein. We examined appetite-mediated gene expression in the hypothalamus and small intestine during the 3 meals per day feeding method. Daidzein had an anorectic effect specifically at the second feeding. Neuropeptide-Y (NPY) and galanin mRNA levels in the hypothalamus were significantly higher after feeding in the control but not in the daidzein group, suggesting that daidzein attenuated the postprandial increase in NPY and galanin expression. The daidzein group had higher corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamus after feeding, and increased cholelcystokinin (CCK) mRNA levels in the small intestine, suggesting that CCK is involved in the hypothalamic regulation of this　anorectic effect. Therefore, daidzein may induce anorexia by suppressing expression of NPY and galanin and increasing expression of CRH in the hypothalamus.     

Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Nesfatin‐1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin‐1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin‐1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. As we have previously demonstrated that nesfatin‐1 elicits Ca²⁺ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca²⁺ in cardiac pre‐ganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin‐1 increases cytosolic Ca²⁺ concentration via a Gi/o‐coupled mechanism. The nesfatin‐1‐induced Ca²⁺ rise is critically dependent on Ca²⁺ influx via P/Q‐type voltage‐activated Ca²⁺ channels. Repeated administration of nesfatin‐1 leads to tachyphylaxis. Furthermore, nesfatin‐1 produces a dose‐dependent depolarization of cardiac vagal neurons via a Gi/o‐coupled mechanism. In vivo studies, using telemetric and tail‐cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin‐1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin‐1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus.

     

Studies on thyrotropin releasing hormone in cerebellar ataxia mutant mouse brain

The effects of cathecholamine on the regional TRH distribution in the brain was studied in rolling mouse Nagoya (RMN) and non-affected C3H mice. TRH was extracted from the hypothalamus, brain stem, cerebellum, and cerebrum one hour after i.p. injection of the precursor or inhibitors of cathecholamine. TRH was distributed throughout the brain of both affected and non-affected mice; however, in RMN, TRH levels were lower in the hypothalamus and higher in other areas. 1-Dopa caused a decrease of TRH in the brain stem but no change in other regions in the RMN brain, whereas it caused an increase in TRH levels in all areas of the C3H brain. Fusaric acid increased TRH in the hypothalamus of RMN and decreased it in the cerebellum; alpha-MPT also caused a decrease in the TRH level in the cerebellum. Reserpine increased the TRH level in the hypothalamus and decreased it in the cerebrum. From these results, it appears that cerebellar ataxia in RMN does not result from a decrease in the TRH, which is actually increased in the cerebellum. Catecholamine had different effects on TRH levels in RMN and the controls; this might be due to the excess accumulation of noradrenaline in the RMN brain.     

Histamine H1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin

In the present study we investigated the role of hypothalamic histamine H(1) receptors in the mediation of peripheral amylin's anorectic effect. Rats with chronically implanted bilateral cannulas were infused into the ventromedial hypothalamus (VMH) with the specific histamine H(1) receptor antagonists pyrilamine (PYR, 104 nmol/rat) or chlorpheniramine (CPA, 52 nmol/rat), respectively, combined with an intraperitoneal (IP) injection of amylin (5 microg/kg). Amylin's inhibitory effect on food intake (i.e. 50% reduction in cumulative food intake 30 min after ingestion) was markedly reduced by CPA and PYR (e.g. amylin and CPA: 5% reduction versus control). We therefore suggest an important role of hypothalamic H(1) receptors in the signal transduction of peripheral amylin's anorectic action.     

Effects of histamine and related compounds on thyrotropin secretion in rats

The effects of histamine (HA) and related compounds on thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) secretion in rats were studied. Histidine (1.0 g/kg), HA (5.0 mg/kg) or histamine antagonists mepyramine (MP) (100 mg/kg) or famotidine (FA) (5.0 mg/kg) were injected intraperitoneally, and the rats were decapitated at various intervals after the injection. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after histidine or HA injection, decreased significantly after FA injection, but was not changed by MP. The plasma ir-TRH concentration did not change significantly after injection of these drugs. The plasma TSH levels decreased significantly in a dose-related manner after histidine or HA injection and increased significantly in a dose-related manner after FA injection. The plasma thyroid hormone levels showed no changes. In the FA-pretreated group, the inhibitory effect of histidine or HA on TSH levels was prevented, but not in the MP-pretreated group. The plasma ir-TRH and TSH responses to cold were inhibited by histidine or HA and enhanced by FA. The plasma TSH response to TRH was inhibited by histidine or HA and enhanced by FA. The inactivation of TRH immunoreactivity by hypothalamus or plasma in vitro after histidine, HA, MP or FA was not different from that of the control. These findings suggest that histamine may act both on the hypothalamus and the pituitary to inhibit TRH and TSH release, and that its effects may be mediated via H2-receptor.     

Developmental expression of corticotropin releasing hormone messenger RNA and peptide in rat hypothalamus

We have examined corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and somatostatin (SOM) mRNA expression and peptide content in the rat hypothalamus from day 20 of fetal life (F20) to the fifteenth day of postnatal life (P15). During this time, hypothalamic CRH mRNA levels did not change significantly, whereas there was a gradual six-fold rise in CRH peptide levels. AVP mRNA levels fell three-fold between F20 and P1 and increased six-fold between P1 and P15. AVP peptide levels increased three-fold, with most of the rise occurring between P1 and P15. From F20 to P15, SOM mRNA and peptide levels rose four- and eight-fold, respectively. The changes in the levels of these three hypothalamic gene products correlate with the previously described alterations in the responsiveness of the HPA axis observed in fetal and early postnatal rats, suggesting a role for these neuropeptides in the modulation of the HPA axis during this developmental period.     

The balance between stress resilience and vulnerability is regulated by corticotropin‐releasing hormone during the critical postnatal period for sensory development

Determining whether a stressful event will lead to stress‐resilience or vulnerability depends probably on an adjustable stress response set point, which is most likely effective during postnatal sensory development and involves the regulation of corticotrophin‐releasing hormone (CRH) expression. During the critical period of thermal‐control establishment in 3‐day‐old chicks, heat stress was found to render resilient or sensitized response, depending on the ambient temperature. These two different responses were correlated with the amount of activation of the hypothalamic–pituitary–adrenal (HPA) axis. The expression of CRH mRNA in the hypothalamic paraventricular nucleus was augmented during heat challenge a week after heat conditioning in chicks which were trained to be vulnerable to heat, while it declined in chicks that were trained to be resilient. To study the role of CRH in HPA‐axis plasticity, CRH or Crh‐antisense were intracranially injected into the third ventricle. CRH caused an elevation of both body temperature and plasma corticosterone level, while Crh‐antisense caused an opposite response. Moreover, these effects had long term implications by reversing a week later, heat resilience into vulnerability and vice versa. Chicks that had been injected with CRH followed by exposure to mild heat stress, normally inducing resilience, demonstrated, a week later, an elevation in body temperature, and Crh mRNA level similar to heat vulnerability, while Crh‐antisense injected chicks, which were exposed to harsh temperature, responded in heat resilience. These results demonstrate a potential role for CRH in determining the stress resilience/vulnerability balance. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 842–853, 2015     

The effects of nesfatin‐1 in the paraventricular nucleus on gastric motility and its potential regulation by the lateral hypothalamic area in rats

The current study investigated the effects of nesfatin‐1 in the hypothalamic paraventricular nucleus (PVN) on gastric motility and the regulation of the lateral hypothalamic area (LHA). Using single unit recordings in the PVN, we show that nesfatin‐1 inhibited the majority of the gastric distention (GD)‐excitatory neurons and excited more than half of the GD‐inhibitory (GD‐I) neurons in the PVN, which were weakened by oxytocin receptor antagonist H4928. Gastric motility experiments showed that administration of nesfatin‐1 in the PVN decreased gastric motility, which was also partly prevented by H4928. The nesfatin‐1 concentration producing a half‐maximal response (EC50) in the PVN was lower than the value in the dorsomedial hypothalamic nucleus, while nesfatin‐1 in the reuniens thalamic nucleus had no effect on gastric motility. Retrograde tracing and immunofluorescent staining showed that nucleobindin‐2/nesfatin‐1 and fluorogold double‐labeled neurons were observed in the LHA. Electrical LHA stimulation changed the firing rate of GD‐responsive neurons in the PVN. Pre‐administration of an anti‐ nucleobindin‐2/nesfatin‐1 antibody in the PVN strengthened gastric motility and decreased the discharging of the GD‐I neurons induced by electrical stimulation of the LHA. These results demonstrate that nesfatin‐1 in the PVN could serve as an inhibitory factor to inhibit gastric motility, which might be regulated by the LHA.