Effects of electrical stimulation of the medullary raphe nuclei on respiratory movement in rats

The present study was undertaken to examine the effects of electrical stimulation of the medullary raphe nuclei on respiration in rats anesthetized with ketamine and xylazine. Train pulse stimuli (100 Hz, 10–30 μA) were applied in the regions of the caudal raphe nuclei: the raphe magnus (RM), raphe pallidus (RP) and raphe obscurus (RO). Stimulation of the RM depressed inspiratory movements measured by means of an abdominal pneumograph, whereas stimulation of the RP augmented inspiratory movements. It was revealed that stimulation of the RO induced either inhibitory or facilitatory effects on respiratory movements depending on the stimulation sites. These findings confirm and extend previous studies concerning the effects of raphe stimulation on respiratory activity in cats. The present results demonstrate that in rats the caudal raphe nuclei are involved in respiratory control.An erratum to this article can be found at     

Possible role of CRF peptides in burn-induced hypermetabolism

Hypermetabolism and anorexia are significant problems associated with major burn trauma. Recent studies have shown that hypothalamic corticotropin releasing factor (CRF) elevates metabolic rate, while neuropeptide Y (NPY) reduces it. CRF also elicits anorexia, while NPY stimulates feeding. We hypothesized that elevation of CRF and decrease of NPY may be mediators of these negative effects of burn trauma. Therefore, we assessed concentrations of CRF and NPY in hypothalamus of burned rats one, three, and twenty-one days after a 30% body surface area, full-thickness, open flame burn. In addition we determined whether a biochemical lesion of CRF receptors using 3rd ventricle injections of a saporin-CRF conjugated peptide would decrease resting energy expenditure (REE). We found a three-day period of anorexia, with REE significantly increasing three days after the burn trauma. Concentrations of NPY were increased in the PVN-containing dorsomedial region of the hypothalamus 1 and 3 days after burn trauma, but were increased further in the day 1 pair-fed rats suggesting this change was a consequence of the anorexia. Levels of CRF were decreased in the ventromedial region of the hypothalamus in day 1 and day 3 burned and PF rats. Treatment with the saporin-CRF conjugate normalized REE and reduced CRF receptor-2 density in the hypothalamus of burned rats, and blocked CRF-induced hypermetabolism in sham-burned rats. Although these results suggest a role of CRF receptors in mediating burn-induced hypermetabolism, CRF itself may not be the principle ligand, as suggested by the significant elevation of hypothalamic urocortin 15 days after burn injury.     

大鼠中缝核群中生长抑素样神经元对咽肌前运动神经元的支配-PRV和SOM免疫荧光双标记法研究

用PRV和SOM免疫荧光双标记法研究了大鼠中缝核群中SOM样神经元对咽肌前运动神经元的调控。PRV注射大鼠咽肌后,在中缝苍白核、中缝隐核、中缝大核和中缝背核中可见少量PRV和SOM双标记细胞。首次证明了大鼠中缝核群中SOM样神经元对咽肌前运动神经元的支配。推测中缝核群中的SOM可能和咽肌运动的精确调控有关。     

First Characterization of 6-Hydroxytryptamine in the Rat Midbrain by Using Specific Antibodies

The visualization of serotonin, 5-methoxytryptamine, and tryptamine in the rat midbrain has been made possible by the development of antibodies raised against these conjugated molecules. It has been suggested that 6-hydroxytryptamine (6-HT) might also be a neurotransmitter in this region. To test this hypothesis, 6-HT was synthesized and antibodies were raised in the rabbit. The high avidity (IC50 = 5 x 10(-9) M) and specificity [cross-reactivity ratio between 6-HT-glutaraldehyde (G)-bovine serum albumin (BSA) and 5-HT-G-BSA, the most immunoreactive compound, was 1,500] rendered these antibodies reliable tools for specific molecular detection of 6-HT in the G-fixed tissues. In the dopaminergic region, 6-HT immunoreactivity was noted in the substantia nigra but was particularly intense in the red nuclei, where it seems to be localized in the magnocellular division in the form of large 6-HT neurons. In contrast, there were few 6-HT neurons in the raphe nuclei. Thus, 6-HT may be a new putative neurotransmitter existing in the red nuclei, in addition to the other neurotransmitters already described in this region, in the nigro-rubral pathway, and in the rubral projection from the dorsal raphe nuclei. 6-HT is possibly implicated in motor control and might exert hallucinogenic properties as do other 6-hydroxylated indoleamines.     

Depression Scores Associate With Chronotype and Social Jetlag in a Rural Population

In public health, mood disorders are among the most important mental impairments. Patients with depressive episodes exhibit daily mood variations, abnormal patterns in sleep-wake behavior, and in the daily rhythms of several endocrine-metabolic parameters. Although the relationship between the sleep/circadian processes and mood disorders is poorly understood, clock-related therapies, such as light therapy, sleep deprivation, and rigid sleep schedules, have been shown to be effective treatments. Several studies investigated the relationship between circadian phenotype (chronotype) and depression. These focused mainly on urban populations and assessed diurnal preferences (Morningness-Eveningness score) rather than the actual timing of sleep and activity. Here, we used the Beck Depression Inventory (BDI) in an essentially rural population (N?=?4051), and investigated its relation to circadian phenotype (chronotype and social jetlag), assessed with the Munich Chronotype Questionnaire (MCTQ). In our study design, we (i) normalized both chronotype and BDI scores for age and sex (MSF_sas and BDI_as, respectively); (ii) calculated individual social jetlag (misalignment of the biological and social time); and (iii) investigated the relationship between circadian phenotypes and BDI scores in a population homogeneous in respect to culture, socioeconomic factors, and daily light exposure. A 15.65% (N?=?634) of the participants showed mild to severe depressive BDI scores. Late chronotypes had a higher BDI_as than intermediate and early types, which was independent of whether or not the participants were smokers. Both chronotype and BDI_as correlated positively with social jetlag. BDI_as was significantly higher in subjects with >2?h of social jetlag than in the rest of the population—again independent of smoking status. We also compared chronotype and social jetlag distributions between BDI categories (no symptoms, minimal symptoms, and mild to severe symptoms of depression) separately for men and women and for four age groups; specifically in the age group 31–40 yrs, subjects with mild to severe BDI scores were significantly later chronotypes and suffered from higher social jetlag. Our results indicate that misalignment of circadian and social time may be a risk factor for developing depression, especially in 31- to 40-yr-olds. These relationships should be further investigated in longitudinal studies to reveal if reduction of social jetlag should be part of prevention strategies. (Author correspondence: karla.allebrandt@med.uni-muenchen.de)     

大白鼠中缝核一氧化氮合酶阳性神经元的组织化学观察

中脑和脑桥部中缝核被认为与睡眠有直接和间接关系的重要脑结构。本文用一氧化氮合酶（ＮＯＳ）组织化学结合荧光组织化学方法证实在中缝核群中,ＮＯＳ阳性神经元主要定位于这两个脑部的中缝核内,ＮＯＳ产生的ＮＯ能使脑血管扩张,参与脑血流的调节。提示这二个脑部中缝核内的ＮＯＳ阳性神经元可能作为多种因素之一,参于睡眠状态下基本脑血流的维持     

Peripheral insulin administration attenuates the increase in neuropeptide Y concentrations in the hypothalamic arcuate nucleus of fasted rats

Fasting increases neuropeptide Y (NPY) concentrations in the arcuate nucleus (ARC), its site of synthesis, and in other regions of the rat hypothalamus. Neuropeptide Y is a potent central orexigenic agent and may therefore stimulate appetite during fasting. We tested the hypothesis that low plasma insulin levels stimulate ARC levels of NPY in fasted rats. Compared with freely fed controls (n = 8), rats fasted for 72 h (n = 8) showed significantly lower plasma insulin levels (28.9 ± 1.6 vs. 52.6 ± 5.7 pmol/l; p < 0.001) and higher ARC NPY concentrations (14.2 ± 1.8 vs. 8.4 ± 2.2 fmol/μg protein; p < 0.001). Fasted rats treated with subcutaneous insulin (5 U/kg/day; n = 10), which nearly normalized plasma insulin (46.6 ± 2.8 pmol/l), showed intermediate ARC NPY levels (11.2 ± 1.4 fmol/μg protein; p < 0.01 vs. controls and untreated fasted rats). Insulin administered peripherally, therefore, attenuates fasting-induced NPY increases in the ARC, supporting the hypothesis that hypoinsulinemia stimulates hypothalamic NPY.     

Intraperitoneal injection of neuropeptide Y (NPY) alters neurotrophin rat hypothalamic levels: Implications for NPY potential role in stress-related disorders

Neuropeptide Y (NPY) is a 36-amino acid peptide which exerts several regulatory actions within peripheral and central nervous systems. Among NPY actions preclinical and clinical data have suggested that the anxiolytic and antidepressant actions of NPY may be related to its antagonist action on the hypothalamic-pituitary-adrenal (HPA) axis. The neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are proteins involved in the growth, survival and function of neurons. In addition to this, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has been proposed. To characterize the effect of NPY on the production of neurotrophins in the hypothalamus we exposed young adult rats to NPY intraperitoneal administration for three consecutive days and then evaluated BDNF and NGF synthesis in this brain region. We found that NPY treatment decreased BDNF and increased NGF production in the hypothalamus. Given the role of neurotrophins in the hypothalamus, these findings, although preliminary, provide evidence for a role of NPY as inhibitor of HPA axis and support the idea that NPY might be involved in pathologies characterized by HPA axis dysfunctions.     

An evolutionary model of low mood states

It has been suggested that low mood in humans is an adaptive response to unfavourable circumstances, and that the anhedonia, pessimism and fatigue that often accompany it function to minimise risk until circumstances improve. While this is plausible, it would be possible to make the opposite prediction equally plausibly: individuals in bad circumstances should take greater risks in order to improve their situations. Here, I present a simple analytical model adapted from the risk-sensitive foraging literature. It shows that in dire states, individuals should be risk-prone, in poor states, risk-averse, and in good states, risk-prone again. I discuss how the various kinds of mood state observed in humans might be understood as mechanisms for adaptively adjusting behavioural risk-taking to the current situation.     

p-Chlorophenylalanine-Induced Alteration of Somatodendritic Levels of Tryptophan Hydroxylase Within the Rat Mesencephalic Raphe Nuclei

Abstract: Tryptophan hydroxylase distribution was examined across the nuclei raphe dorsalis, medianus, and pontis of the adult rat, under basal conditions and 2 days after a single injection of p -chlorophenylalanine, an irreversible tryptophan hydroxylase inhibitor. Tryptophan hydroxylase-expressing cells were numbered in transverse sections processed for immunohistochemistry, and the area of tryptophan hydroxylase distribution was delineated in adjacent sections transferred onto nitrocellulose and processed for immunoautoradiography. Two distinct areas were visualized: an inner zone, corresponding to the area displaying tryptophan hydroxylase-immunoreactive cells (so-called somatic area), and an outer zone, here called perisomatic, devoid of perikarya yet rich in tryptophan hydroxylase-positive neuropil in the histological sections. After treatment with p -chlorophenylalanine, a significant decrease in the number of tryptophan hydroxylase-immunoreactive cells could be observed only in the rostral raphe dorsalis, particularly within its ventromedian and dorsomedian subdivisions. In all raphe nuclei, the topological reconstruction of the somatic area was not modified. Based on the densitometric measurements in the immunoautoradiographs, however, a dramatic decrease in the content, concentration, and volume of expression of tryptophan hydroxylase could be documented in the three raphe nuclei. Detailed analysis of these results led to the conclusion that (a) tryptophan hydroxylase expression is differentially regulated in different serotoninergic cell body subpopulations of the raphe, some of which are more sensitive to p -chlorophenylalanine, and (b) distribution of tryptophan hydroxylase protein is modified also in the somatodendritic area in all raphe nuclei.     

5-羟色胺和一氧化氮合酶在大鼠中脑导水管周围灰质 和中缝核簇神经元内的共存

实验采用 NADPH组织化学和 5 - HT免疫组织化学双重显色方法研究了 5 - HT和一氧化氮合酶在大鼠中脑导水管周围灰质 (PAG)和中缝核簇神经元的分布特征及共存情况。结果表明 ;(1 )在 PAG腹外侧区中观察到大量的 NOS阳性神经元和 5 - HT样免疫阳性神经元 ,但是 NOS/ 5 - HT双标神经元较少 ,仅占该区 5 - HT样免疫阳性神经元 2 0 .1 % ,并且主要分布在该区的内侧部 ;在 PAG的背外侧区中观察到密集的 NOS阳性神经元 ,但是几乎未见 5 - HT免疫阳性神经元分布。(2 )在中缝核簇的大多数亚核内均可观察到大量的 NOS神经元和 5 - HT免疫阳性神经元。在中缝背核的内侧部、中缝背核的尾侧部、中缝正中核、尾侧线形核、中缝大核和中缝隐核内双标神经元分别占所在部位中 5 - HT免疫阳性神经元的 44 .6 %、5 3.4%、 44 .4%、 2 6 .2 %、 2 6 .7%和 2 1 .8%。然而在中缝苍白核内仅偶见少数双标神经元。研究结果表明 ,在 PAG和中缝核簇的一些神经元内 5 - HT可以与 NOS共存 ,提示这两种神经活性物质在功能上可能存在着某种相关性 ,有关这些双标神经元的功能意义尚需进一步研究。     

T3111C CLOCK SINGLE NUCLEOTIDE POLYMORPHISM AND MOOD DISORDERS: A META-ANALYSIS

It has been hypothesized that abnormalities in the molecular clock underlie the development of mood disorders, in the direction of higher prevalence in individuals with a reduced flexibility to adapt to important regulations of mood in response to changes in seasons, stress levels, sleep schedules, and time zones. In particular, a T/C change (rs1801260) at the 3111 position of the circadian locomotor output cycles kaput (CLOCK) gene has been explored in psychiatry disorders. This meta-analysis has been undertaken to investigate the association between rs1801260 and both mood disorders and depression severity, shedding light on previous controversial results and providing better power to detect smaller effect sizes. PubMed and ISI databases were searched for studies focused on the association between rs1801260 and mood disorders spectrum. Quality of studies was assessed. We found no association between CLOCK genotypes and mood disorders, even when we separately investigated ethnical homogeneous or unipolar disorder studies. No association was found regarding severity of depression either. The methodological quality of the studies has been found to be medium-high. Our meta-analysis shows no association between rs1801260 and mood disorders (as a complete phenotype) or depression severity and points out the necessity of further research in order to better understand the underlying biological machinery of circadian dysfunction in subjects affected by mood disorders. (Author correspondence: alessandro.serretti@unibo.it)     

Immunocytochemical localization of neuropeptide Y (NPY) in the human hypothalamus

Summary In order to study the distribution of neuropeptide Y-like immunoreactivity in the human hypothalamus, an immunocytochemical localization of this peptide was performed. Using antibodies developed against synthetic porcine neuropeptide Y (NPY), we have been able to localize immunoreactivity in neuronal cell bodies located exclusively in the infundibular nucleus. Immunostained fibers were found in several regions in the hypothalamus with a high concentration in the periventricular areas. Fibers were also found in the neurovascular zone of the median eminence, the pituitary stalk and the posterior pituitary. These results suggest that immunoreactive material related to porcine NPY is present in the human hypothalamus, with a distribution similar to that observed in the rat.     

Reduced Neuropeptide Y Concentrations in Suicide Brain

Neuropeptide Y (NPY) was measured in postmortem brain tissue from victims of suicide and from individuals dying a sudden natural or accidental death (controls). Concentrations of NPY-immunoreactivity were measured by radioimmunoassay in frontal cortex (BA 10), temporal cortex (BA 22), caudate nucleus, and cerebellum. Concentrations of NPY-immunoreactivity were significantly lower in postmortem frontal cortex (-14%) and caudate nucleus (-27%) from suicide victims compared with age-matched controls. A subgroup of suicides with evidence of a history of depression revealed more robust reductions in concentrations of NPY-immunoreactivity in frontal cortex and caudate nucleus, as did four individuals who died from natural causes and also were described as having a possible history of depression. Concentrations of NPY-immunoreactivity in temporal cortex and cerebellum from victims of suicide or from the subgroup of subjects with a possible history of depression were not significantly different from those of age-matched controls. We suggest there is a deficit in the brain NPY system leading to region-specific reductions in peptide concentrations in subjects who have a history of depression.     

C1q/TNF-related Protein 4 (CTRP4) Is a Unique Secreted Protein with Two Tandem C1q Domains That Functions in the Hypothalamus to Modulate Food Intake and Body Weight

CTRP4 is a unique member of the C1q family, possessing two tandem globular C1q domains. Its physiological function is poorly defined. Here, we show that CTRP4 is an evolutionarily conserved, ∼34-kDa secretory protein expressed in the brain. In human, mouse, and zebrafish brain, CTRP4 expression begins early in development and is widespread in the central nervous system. Neurons, but not astrocytes, express and secrete CTRP4, and secreted proteins form higher-order oligomeric complexes. CTRP4 is also produced by peripheral tissues and circulates in blood. Its serum levels are increased in leptin-deficient obese (ob/ob) mice. Functional studies suggest that CTRP4 acts centrally to modulate energy metabolism. Refeeding following an overnight fast induced the expression of CTRP4 in the hypothalamus. Central administration of recombinant protein suppressed food intake and altered the whole-body energy balance in both chow-fed and high-fat diet-fed mice. Suppression of food intake by CTRP4 is correlated with a decreased expression of orexigenic neuropeptide (Npy and Agrp) genes in the hypothalamus. These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance.