食欲素神经肽在应激过程中的作用

食欲素因其在调节能量代谢、睡眠和唤醒等生理功能中的作用而备受关注.近年来研究逐渐发现,食欲素参与应激和奖赏过程的调节,特别是其在药物成瘾过程中的作用是目前的研究热点.主要介绍食欲素系统与应激相关系统之间的神经联系,阐述了其在应激相关的生理、神经内分泌与行为反应中的作用.并进一步介绍了食欲素系统在应激诱发药物成瘾复吸过程中的作用.食欲素对应激反应的调控作用具有相对特异性,受应激的种类、其他应激相关神经递质系统及食欲素神经元的投射通路等多种因素影响.     

食欲素信号系统在成瘾中的作用

成瘾是对成瘾物质的强迫性、持续性需求并缺乏控制能力的行为,它会导致大脑中枢奖赏回路的改变。下丘脑是调控自然奖赏的重要脑区,它能特异性地表达一种被称为食欲素(orexins/hypocretins)的神经肽。食欲素通过作用于食欲素受体调控睡眠、觉醒状态,同时,食欲素受体在药物成瘾和奖赏相关的行为中也有重要作用,投射到不同脑区的食欲素对不同药物导致的成瘾调节作用也不同,调控食欲素信号系统,将可能成为治疗成瘾的重要方法。本文重点总结了食欲素信号系统在不同药物成瘾过程中的作用的最新研究进展。     

Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants

Background

Feeding behavior is regulated through an intricate array of anorexic and orexigenic hormones acting on the central nervous system (CNS). Some of these hormones may have differential effects in males and females, effects potentially attributed to actions of gonadal steroids, especially estrogens. Central stimulation of the glucagon-like peptide-1 (GLP-1) receptors reduces feeding and food-reward behavior by acting on CNS regions important for the anorexic actions of estrogens. Thus, we propose that the action of GLP-1 on food intake and reward may differ between sexes.

Methods

Male and female rats were centrally injected with the GLP-1 analog exendin-4 (Ex4) in a non-deprived or food-restricted state; reward behavior was measured in a progressive ratio operant conditioning task. Intake of chow and palatable food were also measured. To determine if sex differences in the actions of Ex4 are due to interactions with estrogens, Ex4 treatment was preceded by treatment with a nonselective estrogen receptor-α (ERα) and ERβ or ERα-selective antagonist.

Results

Central injection of Ex4 revealed increased reward behavior suppression in females, compared to males, in the operant conditioning task. This increase was present in both non-deprived and food-restricted animals with larger differences in the fed state. Intake of chow and palatable food, after Ex4, were similar in males and females. Food reward, but not food intake, effect of Ex4 was attenuated by pretreatment with ER antagonist in both sexes, suggesting that estrogens may modulate effects of Ex4 in both sexes. Furthermore, central pretreatment with ERα-selective antagonist was sufficient to attenuate effects of Ex4 on reward.

Conclusions

Collectively, these data reveal that females display much higher sensitivity to the food reward impact of central GLP-1 receptor activation. Surprisingly, they also demonstrate that central ERα signaling is necessary for the actions of GLP-1 on food-reward behavior in both sexes.

     

In Situ Regulated Dopamine Transporter Trafficking: There’s No Place Like Home

Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important behaviors, and additionally play a role in DA-related neuropathologies. The presynaptic SLC6 DA transporter (DAT) limits extracellular DA levels by clearing released DA, and is potently inhibited by addictive and therapeutic psychostimulants. Decades of evidence support that the DAT is subject to acute regulation by a number of signaling pathways, and that endocytic trafficking strongly regulates DAT availability and function. DAT trafficking studies have been performed in a variety of model systems, including both in vitro and ex vivo preparations. In this review, we focus on the breadth of DAT trafficking studies, with specific attention to, and comparison of, how context may influence DAT’s response to different stimuli. In particular, this overview highlights that stimulated DAT trafficking not only differs between in vitro and ex vivo environments, but also is influenced by both sex and anatomical subregions.

     

Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey

The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.     

Metabolic state signalling through central hypocretin/orexin neurons

Hypothalamic neurons that produce the peptide transmitters hypocretins/orexins have attracted much recent attention. They provide direct and predominantly excitatory inputs to all major brain areas except the cerebellum, with the net effect of stimulating wakefulness and arousal. These inputs are essential for generating sustained wakefulness in mammals, and defects in hypocretin signalling result in narcolepsy. In addition, new roles for hypocretins/orexins are emerging in reward-seeking, learning, and memory. Recent studies also indicate that hypocretin/orexin neurons can alter their intrinsic electrical activity according to ambient fluctuations in the levels of nutrients and appetite-regulating hormones. These intriguing electrical responses are perhaps the strongest candidates to date for the elusive neural correlates of after-meal sleepiness and hunger-induced wakefulness. Hypocretin/orexin neurons may thus directly translate rises and falls in body energy levels into different states of consciousness.     

Association of flower color with pollen reward may explain increased bumblebee visitation to the Scotch broom yellow morph

Given that pollinators usually visit flowers for hidden rewards, they need to rely on floral traits that indicate reward status (“honest signals”). However, the relationship between pollination, honest signals, and floral rewards is little documented in natural conditions. The Scotch broom (Cytisus scoparius) is an invasive shrub with polymorphism in the color of its flowers that can be yellow, orange, or red. In three areas dominated by the Scotch broom, we described the abundance of the floral morphs and estimated bumblebee (Bombus terrestris) visitation rate. We examined whether bumblebee visitation to the floral morphs was related to pollen reward. We collected flowers and classified their stamens according to their function: reward or pollen export. Then, we measured anther size and estimated pollen quantity. The yellow morph was more abundant and more visited by bumblebees than the orange and red morphs. The yellow flowers did indeed offer more pollen than the other morphs and this occurred only for rewarding anthers, suggesting that bumblebees could use yellow color as an honest signal to visit the most rewarding flowers. We discuss whether innate and/or learned preferences of bumblebees can explain why the yellow morph is more visited, pollinated, and abundant, while the other morphs are maintained at a lower frequency. This is one of the few field works that shows that variation in intra-specific floral traits is associated with variation in floral reward and pollinator visitation rate, helping to understand the foraging preferences of pollinators and the coexistence of floral morphs in nature.

Clinical trials registration: Not applicable.

     

Adding preferred color to a conventional reward method improves the memory of zebrafish in the T-maze behavior model

Zebrafish have become a useful model for studying behavior and cognitive functions. Recent studies have shown that zebrafish have natural color preference and the ability to form associative memories with visual perception. It is well known that visual perception enhances memory recall in humans, and we suggest that a similar phenomenon occurs in zebrafish. This study proposes that adding a visual perception component to a conventional reward method would enhance memory recall in zebrafish. We found that zebrafish showed greater preference for red cellophane over yellow in the training session but could not remember the preferred place in the memory test. However, the test memory recall was greater when the zebrafish were exposed to the red cellophane with a food reward during the training session, when compared with the use of food reward only. Furthermore, the red cellophane with food reward group showed more predictable memory recall than the food reward only group. These results propose that visual perception can increase memory recall by enhancing the consolidation processes. We suggest that color-cued learning with food reward is a more discriminative method than food reward alone for examining the cognitive changes in the zebrafish.

Abbreviations: WM: working memory; LTM: long-term memory     

The hypocretins and sleep

The hypocretins (also called the orexins) are two neuropeptides derived from the same precursor whose expression is restricted to a few thousand neurons of the lateral hypothalamus. Two G-protein coupled receptors for the hypocretins have been identified, and these show different distributions within the central nervous system and differential affinities for the two hypocretins. Hypocretin fibers project throughout the brain, including several areas implicated in regulation of the sleep/wakefulness cycle. Central administration of synthetic hypocretin-1 affects blood pressure, hormone secretion and locomotor activity, and increases wakefulness while suppressing rapid eye movement sleep. Most human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebral spinal fluid and no or barely detectable hypocretin-containing neurons in their hypothalamus. Multiple lines of evidence suggest that the hypocretinergic system integrates homeostatic, metabolic and limbic information and provides a coherent output that results in stability of the states of vigilance.     

Localizing Brain Regions Associated with Female Mate Preference Behavior in a Swordtail

Female mate choice behavior is a critical component of sexual selection, yet identifying the neural basis of this behavior is largely unresolved. Previous studies have implicated sensory processing and hypothalamic brain regions during female mate choice and there is a conserved network of brain regions (Social Behavior Network, SBN) that underlies sexual behaviors. However, we are only beginning to understand the role this network has in pre-copulatory female mate choice. Using in situ hybridization, we identify brain regions associated with mate preference in female Xiphophorus nigrensis, a swordtail species with a female choice mating system. We measure gene expression in 10 brain regions (linked to sexual behavior, reward, sensory integration or other processes) and find significant correlations between female preference behavior and gene expression in two telencephalic areas associated with reward, learning and multi-sensory processing (medial and lateral zones of the dorsal telencephalon) as well as an SBN region traditionally associated with sexual response (preoptic area). Network analysis shows that these brain regions may also be important in mate preference and that correlated patterns of neuroserpin expression between regions co-vary with differential compositions of the mate choice environment. Our results expand the emerging network for female preference from one that focused on sensory processing and midbrain sexual response centers to a more complex coordination involving forebrain areas that integrate primary sensory processing and reward.     

Early Effects of Reward Anticipation Are Modulated by Dopaminergic Stimulation

The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2×2 factorial design), while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude) emerged at ∼100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20–30 Hz) and low (13–20 Hz) beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine.     

Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning

Previous studies suggest that a single nucleotide polymorphism in the catechol‐O‐methyltransferase (COMT) gene (val158met) may modulate reward‐guided decision making in healthy individuals. The polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial × COMT genotype interaction (P = 0.047; η² = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias [response bias at block 3 ? block 1 (met/met > val/val: P = 0.028) and block 3 ? block 2 (met/met > val/val: P = 0.007)], suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk‐seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk‐seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia.     

CSF orexin-A/hypocretin-1 concentrations in patients with intracerebral hemorrhage (ICH)

Orexins/hypocretins are neuropeptides that have various physiological effects, including the regulation of both the feeding behavior neuroendocrine functions and sleep-wakefulness cycle. Recent studies have suggested that the orexin system may also be involved in neuronal damage in the clinical setting and animal experiments. The aim of this study was to examine the role of the hypothalamic orexin-A/hypocretin-1 system in patients with intracerebral hemorrhage (ICH). The CSF orexin-A/hypocretin-1 levels were measured in 11 ICH patients. CSF orexin-A/hypocretin-1 levels were low in ICH patients during the 13 days following the ICH event. The mean CSF orexin-A/hypocretin-1 levels were 61.1+/-22.3 (S.D.) pg/ml (range 27.5-106.9 pg/ml).The decreasing in the CSF orexin-A/hypocretin-1 levels was not related to the severity of ICH. The CSF orexin-A/hypocretin-1 levels were lower in the thalamic hemorrhage patients than those in other patients (48.5+/-23.3 pg/ml vs. 65.2+/-21.2 pg/ml; p=0.03.) These data indicate that orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in ICH patients.     

Interaction of the hypocretins with neurotransmitters in the nucleus accumbens

The hypocretins (hcrt1 and hcrt2), also known as orexins, are two neuropeptides derived from the same precursor, expressed in a few thousand cells in the lateral hypothalamus. Hypocretin-containing cells project throughout the brain, including ascending projections to the olfactory bulb and cerebral cortex, through the medial septum and the nucleus accumbens. Here, we have studied the interactions of the hypocretins with different neurotransmitters by patch clamp recording of acutely dissociated cells from the nucleus accumbens. Application of hcrt1 or hcrt2 decreased postsynaptic NMDA currents, enhanced GABA currents but did not affect glycine-activated conductances. Our results strongly suggest that the hypocretin peptides may be inhibitory peptides, probably via binding hcrt receptor 2.     

Examination of Rapid Dopamine Dynamics with Fast Scan Cyclic Voltammetry During Intra-oral Tastant Administration in Awake Rats

Rapid, phasic dopamine (DA) release in the mammalian brain plays a critical role in reward processing, reinforcement learning, and motivational control. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique with high spatial and temporal (sub-second) resolution that has been utilized to examine phasic DA release in several types of preparations. In vitro experiments in single-cells and brain slices and in vivo experiments in anesthetized rodents have been used to identify mechanisms that mediate dopamine release and uptake under normal conditions and in disease models. Over the last 20 years, in vivo FSCV experiments in awake, freely moving rodents have also provided insight of dopaminergic mechanisms in reward processing and reward learning. One major advantage of the awake, freely moving preparation is the ability to examine rapid DA fluctuations that are time-locked to specific behavioral events or to reward or cue presentation. However, one limitation of combined behavior and voltammetry experiments is the difficulty of dissociating DA effects that are specific to primary rewarding or aversive stimuli from co-occurring DA fluctuations that mediate reward-directed or other motor behaviors. Here, we describe a combined method using in vivo FSCV and intra-oral infusion in an awake rat to directly investigate DA responses to oral tastants. In these experiments, oral tastants are infused directly to the palate of the rat – bypassing reward-directed behavior and voluntary drinking behavior – allowing for direct examination of DA responses to tastant stimuli.     

Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity

The hypocretins (orexins) are recently discovered neuropeptides initially associated with feeding behavior and sleep regulation. However, the normal function of these peptides is unclear and a number of studies have reported a role in energy homeostasis and locomotor activity. Exercise (or physical activity) is the most powerful way of challenging the internal homeostatic process. This study examines the circadian differences in response to forced activity and homeostatic challenges on hypocretin-1 (Hcrt-1) levels in the cerebrospinal fluid (CSF) of rats. Hcrt-1 levels were decreased after long-term immobilization at the end of active phase (zeigeber time-0, ZT-0) and increased after short-term forced swimming in the rest phase (ZT-8). Nevertheless, no effects were observed after short-term immobilization, total sleep deprivation or cold exposure. We concluded that despite the relation between hypocretins, stress and sleep regulation reported in the literature, short-term total sleep deprivation, immobilization and cold exposure did not induce increases in CSF Hcrt-1 levels at ZT-0 and ZT-8. On the other hand, the relationship between hypocretinergic system activation and motor activation is reinforced by decrease in Hcr-1 levels after long-term immobilization at ZT-0 and its increased levels after short-term forced swimming at ZT-8 in CSF of rats.     

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.     

Ghrelin Influences Novelty Seeking Behavior in Rodents and Men

Recent discoveries indicate an important role for ghrelin in drug and alcohol reward and an ability of ghrelin to regulate mesolimbic dopamine activity. The role of dopamine in novelty seeking, and the association between this trait and drug and alcohol abuse, led us to hypothesize that ghrelin may influence novelty seeking behavior. To test this possibility we applied several complementary rodent models of novelty seeking behavior, i.e. inescapable novelty-induced locomotor activity (NILA), novelty-induced place preference and novel object exploration, in rats subjected to acute ghrelin receptor (growth hormone secretagogue receptor; GHSR) stimulation or blockade. Furthermore we assessed the possible association between polymorphisms in the genes encoding ghrelin and GHSR and novelty seeking behavior in humans. The rodent studies indicate an important role for ghrelin in a wide range of novelty seeking behaviors. Ghrelin-injected rats exhibited a higher preference for a novel environment and increased novel object exploration. Conversely, those with GHSR blockade drastically reduced their preference for a novel environment and displayed decreased NILA. Importantly, the mesolimbic ventral tegmental area selective GHSR blockade was sufficient to reduce the NILA response indicating that the mesolimbic GHSRs might play an important role in the observed novelty responses. Moreover, in untreated animals, a striking positive correlation between NILA and sucrose reward behavior was detected. Two GHSR single nucleotide polymorphisms (SNPs), rs2948694 and rs495225, were significantly associated with the personality trait novelty seeking, as assessed using the Temperament and Character Inventory (TCI), in human subjects. This study provides the first evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also points to an association between food reward and novelty seeking in rodents.     

Let-7d modulates the proliferation,migration, tubulogenesis of endothelial cells

Calcitriol, vitamin D3 (VD3), and structurally related VD3 analogues are inhibitors of Hh signaling in multiple contexts and are promising anti-cancer agents in Hh-dependent forms of cancer; however, the cellular mechanisms through which these compounds regulate Hh signal transmission are not clearly defined. Previous studies in this area have implicated both Smoothened, a key mediator of Hh signaling, and the vitamin D receptor (VDR) as potential mediators of Hh inhibition for this class of seco-steroids. We have performed a series of in vitro studies to more fully probe the cellular mechanisms that govern seco-steroid-mediated inhibition of Hh signaling. Our results support a role for both the Hh and VDR pathways in this process, as well as the possibility that other, as yet unidentified proteins, are also central to seco-steroid-mediated inhibition of Hh signaling.