Synaptic plasticity of feeding circuits: hormones and hysteresis

The drive to eat is controlled by neuronal circuits in the hypothalamus that respond to hormones signaling hunger or satiety. In this issue of Cell, Yang et al. (2011) reveal an AMPK-dependent synaptic pathway that sustains excitatory stimulation of the NPY/AgRP neurons that promote feeding behavior until satiety signals kick in.     

下丘脑Kiss1神经元在能量代谢调节中的作用

代谢是机体生存和延续的基础,机体通过影响行为并诱发一系列的生理反应,调节代谢状态。能量代谢失衡可能导致机体消瘦或肥胖,甚至会造成生长发育和生殖功能的障碍等。因此,维持机体的能量平衡至关重要,而这一状态的维持受中枢神经系统的严格控制。中枢神经系统,特别是下丘脑,在调节机体生理功能和能量平衡中发挥着重要的作用。下丘脑Kisspeptin被认为在调节性腺轴、营养性发育和生殖中发挥重要作用。近些年来,关于其在能量代谢调控中的作用也引起广泛关注。本文将从能量摄入和能量消耗两个方面对下丘脑Kisspeptin在能量代谢调控中的作用进行综述,以期为防治因能量失衡诱发的代谢性疾病提供新的研究思路和依据。     

大鼠下丘脑室旁核神经元对电刺激迷走神经的反应

用玻璃微电极记录了93只大鼠的1059个PVH单位的电活动,观察了电刺激颈部迷走神经对PVH单位自发放电的效应和所引起的PVH单位的诱发反应。电刺激迷走神经分别使46个及10个PVH单位呈诱发兴奋和抑制反应。给予迷走神经以不同强度的刺激时,发现PVH神经元对激活A和C两类纤维的强刺激反应,而对仅激活A类纤维的弱刺激则不反应。PVH单位对电刺激坐骨神经或迷走神经的反应有以下几种:对迷走神经和坐骨神经刺激均作出兴奋或抑制反应;仅对迷走刺激作出兴奋或兴奋-抑制反应,而对坐骨神经刺激不反应;对坐骨神经刺激作出兴奋反应,而对迷走神经刺激不反应。讨论了迷走神经到室旁核的中枢传导特点以及内脏传入和躯体传入信息在PVH单位会聚的可能意义。     

Dopaminergic modulation of visual responses in toads II. Influences of apomorphine on retinal ganglion cells and tectal cells

The behavioral studies of Part I have shown in common toads that after systemic administration of the dopamine agonist apomorphine the prey-directed orienting turning movements are suppressed while prey snapping is facilitated. Part II focusses on retinal and tectal single cell responses to moving objects. (1) After systemic administration of apomorphine, the discharge rates of retinal class R2 and R3 ganglion cell fibres – recorded from the retino-tectal projection – speeded up in response to visual objects traversing their excitatory receptive fields. This enhancing effect was independent of the recording site in the retino-tectal map. (2) The diameters of the excitatory receptive fields of R2 and R3 neurons doubled their sizes. Probably, apomorphine enhances the center-dominated excitatory responses at the expense of the strength of the inhibitory surround. (3) The apomorphine-induced effects were fully developed 20–35 min after drug administration. (4) At the same time the discharge rates of T5.1 and T5.2 tectal neurons were reduced under apomorphine. The effect was independent of the recording site in the retino-tectal map. The diameters of the excitatory receptive fields of these tectal neurons were not influenced. (5) To changes in configurational stimulus features, the basic pattern of discrimination was maintained. (6) It is suggested that tectal output to the turn-generating motor network – mediated by T5.1 and T5.2 neurons – is modulated by a pretecto-tectal pathway which involves dopaminergic pretectal cells. (7) The enhanced snapping can be interpreted in terms of a modulation of reticular/hypoglossal structures by dopaminergic preoptic/hypothalamic/solitary systems.     

Medullary reticular neurons in the Japanese toad: morphologies and excitatory inputs from the optic tectum

1. To elucidate the neural mechanisms that mediate visual responses of optic tectum (OT) to medullary and spinal motor systems, we analyzed medullary reticular neurons in paralyzed Japanese toads (Bufo japonicus). We examined their responses to electrical stimulation of OT, and stained some neurons intracellularly. Responses to stimulation of the glossopharyngeal nerve (IX) were also analyzed. 2. Extracellular single unit recording revealed excitatory responses of medullary neurons to OT and IX stimulation. Among 92 units encountered, 79 responded to OT stimuli, 10 to IX stimuli, and 3 to both. Some units responded to successive stimuli of short intervals with relatively stable lags. 3. Intracellular recording and staining experiments revealed morphologies of reticular neurons that received excitatory inputs from OT. Thirteen units were identified after complete reconstruction of somata and dendrites. Neurons in the nucleus reticularis medius received excitatory inputs from bilateral OT. They had wide dendrites in ventral, ventrolateral and lateral funiculi, and single axons descending in the ipsilateral ventral funiculus as far caudally as the cervical spinal cord. Some collaterals of these axons projected directly to the hypoglossal and spinal motor nuclei. Some neurons in other medullary nuclei (nuc. reticularis superior, pretrigeminal nucleus, nuc. reticularis inferior, and nuc. tractus spinalis nervi trigemini) also responded to the OT stimulation. 4. Activities in bilateral OT converge onto medullary reticular neurons, which may directly control medullary and spinal motor systems.     

Multiple hypothalamic circuits sense and regulate glucose levels

The hypothalamus monitors body energy status in part through specialized glucose sensing neurons that comprise both glucose-excited and glucose-inhibited cells. Here we discuss recent work on the elucidation of neurochemical identities and physiological significance of these hypothalamic cells, including caveats resulting from the currently imprecise functional and molecular definitions of glucose sensing and differences in glucose-sensing responses obtained with different experimental techniques. We discuss the recently observed adaptive glucose-sensing responses of orexin/hypocretin-containing neurons, which allow these cells to sense changes in glucose levels rather than its absolute concentration, as well as the glucose-sensing abilities of melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin-containing neurons and the recent data on the role of ventromedial hypothalamic steroidogenic factor-1 (SF-1)/glutamate-containing cells in glucose homeostasis. We propose a model where orexin/hypocretin and SF-1/glutamate neurons cooperate in stimulating the sympathetic outflow to the liver and pancreas to increase blood glucose, which in turn provides negative feedback inhibition to these cells. Orexin/hypocretin neurons also stimulate feeding and reward seeking and are activated by hunger and stress, thereby providing a potential link between glucose sensing and goal-oriented behavior. The cell-type-specific neuromodulatory actions of glucose in several neurochemically distinct hypothalamic circuits are thus likely to be involved in coordinating higher brain function and behavior with autonomic adjustments in blood glucose levels.     

The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis

The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. We discovered expression of ghrelin in a previously uncharacterized group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing neuropeptide Y (NPY), Agouti-related protein (AGRP), proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiological recordings, we found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH). We propose that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.     

Orexins and feeding: special occasions or everyday occurrence?

Neurons expressing prepro-orexin, the precursor of orexin-A and -B, are found in the lateral hypothalamic area, a region classically implicated in driving feeding. Orexin-A induces feeding transiently when injected centrally, and food intake can be decreased when orexin action is disrupted by immunoneutralization of orexin-A, or by pharmacological blockade of orexin receptors, or by transgenic knockout of orexin. Here, we argue that orexin neurons may act to stimulate feeding in the short term, and that important regulatory signals may be a fall in plasma glucose (stimulatory), countered by satiety signals generated by eating, such as gastric distention (inhibitory).     

Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats

Neuropeptide Y (NPY) produced in the arcuate nucleus (ARC) of the hypothalamus stimulates feeding both directly by activating NPY receptors and indirectly through release of the orexigenic peptides, galanin and beta-endorphin (beta-END), in the paraventricular nucleus (PVN) and surrounding neural sites. Orexin A and orexin B, produced outside the ARC in the lateral hypothalamic area (LH), have recently been shown to stimulate feeding. In the present studies we tested the hypothesis that NPYergic signaling may mediate feeding stimulated by orexins. In adult male rats injected intracerebroventricularly (i.c.v.) with orexin A (3, 10, 15 nmol) or orexin B (3, 10, 30 nmol) feeding was stimulated in a dose-dependent manner; maximal feeding was seen after 15 nmol orexin A and 30 nmol orexin B. To determine whether NPY may mediate this orexin stimulated feeding, we used 1229U91, a selective NPY Y1 receptor antagonist (NPY-A). Whereas NPY-A on its own was ineffective, it suppressed NPY-induced feeding. Furthermore, NPY-A completely blocked the feeding evoked by either orexin A (15 nmol) or orexin B (30 nmol). These results show that orexin A and B stimulate feeding and further suggest that these excitatory effects may be mediated by NPYergic signaling through Y1 receptors. These findings are in accord with the view that the orexin-NPY pathway may comprise a functional link upstream from NPY within the hypothalamic appetite regulating network.     

Glucose-sensing neurons of the hypothalamus

Specialized subgroups of hypothalamic neurons exhibit specific excitatory or inhibitory electrical responses to changes in extracellular levels of glucose. Glucose-excited neurons were traditionally assumed to employ a 'beta-cell' glucose-sensing strategy, where glucose elevates cytosolic ATP, which closes KATP channels containing Kir6.2 subunits, causing depolarization and increased excitability. Recent findings indicate that although elements of this canonical model are functional in some hypothalamic cells, this pathway is not universally essential for excitation of glucose-sensing neurons by glucose. Thus glucose-induced excitation of arcuate nucleus neurons was recently reported in mice lacking Kir6.2, and no significant increases in cytosolic ATP levels could be detected in hypothalamic neurons after changes in extracellular glucose. Possible alternative glucose-sensing strategies include electrogenic glucose entry, glucose-induced release of glial lactate, and extracellular glucose receptors. Glucose-induced electrical inhibition is much less understood than excitation, and has been proposed to involve reduction in the depolarizing activity of the Na+/K+ pump, or activation of a hyperpolarizing Cl- current. Investigations of neurotransmitter identities of glucose-sensing neurons are beginning to provide detailed information about their physiological roles. In the mouse lateral hypothalamus, orexin/hypocretin neurons (which promote wakefulness, locomotor activity and foraging) are glucose-inhibited, whereas melanin-concentrating hormone neurons (which promote sleep and energy conservation) are glucose-excited. In the hypothalamic arcuate nucleus, excitatory actions of glucose on anorexigenic POMC neurons in mice have been reported, while the appetite-promoting NPY neurons may be directly inhibited by glucose. These results stress the fundamental importance of hypothalamic glucose-sensing neurons in orchestrating sleep-wake cycles, energy expenditure and feeding behaviour.     

Immunotoxic catecholamine lesions attenuate 2DG-induced increase of AGRP mRNA

Injections of the immunotoxin, saporin conjugated to anti-dopamine-beta-hydroxylase (DSAP), into the hypothalamic paraventricular nucleus (PVH) selectively destroy norepinephrine (NE) and epinephrine (E) terminals in the medial hypothalamus and abolish glucoprivic feeding. We utilized PVH DSAP injections to examine the role of NE/E neurons in the previously reported 2-deoxy-D-glucose (2DG)-induced increases in mRNA levels for the orexigenic peptides, AGRP and NPY. Northern blot analysis revealed that DSAP lesions elevated basal but blocked 2DG-induced increases in AGRP mRNA levels. Changes in NPY mRNA were not detectable. AGRP neurons may contribute to circuitry activated by NE/E neurons for elicitation of glucoregulatory responses.     

Generation of motor neurons requires spatiotemporal coordination between retinoic acid and Mib-mediated Notch signaling

Mind bomb (Mib) is an E3 ubiquitin ligase that activates the Notch signaling pathway. A previous study demonstrated that the generation of late-born GABAergic neurons may be regulated by the interplay between Mib and retinoic acid (RA). However, the relationship between Mib function and the retinoid pathway during the generation of late-born motor neurons remains unclear. We investigated the differentiation of neural progenitors into motor neurons by inhibition of Notch signaling and administration of RA to Tg[hsp70-Mib:EGFP] embryos. The number of motor neurons in the ventral spinal cord increased or decreased depending on the temporal inhibition of Mib-mediated Notch signaling. Inhibition of the retinoid pathway by citral treatment had a synergistic effect with overexpression of Mib:EGFP on the generation of ectopic motor neurons. Additionally, the proteolytic fragment of Mib was detected in differentiated P19 cells following treatment with RA. Our observations imply that the function of Mib may be attenuated by the retinoid pathway, and that Mib-mediated Notch signaling and the retinoid pathway play critical roles in the spatiotemporal differentiation of motor neurons.     

Musings on the wanderer: what's new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut

Vagal efferents, consisting of distinct lower motor and preganglionic parasympathetic fibers, constitute the motor limb of vagally mediated reflexes. Arising from the nucleus ambiguus, vagal lower motor neurons (LMN) mediate reflexes involving striated muscles of the orad gut. LMNs provide cholinergic innervation to motor end plates that are inhibited by myenteric nitrergic neurons. Preganglionic neurons from the dorsal motor nucleus implement parasympathetic motor and secretory functions. Cholinergic preganglionic neurons form parallel inhibitory and excitatory vagal pathways to smooth muscle viscera and stimulate postganglionic neurons via nicotinic and muscarinic receptors. In turn, the postganglionic inhibitory neurons release ATP, VIP, and NO, whereas the excitatory neurons release ACh and substance P. Vagal motor effects are dependent on the viscera's intrinsic motor activity and the interaction between the inhibitory and excitatory vagal influences. These interactions help to explain the physiology of esophageal peristalsis, gastric motility, lower esophageal sphincter, and pyloric sphincter. Vagal secretory pathways are predominantly excitatory and involve ACh and VIP as the postganglionic excitatory neurotransmitters. Vagal effects on secretory functions are exerted either directly or via release of local mediators or circulating hormones.     

5-Hydroxytryptamine involvement in the intrinsic control of oesophageal EMG activity

The effects and the sites of action of 5-Hydroxytryptamine (5HT) were examined in transverse muscular strips of pigeon oesophagus. 5-Hydroxytryptamine (0.001 to 30 microM) induced a concentration-dependent excitatory effect on the EMG activity. This response was mainly characterized by an increase in burst frequency. The maximum 5-HT-induced excitatory effect was not altered by methysergide (10 microM), but was abolished by tetrodotoxin (3 microM). Excitatory response to 5-HT was partly opposed by atropine (1 microM), potentiated by 5-methoxy-N, N-dimethyltryptamine (1 microM) and was not altered by guanethidine (10 microM). These results indicate that 5-HT activates the pigeon oesophagus indirectly via neural elements and has no direct action on the smooth muscle cells. 5-HT is thought to stimulate three different intramural neuron types: excitatory cholinergic neurons, excitatory non-cholinergic neurons and inhibitory non-cholinergic non-adrenergic neurons. The action on these different neurons seems to be mediated via different receptors.     

FoxO1对下丘脑摄食中枢的影响研究进展

下丘脑是人体的摄食中枢,它通过抑制食欲的阿黑皮素原(POMC)神经元和促进食欲的神经肽相关蛋白(AgRP)神经元调节摄食及能量代谢。叉头转录因子O亚族1(FoxO1)是胰岛素信号通路和瘦素信号通路中重要的调节蛋白,FoxO1的生理作用是促进下丘脑Agrp基因表达、抑制Pomc基因表达,抑制瘦素信号通路的转录激活因子3(STAT3)蛋白对Pomc基因转录的促进作用,从而促进食欲。瘦素和胰岛素均可激活经典的IRS/PI(3)K/Akt信号通路,使FoxO1磷酸化失去活性,抑制食欲。此外,沉默信息调节因子Sirt1也可以通过去乙酰化,影响FoxO1的转录活性。本文综述了胰岛素、瘦素、Sirt1通过FoxO1调节下丘脑摄食中枢的作用机制。     

Corticofugal influences on the neurons of different regions of the hypothalamus

Responses of the neurons of the lateral and ventromedial hypothalamic regions (HL andHvm, respectively), as well as of the area of the dorsal hypothalamus (aHd) and the projection region of the medial forelimb bundle (MFB), evoked by stimulation of the proreal cortex (field 8), cingular cortex (field 24), pyriform lobula (periamigdalar cortex), and hippocampus (CA3) were studied in acute experiments on cats under ketamine anesthesia. Distributions of the latent periods of the responses recorded from hypothalamic neurons at stimulation of the above cortical structures were analyzed. The responses were classified into primary excitatory and primary inhibitory. Stimulation of the proreal gyrus evoked four times more excitatory responses than inhibitory responses. With stimulation of the cingular gyrus, the ratio of excitatory/inhibitory responses was 1.5∶1. Stimulation of the pyriform cortex evoked activatory and inhibitory responses with a similar probability. With hippocampal stimulation, inhibitory responses appeared two times more frequently than excitatory reactions. The hypothalamus was found to be a zone of wide convergence: one-half of all responding neurons in theHL andHvm responded to stimulations of two or more tested cortical zones. In 26% of the cells, only excitatory convergence was observed, while in 10% only inhibitory convergence was found; 21% of the cells revealed mixed convergence.     

A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior

Behavioral output of neural networks depends on a delicate balance between excitatory and inhibitory synaptic connections. However, it is not known whether network formation and stability is constrained by the sign of synaptic connections between neurons within the network. Here we show that switching the sign of a synapse within a neural circuit can reverse the behavioral output. The inhibitory tyramine-gated chloride channel, LGC-55, induces head relaxation and inhibits forward locomotion during the Caenorhabditis elegans escape response. We switched the ion selectivity of an inhibitory LGC-55 anion channel to an excitatory LGC-55 cation channel. The engineered cation channel is properly trafficked in the native neural circuit and results in behavioral responses that are opposite to those produced by activation of the LGC-55 anion channel. Our findings indicate that switches in ion selectivity of ligand-gated ion channels (LGICs) do not affect network connectivity or stability and may provide an evolutionary and a synthetic mechanism to change behavior.     

Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions

Central noradrenergic (NA) signaling is broadly implicated in behavioral and physiological processes related to attention, arousal, motivation, learning and memory, and homeostasis. This review focuses on the A2 cell group of NA neurons, located within the hindbrain dorsal vagal complex (DVC). The intra-DVC location of A2 neurons supports their role in vagal sensory-motor reflex arcs and visceral motor outflow. A2 neurons also are reciprocally connected with multiple brain stem, hypothalamic, and limbic forebrain regions. The extra-DVC connections of A2 neurons provide a route through which emotional and cognitive events can modulate visceral motor outflow and also a route through which interoceptive feedback from the body can impact hypothalamic functions as well as emotional and cognitive processing. This review considers some of the hallmark anatomical and chemical features of A2 neurons, followed by presentation of evidence supporting a role for A2 neurons in modulating food intake, affective behavior, behavioral and physiological stress responses, emotional learning, and drug dependence. Increased knowledge about the organization and function of the A2 cell group and the neural circuits in which A2 neurons participate should contribute to a better understanding of how the brain orchestrates adaptive responses to the various threats and opportunities of life and should further reveal the central underpinnings of stress-related physiological and emotional dysregulation.     

Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses.

This review summarizes recent work on two basic processes of central nervous system (CNS) control of cholinergic outflow to the airways: 1) transmission of bronchoconstrictive signals from the airways to the airway-related vagal preganglionic neurons (AVPNs) and 2) regulation of AVPN responses to excitatory inputs by central GABAergic inhibitory pathways. In addition, the autocrine-paracrine modulation of AVPNs is briefly discussed. CNS influences on the tracheobronchopulmonary system are transmitted via AVPNs, whose discharge depends on the balance between excitatory and inhibitory impulses that they receive. Alterations in this equilibrium may lead to dramatic functional changes. Recent findings indicate that excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second-order neurons within the nucleus of the solitary tract (NTS), via a glutamate-AMPA signaling pathway. These neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command to airway effector organs: smooth muscle, submucosal secretory glands, and the vasculature, through intramural ganglionic neurons. The strength and duration of reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs and autocrine-paracrine controlling mechanisms. Downregulation of GABAergic inhibitory influences may result in a shift from inhibitory to excitatory drive that may lead to increased excitability of AVPNs, heightened airway responsiveness, and sustained narrowing of the airways. Hence a better understanding of these normal and altered central neural circuits and mechanisms could potentially improve the design of therapeutic interventions and the treatment of airway obstructive diseases.     

TrkB受体依赖的PV神经元调控小鼠视觉方位辨别能力的机制

神经营养因子-酪氨酸受体激酶B （tyrosine receptor kinase B,TrkB）信号通路在调控初级视皮层（primary visual cortex,V1）兴奋与抑制平衡上发挥着重要的作用,以往的研究揭示了其通过增加兴奋性传递效率来调控皮层兴奋性水平的机制,却并未阐明TrkB受体如何通过抑制系统来调控兴奋与抑制平衡,进而影响视觉皮层功能。为了探讨TrkB信号通路如何特异性地调控最主要的抑制性神经元——PV神经元进而对小鼠视觉皮层功能产生影响,本研究通过病毒特异性地降低V1区的PV神经元上TrkB受体的表达水平,并通过在体多通道电生理手段记录初级视皮层抑制性与兴奋性神经元功能变化,通过行为学实验测试小鼠的方位辨别能力改变。结果表明,初级视觉皮层中的PV抑制性神经元上的TrkB受体表达减少会显著增加兴奋性神经元的反应强度,减弱抑制性神经元与兴奋性神经元的方位辨别能力,增加二者的信噪比,但是小鼠个体水平的方位辨别能力出现下降。这些结果说明,TrkB信号通路并非单纯通过增加靶向PV神经元的兴奋性传递来调控PV神经元的功能,其对神经元信噪比的影响也并非由于抑制系统的增强所致。