Control of ventricular ciliary beating by the melanin concentrating hormone-expressing neurons of the lateral hypothalamus: a functional imaging survey

The cyclic peptide Melanin Concentrating Hormone (MCH) is known to control a large number of brain functions in mammals such as food intake and metabolism, stress response, anxiety, sleep/wake cycle, memory, and reward. Based on neuro-anatomical and electrophysiological studies these functions were attributed to neuronal circuits expressing MCHR1, the single MCH receptor in rodents. In complement to our recently published work (1) we provided here new data regarding the action of MCH on ependymocytes in the mouse brain. First, we establish that MCHR1 mRNA is expressed in the ependymal cells of the third ventricle epithelium. Second, we demonstrated a tonic control of MCH-expressing neurons on ependymal cilia beat frequency using in vitro optogenics. Finally, we performed in vivo measurements of CSF flow using fluorescent micro-beads in wild-type and MCHR1-knockout mice. Collectively, our results demonstrated that MCH-expressing neurons modulate ciliary beating of ependymal cells at the third ventricle and could contribute to maintain cerebro-spinal fluid homeostasis.

Participation of alpha-1 and alpha-2 adrenoceptors of the lateral hypothalamic area in water intake, and renal sodium, potassium and urinary Volume excretion induced by central administration of angiotensin II

The circumventricular structures and the lateral hypothalamus (LH) have been shown to be important for the central action of angiotensin II (ANGII) on water and electrolyte regulation. Several anatomical findings have demonstrated neural connection between circumventricular structures and the LH, the present experiments were conducted to investigate the role of the alpha-adrenergic antagonists and agonistic injected into the LH on the water intake, sodium and potassium excretion elicited by injections of ANGII into the lateral ventricle (LV), the water intake was measured every 30 min over a period of 120 min. The sodium, potassium and urinary volume were measured over a period of 120 min in water-loaded rats. The injection of ANGII into the LV increased the water intake, which was reduced by previous injection of clonidine (an alpha-2-adrenergic agonist) into the LH. The injection of yohimbine (an alpha-2-adrenergic antagonist) and prazosin (an alpha-l-adrenergic antagonist) into the LH, which was done before injecting ANGII into the LV, also reduced the water intake induced by ANGII. The injection of ANGII into the LV reduced the sodium, potassium and urinary volume. Previous treatment with clonidine attenuated the action of ANGII in reducing the sodium, potassium and urinary volume, whereas previous treatment with yohimbine attenuated the effects of ANGII but with less intensity than that caused by clonidine. Previous treatment with prazosin increased the inhibitory effects of ANGII in those parameters. The injection of yohimbine and prazosin, which was done before the injection of clonidine, attenuated the effect of clonidine on the ANGII mechanism. The results of this study led us to postulate that when alpha-2-adrenergic receptors are blocked, the clonidine may act on the imidazoline receptors to produce its effects on the ANGII mechanism. We may also conclude that the LH is involved with circumventricular structures, which present excitatory and inhibitory mechanisms. Such mechanisms are responsible for regulating the renal excretion of sodium, potassium and water, (C) 2000 Elsevier B.V.

Role of alpha1 and alpha2-adrenoceptors of the lateral hypothalamic area on urinary excretion caused by centrally administered angiotensin II

To determine whether central α1 and α2-adrenergic mechanisms are involved in urinary sodium and potassium excretion and urine volume induced by angiotensin II (ANGII), these renal parameters were measured in volume-expanded Holtzman rats with cannulas implanted into lateral ventricle (LV) and lateral hypothalamus (LH). The injection of ANGII into LV in rats with volume expansion reduced the sodium, potassium and urine excretion in comparison to the control injections of isotonic saline, whereas prazosin (α1 antagonist) potentiated these effects. Clonidine (α2 agonist) and yohimbine (α2 antagonist) injected into LH previous to injection of ANGII into LV also abolished the inhibitory effect of ANGII. These results suggest that the discharge of central alpha-adrenergic receptors has dual inhibitory and excitatory effect on antinatriuretic, antikaliuretic and antidiuretic effect induced by central ANGII in volume-expanded rats. © 1995.

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat

The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1β injected into the rat striatum with the excitotoxin α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1β (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1β mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1β into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1β was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1β can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.

Stimulation of GABAergic neurons of the lateral septum and its effect on movement speed

The lateral septum is associated with the regulation of innate behavior, motivation, and locomotion. Its complex interconnections with cognitive and affective regions such as the hippocampus, hypothalamus, and medial septum have made it an attractive region for studying how motivation regulates behavior in context-specific settings. This GABAergic brain region’s main output is the lateral hypothalamus, which provides downstream signaling of motor commands. Even though stimulation of lateral septum projections to the hypothalamus have shown to decrease running speed in free behaving mice, characterizing movement kinematics due to LS activation has not been studied. GABAergic medium spiny neurons of the lateral septum were selectively activated through the use of optogenetic techniques in transgenic mice. Photostimulation of the lateral septum at theta frequencies caused a non-significant decrease in head and back speed. 3D motion analysis of body movement under photostimulation was quantified, revealing a slow, linear decrease of body speed as photostimulation progressed. These results support the role of lateral septum activation in movement regulation and shed light on the specific manner in which stimulation of the LS gradually decreases movement speed.

VTA-NAc内orexin A在吗啡和性奖赏相关行为中作用的研究

There are a lot of differences in the neural mechanisms underlying between drug reward and natural reward despite the common neual basis. Undoubtedly, revealing the common and the different mechanisms underlying drug reward and natural reward will promote the development of research on drug addiction. Among diversified natural rewards, sex is often compared to drug because sexual reward has more similarities to drug. The mesolimbic dopamine system (VTA-NAc pathway) is a common pathway activated by natural reinforcers and addictive drugs, mediating reward, emotion and motivation under physiological conditions. The neuroadaptations taking place in the central nervous system including the mesolimbic dopamine system after repeatedly drug taking leads to persistent drug craving, Orexin, a neuropeptide produced in the lateral hypothalamus, plays an important role in reward-associated, motivated behaviors. Orexin neurons have extensive projections to the mesolimbic dopamine system. In order to further investigate the roles of orexin A in drug reward, this study examined the regulatory roles of orexin A in the VTA and NAcSh on drug reinforcement (acqusition of morphine CPP) and drug-seeking behavior (expression of morphine CPP). Moreover, the roles of orexin A on drug reward were compared with sexual reward. The main results are as follows: 1. The expression of morphine CPP was inhibited by intracerebroventricularly (i.c.v.) administered OX1R antagonist SB334867; 2. The male unconditioned sexual motivation was not affected by i.c.v. administered SB334867. However, i.c.v. given orexin A inhibited unconditioned sexual motivation in sexually high-motivated rats but did not affect sexual motivation in low-motivated rats; 3. The acquisition and expression of morphine CPP was inhibited by SB334867 microinjected into the VTA. SB334867 or orexin A injected into the NAcSh did not influence the acquisition of morphine CPP, but orexin A increased the locomotor activity in rats treated with morphine (3mg/kg); 4. SB334867 microinjected into the VTA did not affect male copulatory behavior, neither affect the acqusition of copulatory CPP; 5. The expression of copulatory CPP was associated with increased Fos protein expression in hypothalamic orexin A neurons, and SB334867 microinjected into the VTA inhibited expression of copulatory CPP. These results suggest that, (1) endogenous orexin A is not involved in male unconditioned sexual motivation, but involved in drug craving; (2) orexin A in the VTA instead of in the NAc is involved in drug reinforcement; (3) orexin A in the VTA is critical for drug-seeking behavior, but it is still unclear for the role of orexin A in the NAcSh; (4) in contrast to drug reinforcement, orexin A in the VTA is not involved in reinforcing effect of sexual reward. Orexin A plays a role both in drug-seeking behavior and in sexual reward-seeking behavior, but the different orexin A neuron populations may be responsible for the roles of orexin A in two types of reward. In a word, the differential roles of orexin A in drug and sexual reward are found in the present study, which provides some evidence for further research on the mechanisms of drug addiction.

Dopaminergic and Non-Dopaminergic Value Systems in Conditioning and Outcome-Specific Revaluation

Animals are motivated to choose environmental options that can best satisfy current needs. To explain such choices, this paper introduces the MOTIVATOR (Matching Objects To Internal Values Triggers Option Revaluations) neural model. MOTIVATOR describes cognitiveemotional interactions between higher-order sensory cortices and an evaluative neuraxis composed of the hypothalamus, amygdala, and orbitofrontal cortex. Given a conditioned stimulus (CS), the model amygdala and lateral hypothalamus interact to calculate the expected current value of the subjective outcome that the CS predicts, constrained by the current state of deprivation or satiation. The amygdala relays the expected value information to orbitofrontal cells that receive inputs from anterior inferotemporal cells, and medial orbitofrontal cells that receive inputs from rhinal cortex. The activations of these orbitofrontal cells code the subjective values of objects. These values guide behavioral choices. The model basal ganglia detect errors in CS-specific predictions of the value and timing of rewards. Excitatory inputs from the pedunculopontine nucleus interact with timed inhibitory inputs from model striosomes in the ventral striatum to regulate dopamine burst and dip responses from cells in the substantia nigra pars compacta and ventral tegmental area. Learning in cortical and striatal regions is strongly modulated by dopamine. The model is used to address tasks that examine food-specific satiety, Pavlovian conditioning, reinforcer devaluation, and simultaneous visual discrimination. Model simulations successfully reproduce discharge dynamics of known cell types, including signals that predict saccadic reaction times and CS-dependent changes in systolic blood pressure.

Identifying novel molecular mechanisms of ghrelin receptor signalling underlying neural control of food intake: interaction with stress and impulsivity

The gut-hormone, ghrelin, activates the centrally expressed growth hormone secretagogue 1a (GHS-R1a) receptor, or ghrelin receptor. The ghrelin receptor is a G-protein coupled receptor (GPCR) expressed in several brain regions, including the arcuate nucleus (Arc), lateral hypothalamus (LH), ventral tegmental area (VTA), nucleus accumbens (NAcc) and amygdala. Activation of the GHS-R1a mediates a multitude of biological activities, including release of growth hormone and food intake. The ghrelin signalling system also plays a key role in the hedonic aspects of food intake and activates the dopaminergic mesolimbic circuit involved in reward signalling. Recently, ghrelin has been shown to be involved in mediating a stress response and to mediate stress-induced food reward behaviour via its interaction with the HPA-axis at the level of the anterior pituitary. Here, we focus on the role of the GHS-R1a receptor in reward behaviour, including the motivation to eat, its anxiogenic effects, and its role in impulsive behaviour. We investigate the functional selectivity and pharmacology of GHS-R1a receptor ligands as well as crosstalk of the GHS-R1a receptor with the serotonin 2C (5-HT2C) receptor, which represent another major target in the regulation of eating behaviour, stress-sensitivity and impulse control disorders. We demonstrate, to our knowledge for the first time, the direct impact of GHS-R1a signalling on impulsive responding in a 2-choice serial reaction time task (2CSRTT) and show a role for the 5-HT2C receptor in modulating amphetamine-associated impulsive action. Finally, we investigate differential gene expression patterns in the mesocorticolimbic pathway, specifically in the NAcc and PFC, between innate low- and high-impulsive rats. Together, these findings are poised to have important implications in the development of novel treatment strategies to combat eating disorders, including obesity and binge eating disorders as well as impulse control disorders, including, substance abuse and addiction, attention deficit hyperactivity disorder (ADHD) and mood disorders.

CARDIOVASCULAR EFFECTS OF CENTRAL CLONIDINE IN CONSCIOUS RATS AFTER HYPOTHALAMIC-LESIONS

The central injection of clonidine (an alpha-2-adrenoceptor agonist) in conscious normotensive rats produces hypertensive responses and bradycardia. The present study was performed to investigate the effect of electrolytic lesions in the anteroventral third ventricle (AV3V) region or in the lateral hypothalamus (LH) on the pressor and bradycardic responses induced by central clonidine in rats. Mean arterial pressure and heart rate were recorded in sham or AV3V-lesioned rats with cerebral stainless steel cannulae implanted into the lateral cerebral ventricle (ICV) or LH. and in sham or bilateral LH-lesioned rats with cannulae-implanted ICV. The injection of clonidine (40 nmol) ICV or into the LH of sham rats produced a pressor response (37 +/- 2-48 +/- 3 mmHg) and bradycardia (-45 +/- 10--93 +/- 6 bpm). After AV3V-lesion (3 and 12 days) or LH-lesion (3 days) the pressor response was abolished and a small hypotensive response was induced by the injection of clonidine (-1 +/- 3--16 +/- 3 mmHg). The bradycardia (-27 +/- 6--57 +/- 11 bpm) was reduced, but not abolished by the lesions. These results show that the AV3V region and LH are important cerebral structures that participate in the excitatory pathways involved in the pressor response to central clonidine in rats. They also suggest that, in the absence of these pressor pathways, the hypotensive responses to central clonidine may appear in conscious rats.

Immunohistochemical localization of nicotinic acetylcholine-receptor subunits in the mesencephalon and diencephalon of the chick (Gallus-gallus)

Monoclonal antibodies against two alpha-bungarotoxin-binding subunits (alpha-7 and alpha-8) of the nicotinic acetylcholine receptors (nAChRs) were used as immunohistochemical probes to map their distribution in the chick diencephalon and mesencephalon. The distribution of the alpha-7 and alpha-8 nAChR subunits was compared to the distribution of immunoreactivity produced by a monoclonal antibody against the beta-2 structural subunit of the nAChRs.Structures that contained high numbers of alpha-7-like immunoreactive (LI) somata included the intergeniculate leaflet, nucleus intercalatus thalami, nucleus ovoidalis, organum paraventricularis, nucleus rotundus, isthmic nuclei, nucleus trochlearis, oculomotor complex, nucleus interstitio-pretecto-subpretectalis, stratum griseum centrale of the optic tectum, and nucleus semilunaris. Neuropil staining for alpha-7-LI was intense in the nucleus dorsomedialis hypothalami, nucleus geniculatus lateralis ventralis, griseum tecti, isthmic nuclei, nucleus lentiformis mesencephali, nucleus of the basal optic root, and stratum griseum et fibrosum superficiale of the tectum. High numbers of alpha-8-LI somata were found in the stratum griseum et fibrosum superficiale of the tectum and the nucleus interstitio-pretecto-subpretectalis, and intense neuropil staining for alpha-8-LI was found in the dorsal thalamus, nucleus geniculatus lateralis ventralis, lateral hypothalamus, griseum tecti, nucleus lentiformis mesencephali, nucleus interpeduncularis, and stratum griseum et fibrosum superficiale of the tectum. High numbers of beta-2-LI somata were found only in the nucleus spiriformis lateralis, whereas neuropil staining for beta-2-LI was intense in the nucleus geniculatus lateralis ventralis, nucleus suprachiasmaticus, nucleus lateralis anterior, nucleus habenularis lateralis, area pretectalis, griseum tecti, nucleus lentiformis mesencephali, nucleus externus, and nucleus interpeduncularis, and in the stratum griseum centrale, stratum griseum et fibrosum superficiale, and stratum opticum of the tectum.These results indicate that there are major disparities in the localization of the alpha-bungarotoxin-binding alpha-7 and alpha-8 nAChR subunits and the beta-2 structural nAChR subunit in the chick diencephalon and mesencephalon. These nAChR subunits appear, however, to coexist in several regions of the chick brain.

The control of sodium chloride intake: Functional relationship between hypothalamic inhibitory areas and amygdaloid complex stimulating areas

Sodium chloride intake was studied in rats submitted to different neurosurgical procedures. Intake decreased in animals submitted to bilateral destruction of the basolateral amygdaloid complex, and increased after the same animals were submitted to destruction of the anterior lateral hypothalamus, a procedure which is known to cause increased intake in intact rats. In the reverse experiment, where the anterior lateral hypothalamus was destroyed before the basolateral amygdaloid complex, the effect of increased sodium chloride intake induced by destruction of the hypothalamus overcame the decreased expected upon destruction of the amygdaloid complex. These results permit us to conclude that the hypothalamic areas which inhibit sodium chloride intake predominate over the stimulating areas of the amygdaloid complex in the control of sodium chloride intake. © 1981 ANKHO International Inc.

Fructose-Induced Hypothalamic AMPK Activation Stimulates Hepatic PEPCK and Gluconeogenesis due to Increased Corticosterone Levels

Fructose consumption causes insulin resistance and favors hepatic gluconeogenesis through mechanisms that are not completely understood. Recent studies demonstrated that the activation of hypothalamic 5'-AMP-activated protein kinase (AMPK) controls dynamic fluctuations in hepatic glucose production. Thus, the present study was designed to investigate whether hypothalamic AMPK activation by fructose would mediate increased gluconeogenesis. Both ip and intracerebroventricular (icv) fructose treatment stimulated hypothalamic AMPK and acetyl-CoA carboxylase phosphorylation, in parallel with increased hepatic phosphoenolpyruvate carboxy kinase (PEPCK) and gluconeogenesis. An increase in AMPK phosphorylation by icv fructose was observed in the lateral hypothalamus as well as in the paraventricular nucleus and the arcuate nucleus. These effects were mimicked by icv 5-amino-imidazole-4-carboxamide-1-beta-D-ribofuranoside treatment. Hypothalamic AMPK inhibition with icv injection of compound C or with injection of a small interfering RNA targeted to AMPK alpha 2 in the mediobasal hypothalamus (MBH) suppressed the hepatic effects of ip fructose. We also found that fructose increased corticosterone levels through a mechanism that is dependent on hypothalamic AMPK activation. Concomitantly, fructose-stimulated gluconeogenesis, hepatic PEPCK expression, and glucocorticoid receptor binding to the PEPCK gene were suppressed by pharmacological glucocorticoid receptor blockage. Altogether the data presented herein support the hypothesis that fructose-induced hypothalamic AMPK activation stimulates hepatic gluconeogenesis by increasing corticosterone levels. (Endocrinology 153: 3633-3645, 2012)

Pontomedullary and hypothalamic distribution of Fos-like immunoreactive neurons after acute exercise in rats

During exercise, intense brain activity orchestrates an increase in muscle tension. Additionally, there is an increase in cardiac output and ventilation to compensate the increased metabolic demand of muscle activity and to facilitate the removal of CO2 from and the delivery of O-2 to tissues. Here we tested the hypothesis that a subset of pontomedullary and hypothalamic neurons could be activated during dynamic acute exercise. Male Wistar rats (250-350 g) were divided into an exercise group (n = 12) that ran on a treadmill and a no-exercise group (n = 7). Immunohistochemistry of pontomedullary and hypothalamic sections to identify activation (c-Fos expression) of cardiorespiratory areas showed that the no-exercise rats exhibited minimal Fos expression. In contrast, there was intense activation of the nucleus of the solitary tract, the ventrolateral medulla (including the presumed central chemoreceptor neurons in the retrotrapezoid/parafacial region), the lateral parabrachial nucleus, the Kolliker-Fuse region, the perifornical region, which includes the perifornical area and the lateral hypothalamus, the dorsal medial hypothalamus, and the paraventricular nucleus of the hypothalamus after running exercise. Additionally, we observed Fos immunoreactivity in catecholaminergic neurons within the ventrolateral medulla (C1 region) without Fos expression in the A2, A5 and A7 neurons. In summary, we show for the first time that after acute exercise there is an intense activation of brain areas crucial for cardiorespiratory control. Possible involvement of the central command mechanism should be considered. Our results suggest whole brain-specific mobilization to correct and compensate the homeostatic changes produced by acute exercise. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of thyroid status on NEI concentration in specific brain areas related to reproduction during the estrous cycle

We previously showed that short-term hypo- and hyperthyroidism induce changes in neuropeptide glutamic-acid-isoleucine-amide (NEI) concentrations in discrete brain areas in male rats. To investigate the possible effects of hypo- and hyperthyroidism on NEI concentrations mainly in hypothalamic areas related to reproduction and behavior, female rats were sacrificed at different days of the estrous cycle. Circulating luteinizing hormone (LH), estradiol and progesterone concentrations were measured in control, hypothyroid (hypoT, treated with PTU during 7-9 days) and hyperthyroid (hyperT, l-T4 during 4-7 days) animals. Both treatments blunted the LH surge. Hypo- and hyperthyroidism increased estradiol concentrations during proestrus afternoon (P-PM), although hypoT rats showed lower values compared to control during proestrus morning (P-AM). Progesterone levels were higher in all groups at P-PM and in the hyperT during diestrus morning (D2). NEI concentrations were lower in hypoT rats during the estrous cycle except in estrus (E) in the peduncular part of the lateral hypothalamus (PLH). They were also reduced by both treatments in the perifornical part of the lateral hypothalamus (PeFLH) during P-PM. Hypothyroidism led to higher NEI concentrations during P-PM in the organum vasculosum of the lamina terminalis and anteroventral periventricular nucleus (OVLT+AVPV). The present results indicate that NEI concentration is regulated in a complex manner by hypo- and hyperthyroidism in the different areas studied, suggesting a correlation between NEI values and the variations of gonadal steroid levels during estrous cycle. These changes could be, in part, responsible for the alterations observed in the hypothalamic-pituitary-gonadal axis in these pathologies.