Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is ...not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G protein-coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation.
Neuropeptides are key modulators of neuronal activity. Here, van den Pol discusses the interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation.
The neuronal substrate for binge eating, which can at times lead to obesity, is not clear. We find that optogenetic stimulation of mouse zona incerta (ZI) γ-aminobutyric acid (GABA) neurons or their ...axonal projections to paraventricular thalamus (PVT) excitatory neurons immediately (in 2 to 3 seconds) evoked binge-like eating. Minimal intermittent stimulation led to body weight gain; ZI GABA neuron ablation reduced weight. ZI stimulation generated 35% of normal 24-hour food intake in just 10 minutes. The ZI cells were excited by food deprivation and the gut hunger signal ghrelin. In contrast, stimulation of excitatory axons from the parasubthalamic nucleus to PVT or direct stimulation of PVT glutamate neurons reduced food intake. These data suggest an unexpected robust orexigenic potential for the ZI GABA neurons.
Energy homeostasis, food intake, and body weight are regulated by specific brain circuits. Here we introduce an unexpected neuron, the tyrosine hydroxylase (TH) neuron of the arcuate nucleus (ARC), ...that we show makes an orexigenic contribution. Optogenetic stimulation of mouse ARC TH neurons increased food intake; attenuating transmitter release reduced body weight. Optogenetic stimulation of ARC TH cells inhibited pro-opiomelanocortin (POMC) neurons through synaptic mechanisms. ARC TH cells project to the hypothalamic paraventricular nucleus; optogenetic stimulation of ARC TH axons inhibited paraventricular nucleus neurons by dopamine and GABA co-release. Dopamine excited orexigenic neurons that synthesize agouti-related peptide and neuropeptide Y but inhibited anorexigenic neurons that synthesize POMC, as determined by whole cell recording. Food deprivation increased c-fos expression and spike frequency in ARC TH neurons. The gut peptide ghrelin evoked direct excitatory effects, suggesting these neurons monitor metabolic cues. Together these data support the view that ARC TH cells play an unrecognized and influential positive role in energy homeostasis.
Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems, including microcephaly, cortical thinning, ...and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice, this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a Type 1 interferon response (IFNR
), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS and may target different cells at different stages of brain development.
Zika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second-trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested and initially targeted astrocytes throughout the brain. Infections of the retina were detected in all mice, and infection of CNS visual system nuclei in the brain was common. We find that ZIKV can be transported axonally, thereby enhancing virus spread within the brain. These data suggest that ZIKV infects multiple cell types within the brain and that astrocyte infection may play a more important role in initial infection than previously appreciated.
Neurons containing melanin‐concentrating hormone (MCH) are located in the hypothalamus. In mice, optogenetic activation of the MCH neurons induces both non‐rapid eye movement (NREM) and rapid eye ...movement (REM) sleep at night, the normal wake‐active period for nocturnal rodents R. R. Konadhode et al. (2013) J. Neurosci., 33, 10257–10263. Here we selectively activate these neurons in rats to test the validity of the sleep network hypothesis in another species. Channelrhodopsin‐2 (ChR2) driven by the MCH promoter was selectively expressed by MCH neurons after injection of rAAV‐MCHp‐ChR2‐EYFP into the hypothalamus of Long–Evans rats. An in vitro study confirmed that the optogenetic activation of MCH neurons faithfully triggered action potentials. In the second study, in Long–Evans rats, rAAV‐MCH‐ChR2, or the control vector, rAAV‐MCH‐EYFP, were delivered into the hypothalamus. Three weeks later, baseline sleep was recorded for 48 h without optogenetic stimulation (0 Hz). Subsequently, at the start of the lights‐off cycle, the MCH neurons were stimulated at 5, 10, or 30 Hz (1 mW at tip; 1 min on – 4 min off) for 24 h. Sleep was recorded during the 24‐h stimulation period. Optogenetic activation of MCH neurons increased both REM and NREM sleep at night, whereas during the day cycle, only REM sleep was increased. Delta power, an indicator of sleep intensity, was also increased. In control rats without ChR2, optogenetic stimulation did not increase sleep or delta power. These results lend further support to the view that sleep‐active MCH neurons contribute to drive sleep in mammals.
Neurons containing melanin‐concentrating hormone (MCH) or orexin are localized in the posterior hypothalamus. Activation of orexin neurons produces arousal, but the function of the MCH neurons is less clear. In mice, we determined that optogenetic activation of MCH neurons increases sleep at night. We now find that in wild‐type rats, activating these neurons also increases sleep and delta power. Such consistent results in two mammals underscore the role of the MCH neurons as drivers of sleep.
The neuropeptide kisspeptin is necessary for reproduction, fertility, and puberty. Here, we show strong kisspeptin innervation of hypothalamic anorexigenic proopiomelanocortin (POMC) cells, coupled ...with a robust direct excitatory response by POMC neurons (n > 200) to kisspeptin, mediated by mechanisms based on activation of a sodium/calcium exchanger and possibly opening of nonselective cation channels. The excitatory actions of kisspeptin on POMC cells were corroborated with quantitative PCR data showing kisspeptin receptor GPR54 expression in the arcuate nucleus, and the attenuation of excitation by the selective kisspeptin receptor antagonist, peptide 234. In contrast, kisspeptin inhibits orexigenic neuropeptide Y (NPY) neurons through an indirect mechanism based on enhancing GABA-mediated inhibitory synaptic tone. In striking contrast, gonadotropin-inhibiting hormone (GnIH and RFRP-3) and NPY, also found in axons abutting POMC cells, inhibit POMC cells and attenuate the kisspeptin excitation by a mechanism based on opening potassium channels. Together, these data suggest that the two central peptides that regulate reproduction, kisspeptin and GnIH, exert a strong direct action on POMC neurons. POMC cells may hypothetically serve as a conditional relay station downstream of kisspeptin and GnIH to signal the availability of energy resources relevant to reproduction.
We employ transgenic mice with selective expression of tdTomato or cre recombinase together with optogenetics to investigate whether hypothalamic arcuate (ARC) dopamine/tyrosine hydroxylase (TH) ...neurons interact with other ARC neurons, how they respond to hypothalamic neuropeptides, and to test whether these cells constitute a single homogeneous population. Immunostaining with dopamine and TH antisera was used to corroborate targeted transgene expression. Using whole-cell recording on a large number of neurons (n = 483), two types of neurons with different electrophysiological properties were identified in the dorsomedial ARC where 94% of TH neurons contained immunoreactive dopamine: bursting and nonbursting neurons. In contrast to rat, the regular oscillations of mouse bursting neurons depend on a mechanism involving both T-type calcium and A-type potassium channel activation, but are independent of gap junction coupling. Optogenetic stimulation using cre recombinase-dependent ChIEF-AAV-DJ expressed in ARC TH neurons evoked postsynaptic GABA currents in the majority of neighboring dopamine and nondopamine neurons, suggesting for the first time substantial synaptic projections from ARC TH cells to other ARC neurons. Numerous met-enkephalin (mENK) and dynorphin-immunoreactive boutons appeared to contact ARC TH neurons. mENK inhibited both types of TH neuron through G-protein coupled inwardly rectifying potassium currents mediated by δ and μ opioid receptors. Dynorphin-A inhibited both bursting and nonbursting TH neurons by activating κ receptors. Oxytocin excited both bursting and nonbursting neurons. These results reveal a complexity of TH neurons that communicate extensively with neurons within the ARC.
Here, we show that the great majority of mouse hypothalamic arcuate nucleus (ARC) neurons that synthesize TH in the dorsomedial ARC also contain immunoreactive dopamine, and show either bursting or nonbursting electrical activity. Unlike rats, the mechanism underlying bursting was not dependent on gap junctions but required T-type calcium and A-type potassium channel activation. Neuropeptides dynorphin and met-enkephalin inhibited dopamine neurons, whereas oxytocin excited them. Most ventrolateral ARC TH cells did not contain dopamine and did not show bursting electrical activity. TH-containing neurons appeared to release synaptic GABA within the ARC onto dopamine neurons and unidentified neurons, suggesting that the cells not only control pituitary hormones but also may modulate nearby neurons.
Superior predatory skills led to the evolutionary triumph of jawed vertebrates. However, the mechanisms by which the vertebrate brain controls predation remain largely unknown. Here, we reveal a ...critical role for the central nucleus of the amygdala in predatory hunting. Both optogenetic and chemogenetic stimulation of central amygdala of mice elicited predatory-like attacks upon both insect and artificial prey. Coordinated control of cervical and mandibular musculatures, which is necessary for accurately positioning lethal bites on prey, was mediated by a central amygdala projection to the reticular formation in the brainstem. In contrast, prey pursuit was mediated by projections to the midbrain periaqueductal gray matter. Targeted lesions to these two pathways separately disrupted biting attacks upon prey versus the initiation of prey pursuit. Our findings delineate a neural network that integrates distinct behavioral modules and suggest that central amygdala neurons instruct predatory hunting across jawed vertebrates.
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•Stimulation of central amygdala (CeA) elicited hunting of live and artificial prey•CeA projections to the reticular formation (PCRt) control biting attacks•CeA projections to periaqueductal gray (PAG) control locomotion during pursuit•CeA integrates craniofacial and locomotor modules during goal-directed behavior
Two neuronal pathways originating in the central amygdala coordinate distinct behaviors necessary for efficient predatory hunting: the ability to pursue a prey and deliver fatal bites upon capture.
Most brain neurons are active in waking, but hypothalamic neurons that synthesize the neuropeptide melanin-concentrating hormone (MCH) are claimed to be active only during sleep, particularly rapid ...eye movement (REM) sleep. Here we use deep-brain imaging to identify changes in fluorescence of the genetically encoded calcium (Ca
) indicator GCaMP6 in individual hypothalamic neurons that contain MCH. An
electrophysiology study determined a strong relationship between depolarization and Ca
fluorescence in MCH neurons. In 10 freely behaving MCH-cre mice (male and female), the highest fluorescence occurred in all recorded neurons (
= 106) in REM sleep relative to quiet waking or non-REM sleep. Unexpectedly, 70% of the MCH neurons had strong fluorescence activity when the mice explored novel objects. Spatial and temporal mapping of the change in fluorescence between pairs of MCH neurons revealed dynamic activation of MCH neurons during REM sleep and activation of a subset of the same neurons during exploratory behavior. Functional network activity maps will facilitate comparisons of not only single-neuron activity, but also network responses in different conditions and disease.
Functional activity maps identify brain circuits responding to specific behaviors, including rapid eye movement sleep (REM sleep), a sleep phase when the brain is as active as in waking. To provide the first activity map of individual neurons during REM sleep, we use deep-brain calcium imaging in unrestrained mice to map the activity of hypothalamic melanin-concentrating hormone (MCH) neurons. MCH neurons were found to be synchronously active during REM sleep, and also during the exploration of novel objects. Spatial mapping revealed dynamic network activation during REM sleep and activation of a subset of the neurons during exploratory behavior. Functional activity maps at the cellular level in specific behaviors, including sleep, are needed to establish a brain connectome.
Key points
Excitatory glutamate neurons are sparse in the rostral hypothalamic arcuate nucleus (ARC), the subregion that has received the most attention in the past. In striking contrast, excitatory ...neurons are far more common (by a factor of 10) in the caudal ARC, an area which has received relatively little attention.
These glutamate cells may play a negative role in energy balance and food intake. They can show an increase in phosphorylated Stat‐3 in the presence of leptin, are electrically excited by the anorectic neuromodulator cholecystokinin, and inhibited by orexigenic neuromodulators neuropeptide Y, met‐enkephalin, dynorphin and the catecholamine dopamine.
The neurons project local axonal connections that excite other ARC neurons including proopiomelanocortin neurons that can play an important role in obesity.
These data are consistent with models suggesting that the ARC glutamatergic neurons may play both a rapid and a slower role in acting as anorectic neurons in CNS control of food intake and energy homeostasis.
Here we interrogate a unique class of excitatory neurons in the hypothalamic arcuate nucleus (ARC) that utilizes glutamate as a fast neurotransmitter using mice expressing GFP under control of the vesicular glutamate transporter 2 (vGluT2) promoter. These neurons show a unique distribution, synaptic characterization, cellular physiology and response to neuropeptides involved in energy homeostasis. Although apparently not previously appreciated, the caudal ARC showed a far greater density of vGluT2 cells than the rostral ARC, as seen in transgenic vGluT2‐GFP mice and mRNA analysis. After food deprivation, leptin induced an increase in phosphorylated Stat‐3 in vGluT2‐positive neurons, indicating a response to hormonal cues of energy state. Based on whole‐cell recording electrophysiology in brain slices, vGluT2 neurons were spontaneously active with a spike frequency around 2 Hz. vGluT2 cells were responsive to a number of neuropeptides related to energy homeostasis; they were excited by the anorectic peptide cholecystokinin, but inhibited by orexigenic neuropeptide Y, dynorphin and met‐enkephalin, consistent with an anorexic role in energy homeostasis. Dopamine, associated with the hedonic aspect of enhancing food intake, inhibited vGluT2 neurons. Optogenetic excitation of vGluT2 cells evoked EPSCs in neighbouring neurons, indicating local synaptic excitation of other ARC neurons. Microdrop excitation of ARC glutamate cells in brain slices rapidly increased excitatory synaptic activity in anorexigenic proopiomelanocortin neurons. Together these data support the perspective that vGluT2 cells may be more prevalent in the ARC than previously appreciated, and play predominantly an anorectic role in energy metabolism.
Key points
Excitatory glutamate neurons are sparse in the rostral hypothalamic arcuate nucleus (ARC), the subregion that has received the most attention in the past. In striking contrast, excitatory neurons are far more common (by a factor of 10) in the caudal ARC, an area which has received relatively little attention.
These glutamate cells may play a negative role in energy balance and food intake. They can show an increase in phosphorylated Stat‐3 in the presence of leptin, are electrically excited by the anorectic neuromodulator cholecystokinin, and inhibited by orexigenic neuromodulators neuropeptide Y, met‐enkephalin, dynorphin and the catecholamine dopamine.
The neurons project local axonal connections that excite other ARC neurons including proopiomelanocortin neurons that can play an important role in obesity.
These data are consistent with models suggesting that the ARC glutamatergic neurons may play both a rapid and a slower role in acting as anorectic neurons in CNS control of food intake and energy homeostasis.
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