Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

Gonadotropin-inhibitory hormone and its receptors in teleosts: Physiological roles and mechanisms of actions.

Gonadotropin-inhibitory hormone (GnIH) was the first reported hypothalamic neuropeptide inhibiting reproduction in vertebrates. Since its discovery in the quail brain, its orthologs have been identified in a variety of vertebrate species and even protochordates. Depending on the species, the GnIH precursor polypeptides comprise two, three or four mature peptides of the RFamide family. It has been well documented that GnIH inhibits reproduction at the brain-pituitary-gonadal levels and participates in metabolism, stress response, and social behaviors in birds and mammals. However, most studies in fish have mainly been focused on the physiological roles of GnIH in the control of reproduction and results obtained are in some cases conflicting, leaving aside its potential roles in the regulation of other functions. In this manuscript we summarize the information available in fish with respect to the structural diversity of GnIH peptides and functional roles of GnIH in reproduction and other physiological processes. We also highlight the molecular mechanisms of GnIH actions on target cells and possible interactions with other neuroendocrine factors.

Neuroanatomical, electrophysiological, and morphological characterization of melanin-concentrating hormone cells coexpressing cocaine- and amphetamine-regulated transcript.

Melanin-concentrating hormone (MCH) cells in the hypothalamus regulate fundamental physiological functions like energy balance, sleep, and reproduction. This diversity may be ascribed to the neurochemical heterogeneity among MCH cells. One prominent subpopulation of MCH cells coexpresses cocaine- and amphetamine-regulated transcript (CART), and as MCH and CART can have opposing actions, MCH/CART+ and MCH/CART- cells may differentially modulate behavioral outcomes. However, it is not known if there are differences in the cellular properties underlying their functional differences; thus, we compared the neuroanatomical, electrophysiological, and morphological properties of MCH cells in male and female Mch-cre;L10-Egfp reporter mice. Half of MCH cells expressed CART and were most prominent in the medial hypothalamus. Whole-cell patch-clamp recordings revealed differences in their passive and active membrane properties in a sex-dependent manner. Female MCH/CART+ cells had lower input resistances, but male cells largely differed in their firing properties. All MCH cells increased firing when stimulated, but their firing frequency decreases with sustained stimulation. MCH/CART+ cells showed stronger spike rate adaptation than MCH/CART- cells. The kinetics of excitatory events at MCH cells also differed by cell type, as the rising rate of excitatory events was slower at MCH/CART+ cells. By reconstructing the dendritic arborization of our recorded cells, we found no sex differences, but male MCH/CART+ cells had less dendritic length and fewer branch points. Overall, distinctions in topographical division and cellular properties between MCH cells add to their heterogeneity and help elucidate their response to stimuli or effect on modulating their respective neural networks.

Fast neurotransmitter identity of MCH neurons: Do contents depend on context?

Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.

Neuronal responses of melanin-concentrating hormone and corticotropin-releasing hormone to background color in the self-fertilizing fish, Kryptolebias marmoratus.

We examined neuronal responses of hypothalamic melanin-concentrating hormone (MCH) and corticotropin-releasing hormone (CRH) to background color in the self-fertilizing fish, Kryptolebias marmoratus. Fish were individually reared in lidless white or black cylindrical plastic containers for 15 days. The number of MCH-immunoreactive (ir) cell bodies in the nucleus lateralis tuberis (NLT) of the hypothalamus was significantly greater in the white-acclimated fish, while no significant differences were observed in the nucleus anterior tuberis (NAT) of the hypothalamus. Significant differences were not seen in the number of CRH-ir cell bodies in the NLT between the groups. The body of the white- and black-acclimated fish appeared lighter and darker, respectively, compared with the baseline color. In the black-acclimated fish, feeding activity was significantly greater with a tendency toward higher specific growth rate compared with the observations in white-acclimated fish. No significant inter-group cortisol level differences were observed. These results indicate that background color affects MCH neuronal activity in the NLT as well as body color adaptation but does not affect CRH neuronal activity in K. marmoratus.

Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study.

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats.

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes in male rats. Specifically, results reveal that MCH neuron Ca2+ activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating, and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

Melanin-concentrating hormone regulation by estradiol and progesterone in the incerto-hypothalamic area.

Melanin-concentrating hormone (MCH) is a peptide related to the reproductive function by interacting with the hypothalamus-pituitary-gonadal axis. In addition to the MCH central production, it is also found in the blood with a putative role as a neurohormone. Thereby, our focus is on steroid hormones' role in regulating centrally produced MCH in the incerto-hypothalamic area (IHy) and the peripheral MCH in the serum. For this, we investigated the effect of estradiol and/or progesterone injection on the number of MCH immunoreactive (MCH-ir) neurons at the IHy and serum levels. For further study of the role of progesterone, we analyzed the effect of blockade of progesterone receptors by its antagonist on MCH-ir neurons at the IHy and serum. To identify whether such regulation over MCH is established before sexual maturation, we assessed the effect of peripubertal removal of steroid hormones on MCH-ir neurons at the IHy and serum levels at adult age. Our results show that injecting estradiol in ovariectomized female rats reduces the number of MCH-ir neurons in the IHy, in addition to its serum levels. Blockade of progesterone receptors in intact females increases the number of MCH-ir neurons in the IHy and its serum concentration. The regulation of these hormones over the MCH peptidergic system is established before sexual maturation, once the peripubertal removal of the ovaries changes the serum levels of MCH and the number of MCH-ir neurons in the IHy of adult females. Such results support the inhibitory role of steroid hormones over the MCH system.

The effect of estrogen and progesterone on melanin-concentrating hormone producing-neurons in brain areas related to reproductive behavior in lactating dams.

The hypothalamus plays a role in reproductive cycle control, and it is a site of action of steroid hormones. Throughout the production of melanin-concentrating hormone (MCH), the hypothalamus shows adaptive changes during lactation. Therefore, in this work, we aimed to test the effects of estrogen and progesterone manipulation on MCH-immunoreactive (ir) neurons in hypothalamic brain areas related to reproductive behavior and on the MCH serum concentration. Our results show that the removal of steroid hormones by ovariectomy increases the number of MCH-ir neurons in the medial preoptic area (MPOA) and incerto-hypothalamic area (IHy) but not in the anterior part of the paraventricular nucleus of the hypothalamus (PVHa). The MCH in the serum levels also increases. In accordance, the injection of estradiol alone or estradiol and progesterone decreased the number of MCH-ir neurons in the MPOA and IHy, as well as its serum levels. The MPOA and IHy are the brain areas targeted by the steroid hormone inhibitory effect of the MCH system during lactation. This effect is also reflected in the MCH serum levels.

Characterization of Hypothalamic MCH Neuron Development in a 3D Differentiation System of Mouse Embryonic Stem Cells.

Hypothalamic melanin-concentrating hormone (MCH) neurons are important regulators of multiple physiological processes, such as sleep, feeding, and memory. Despite the increasing interest in their neuronal functions, the molecular mechanism underlying MCH neuron development remains poorly understood. We report that a three-dimensional culture of mouse embryonic stem cells (mESCs) can generate hypothalamic-like tissues containing MCH-positive neurons, which reproduce morphologic maturation, neuronal connectivity, and neuropeptide/neurotransmitter phenotype of native MCH neurons. Using this in vitro system, we demonstrate that Hedgehog (Hh) signaling serves to produce major neurochemical subtypes of MCH neurons characterized by the presence or absence of cocaine- and amphetamine-regulated transcript (CART). Without exogenous Hh signals, mESCs initially differentiated into dorsal hypothalamic/prethalamic progenitors and finally into MCH+CART+ neurons through a specific intermediate progenitor state. Conversely, activation of the Hh pathway specified ventral hypothalamic progenitors that generate both MCH+CART- and MCH+CART+ neurons. These results suggest that in vivo MCH neurons may originate from multiple cell lineages that arise through early dorsoventral patterning of the hypothalamus. Additionally, we found that Hh signaling supports the differentiation of mESCs into orexin/hypocretin neurons, a well-defined cell group intermingled with MCH neurons in the lateral hypothalamic area (LHA). The present study highlights and improves the utility of mESC culture in the analysis of the developmental programs of specific hypothalamic cell types.

Short-term Fasting Induces Alternate Activation of Orexin and Melanin-concentrating Hormone Neurons in Rats.

Orexin and melanin-concentrating hormone (MCH) neurons constitute the energy balance circuitry that coordinates the fasting response. Orexin neurons mediate food foraging at the expense of energy storage, while MCH neurons promote energy storage by reducing energy expenditure and increasing food intake. It is unknown if these cell groups undergo plastic changes as hunger and metabolic changes escalate over time during fasting. To address this, we performed in vitro electrophysiological recording on orexin and MCH neurons in the lateral hypothalamus and perifornical area from rats fasted for 12 or 24 h or fed ad-libitum. Orexin neurons showed a transient decrease in presynaptic glutamate release at 12 h. This turned to an increase at 24 h of fasting, while membrane potential depolarized and AMPA receptor conductance increased. In contrast, MCH neurons were transiently depolarized at 12 h fasting along with increased presynaptic glutamate release. These changes reversed at 24 h, while the number of AMPA receptors decreased. Our results indicate that MCH neurons are preferentially activated during the early phase of fasting (12 h), which would protect against weight loss. With a longer fast, orexin neurons become activated, which would promote arousal and exploratory activity required for foraging behaviors. This alternating activation of these cell groups may reflect a dynamic balance of energy conservation and foraging behaviors to optimize energy balance during ongoing fasting.

Melanin-concentrating hormone-producing neurons in the hypothalamus regulate brown adipose tissue and thus contribute to energy expenditure.

KEY POINTS: Melanin-concentrating hormone (MCH) neuron-ablated mice exhibit increased energy expenditure and reduced fat weight. Increased brown adipose tissue (BAT) activity and locomotor activity-independent energy expenditure contributed to body weight reduction in MCH neuron-ablated mice. MCH neurons send inhibitory input to the medullary raphe nucleus to modulate BAT activity. ABSTRACT: Hypothalamic melanin-concentrating hormone (MCH) peptide robustly affects energy homeostasis. However, it is unclear whether and how MCH-producing neurons, which contain and release a variety of neuropeptides/transmitters, regulate energy expenditure in the central nervous system and peripheral tissues. We thus examined the regulation of energy expenditure by MCH neurons, focusing on interscapular brown adipose tissue (BAT) activity. MCH neuron-ablated mice exhibited reduced body weight, increased oxygen consumption, and increased BAT activity, which improved locomotor activity-independent energy expenditure. Trans-neuronal retrograde tracing with the recombinant pseudorabies virus revealed that MCH neurons innervate BAT via the sympathetic premotor region in the medullary raphe nucleus (MRN). MRN neurons were activated by MCH neuron ablation. Therefore, endogenous MCH neuron activity negatively modulates energy expenditure via BAT inhibition. MRN neurons might receive inhibitory input from MCH neurons to suppress BAT activity.

Gonadotropin-inhibitory hormone as a regulator of social interactions in vertebrates.

The social environment changes circulating hormone levels and expression of social behavior in animals. Social information is perceived by sensory systems, leading to cellular and molecular changes through neural processes. Peripheral reproductive hormone levels are regulated by activity in the hypothalamic-pituitary-gonadal (HPG) axis. Until the end of the last century, the neurochemical systems that convey social information to the HPG axis were not well understood. Gonadotropin-inhibitory hormone (GnIH) was the first hypothalamic neuropeptide shown to inhibit gonadotropin release, in 2000. GnIH is now regarded as a negative upstream regulator of the HPG axis, and it is becoming increasingly evident that it responds to social cues. In addition to controlling reproductive physiology, GnIH seems to modulate the reproductive behavior of animals. Here, we review studies investigating how GnIH neurons respond to social information and describe the mechanisms through which GnIH regulates social behavior.

Regulation of stress response on the hypothalamic-pituitary-gonadal axis via gonadotropin-inhibitory hormone.

Under stressful condition, reproductive function is impaired due to the activation of various components of the hypothalamic-pituitaryadrenal (HPA) axis, which can suppress the activity of the hypothalamic-pituitary-gonadal (HPG) axis at multiple levels. A hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH) is a key negative regulator of reproduction that governs the HPG axis. Converging lines of evidence have suggested that different stress types and their duration, such as physical or psychological, and acute or chronic, can modulate the GnIH system. To clarify the sensitivity and reactivity of the GnIH system in response to stress, we summarize and critically review the available studies that investigated the effects of various stressors, such as restraint, nutritional/metabolic and social stress, on GnIH expression and/or its neuronal activity leading to altered HPG action. In this review, we focus on GnIH as the potential novel mediator responsible for stress-induced reproductive dysfunction.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome.

Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have abnormal neurocircuitry engaged in the hedonic and physiological control of feeding behavior. This is translated into diminished production of hypothalamic effector peptides which are responsible for the coordination of energy homeostasis and satiety. So far, studies with animal models for PWS and with human post-mortem hypothalamic specimens demonstrated changes particularly in the infundibular and the paraventricular nuclei of the hypothalamus, both in orexigenic and anorexigenic neural populations. Moreover, many PWS patients have a severe endocrine dysfunction, e.g. central hypogonadism and/or growth hormone deficiency, which may contribute to the development of increased fat mass, especially if left untreated. Additionally, the role of non-neuronal cells, such as astrocytes and microglia in the hypothalamic dysregulation in PWS is yet to be determined. Notably, microglial activation is persistently present in non-genetic obesity. To what extent microglia, and other glial cells, are affected in PWS is poorly understood. The elucidation of the hypothalamic dysfunction in PWS could prove to be a key feature of rational therapeutic management in this syndrome. This review aims to examine the evidence for hypothalamic dysfunction, both at the neuropeptidergic and circuitry levels, and its correlation with the pathophysiology of PWS.

The localization and expression of gonadotropin inhibitory hormone in the hypothalamus of turkey hens during the prepubertal, pubertal and postpubertal phases.

Gonadotropin inhibitory hormone (GnIH), initially discovered in birds as a hypothalamic neuropeptide, inhibits the synthesis and release of gonadotropins by affecting GnRH neurons and gonadotropes. Therefore, it may be a key neuropeptide in reproduction in birds. The aim of the present study was to investigate the prepubertal, pubertal, and postpubertal localization of GnIH and changes in hypothalamic GnIH expression in British United Turkey hens. In prepubertal, pubertal, and postpubertal periods, the brains of turkey hens (n = 15) were removed after fixation. Sections (30 µm) were prepared from the entire hypothalamus and stained immunohistochemically against GnIH antibody. Gonadotropin inhibitory hormone-immunoreactive neurons were observed in the paraventricular nucleus. These neurons were significantly more abundant in the prepubertal turkeys than pubertal and postpubertal turkeys (P < 0.05). The results suggested that GnIH neurons have an important role in regulating the pubertal events in British United Turkey hens.

Genetic deciphering of the antagonistic activities of the melanin-concentrating hormone and melanocortin pathways in skin pigmentation.

The genetic origin of human skin pigmentation remains an open question in biology. Several skin disorders and diseases originate from mutations in conserved pigmentation genes, including albinism, vitiligo, and melanoma. Teleosts possess the capacity to modify their pigmentation to adapt to their environmental background to avoid predators. This background adaptation occurs through melanosome aggregation (white background) or dispersion (black background) in melanocytes. These mechanisms are largely regulated by melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH), two hypothalamic neuropeptides also involved in mammalian skin pigmentation. Despite evidence that the exogenous application of MCH peptides induces melanosome aggregation, it is not known if the MCH system is physiologically responsible for background adaptation. In zebrafish, we identify that MCH neurons target the pituitary gland-blood vessel portal and that endogenous MCH peptide expression regulates melanin concentration for background adaptation. We demonstrate that this effect is mediated by MCH receptor 2 (Mchr2) but not Mchr1a/b. mchr2 knock-out fish cannot adapt to a white background, providing the first genetic demonstration that MCH signaling is physiologically required to control skin pigmentation. mchr2 phenotype can be rescued in adult fish by knocking-out pomc, the gene coding for the precursor of α-MSH, demonstrating the relevance of the antagonistic activity between MCH and α-MSH in the control of melanosome organization. Interestingly, MCH receptor is also expressed in human melanocytes, thus a similar antagonistic activity regulating skin pigmentation may be conserved during evolution, and the dysregulation of these pathways is significant to our understanding of human skin disorders and cancers.

Orexin gene expression is downregulated in alcohol dependent rats during acute alcohol withdrawal.

Alcohol use disorders (AUD) are chronic relapsing brain disorder characterized by compulsive and heavy alcohol consumption. During acute withdrawal, patients with AUD display excessive daytime sleepiness, a condition linked to serious life-threatening complications, however, the mechanism is not known. Orexin and melanin-concentrating hormone (MCH) are the two hypothalamic neuropeptides that regulate many behaviors including sleep-wakefulness, and alcohol consumption, reinforcement, and reinstatement. Importantly, loss of orexin neurons causes narcolepsy, a severe sleep disorder with excessive daytime sleepiness. Does acute alcohol withdrawal reduce orexin gene expression? To investigate this, male Sprague-Dawley rats were divided in two groups: Rats were either administered with alcohol, mixed with infant formula (alcohol group) or control mixture containing water and infant formula (Controls) by gastric intubation every 8 h for 4 days using Majchrowicz's chronic binge drinking protocol. The doses of alcohol were adjusted depending on degree of intoxication, exhibited by animals, prior to each dose. The animals were euthanized after 12 h of last alcohol/water administration. During withdrawal, the hypothalamus was rapidly dissected out, and the expressions of orexin and MCH genes were examined by Real-time PCR. There was a significant reduction in orexin gene expression in rats subjected to alcohol withdrawal as compared to controls. No such change was observed in the MCH gene expression. These results suggest that downregulation of orexin gene expression may be a possible mechanism responsible for excessive daytime sleepiness associated with alcohol withdrawal in patients with AUD.

Control of fear extinction by hypothalamic melanin-concentrating hormone-expressing neurons.

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone-expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.

The hypothalamus as a primary coordinator of memory updating.

In the brain, long-term memories correspond to changes in synaptic weights after certain patterns of neural activity. Behaviourally, this corresponds to a change in action evoked by a repeating experience. Forming and updating memories (learning, remembering, forgetting) is fundamental for most aspects of cognitive and motor performance. The roles of the cortex, hippocampus, and amygdala have been studied extensively in this context. However, the lateral hypothalamus - a brain-wide projecting region traditionally known as a nutrient-sensor and controller of arousal and motivation - is also critical for updating many types of associative and non-associative memories. Does the hypothalamus play a primary role in learning, or are hypothalamic effects on learning secondary to changes in brain state such as attention/motivation? We argue that such primary and secondary effects are distinguishable under experimental conditions where attention/motivation states are constant or absent, e.g. during sleep or in reduced in vitro preparations. The documented control by hypothalamus-unique transmitters, such as orexin and MCH, of synaptic strength in isolated brain slice preparations implies a primary role for the hypothalamus in synaptic weight updating, rather than a secondary role due to changes in arousal/attention/motivation states (which are absent in brain slices). Such hypothalamic control of memory-related synaptic machinery may enable gating/thresholding/permissive/tagging operations within yet poorly defined logic gates for memory updating. Hypothalamic signals may thus facilitate cost-benefit analysis of learning and memory in real-world settings. Whether the hypothalamus controls only specific types of learning, or broadcasts a global signal for memory updating, remains to be elucidated.