RESUMEN
Memory retrieval can become difficult over time, but it is important to note that memories that appear to be forgotten might still be stored in the brain, as shown by their occasional spontaneous retrieval. Histamine in the central nervous system is a promising target for facilitating the recovery of memory retrieval. Our previous study demonstrated that histamine H3 receptor (H3R) inverse agonists/antagonists, activating histamine synthesis and release, enhance activity in the perirhinal cortex and help in retrieving forgotten long-term object recognition memories. However, it is unclear whether enhancing histaminergic activity alone is enough for the recovery of memory retrieval, considering that H3Rs are also located in other neuron types and affect the release of multiple neurotransmitters. In this study, we employed a chemogenetic method to determine whether specifically activating histamine neurons in the tuberomammillary nucleus facilitates memory retrieval. In the novel object recognition test, control mice did not show a preference for objects based on memory 1 week after training, but chemogenetic activation of histamine neurons before testing improved memory retrieval. This selective activation did not affect the locomotor activity or anxiety-related behavior. Administering an H2R antagonist directly into the perirhinal cortex inhibited the recovery of memory retrieval induced by the activation of histamine neurons. Furthermore, we utilized the Barnes maze test to investigate whether chemogenetic activation of histamine neurons influences the retrieval of forgotten spatial memories. Control mice explored all the holes in the maze equally 1 week after training, whereas mice with chemogenetically activated histamine neurons spent more time around the target hole. These findings indicate that chemogenetic activation of histamine neurons in the tuberomammillary nucleus can promote retrieval of seemingly forgotten object recognition and spatial memories.
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Histamina , Neuronas , Animales , Histamina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Recuerdo Mental/efectos de los fármacos , Recuerdo Mental/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones Endogámicos C57BL , Ratones , Ansiedad/fisiopatología , Área Hipotalámica Lateral/fisiología , Área Hipotalámica Lateral/efectos de los fármacos , Antagonistas de los Receptores H2 de la Histamina/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiologíaRESUMEN
Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2âTMN neurons) are crucial for the homeostatic regulation of REMs in mice. POAGAD2âTMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2âTMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2âTMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs.
Asunto(s)
Neuronas GABAérgicas , Homeostasis , Área Preóptica , Sueño REM , Animales , Área Preóptica/fisiología , Sueño REM/fisiología , Ratones , Neuronas GABAérgicas/fisiología , Masculino , Electroencefalografía , Área Hipotalámica Lateral/fisiologíaRESUMEN
OBJECTIVE: Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP-1R) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation. METHODS: Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP-1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP-1R âLHA projections in regulating food intake. RESULTS: Chemogenetic inhibition of dLSGLP-1R neurons increases food intake. LHA is a major downstream target of dLSGLP-1R neurons. The dLSGLP-1RâLHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP-1RâLHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP-1RâLHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP-1R âLHA GABA release. CONCLUSIONS: Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.
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Receptor del Péptido 1 Similar al Glucagón , Área Hipotalámica Lateral , Neuronas , Animales , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/fisiología , Ingestión de Alimentos/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Conducta Alimentaria/fisiología , Ratones Endogámicos C57BLRESUMEN
Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.
Asunto(s)
Neuronas , Reconocimiento en Psicología , Animales , Femenino , Masculino , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Reconocimiento en Psicología/fisiología , Histamina/metabolismo , Ratones Endogámicos C57BL , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/fisiología , Recuerdo Mental/fisiologíaRESUMEN
Maladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.
Asunto(s)
Conducta Alimentaria , Objetivos , Imagen por Resonancia Magnética , Animales , Conducta Alimentaria/fisiología , Masculino , Área Hipotalámica Lateral/fisiología , Neuronas GABAérgicas/fisiología , Tomografía de Emisión de Positrones , Macaca mulatta , Hipotálamo/fisiología , Hipotálamo/diagnóstico por imagen , Neuronas/fisiología , FemeninoRESUMEN
For nearly a century, evidence has accumulated indicating that the lateral hypothalamus (LH) contains neurons essential to sustain wakefulness. While lesion or inactivation of LH neurons produces a profound increase in sleep, stimulation of inhibitory LH neurons promotes wakefulness. To date, the primary wake-promoting cells that have been identified in the LH are the hypocretin/orexin (Hcrt) neurons, yet these neurons have little impact on total sleep or wake duration across the 24-h period. Recently, we and others have identified other LH populations that increase wakefulness. In the present study, we conducted microendoscopic calcium imaging in the LH concomitant with EEG and locomotor activity (LMA) recordings and found that a subset of LH neurons that express Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) are preferentially active during wakefulness. Chemogenetic activation of these neurons induced sustained wakefulness and greatly increased LMA even in the absence of Hcrt signaling. Few LH CaMKIIα-expressing neurons are hypocretinergic or histaminergic while a small but significant proportion are GABAergic. Ablation of LH inhibitory neurons followed by activation of the remaining LH CaMKIIα neurons induced similar levels of wakefulness but blunted the LMA increase. Ablated animals showed no significant changes in sleep architecture but both spontaneous LMA and high theta (8 to 10 Hz) power during wakefulness were reduced. Together, these findings indicate the existence of two subpopulations of LH CaMKIIα neurons: an inhibitory population that promotes locomotion without affecting sleep architecture and an excitatory population that promotes prolonged wakefulness even in the absence of Hcrt signaling.
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Área Hipotalámica Lateral , Vigilia , Animales , Vigilia/fisiología , Área Hipotalámica Lateral/fisiología , Orexinas/metabolismo , Sueño/fisiología , Neuronas/metabolismo , Transducción de SeñalRESUMEN
Excessive consumption of palatable foods that are rich in fats and sugars has contributed to the increasing prevalence of obesity worldwide. Similar to addictive drugs, such foods activate the brain's reward circuit, involving mesolimbic dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the prefrontal cortex. Neuroadaptations occurring in this circuit are hypothesized to contribute to uncontrolled consumption of such foods, a common feature of most of eating disorders and obesity. The rostromedial tegmental nucleus (RMTg), also named tail of the VTA (tVTA), is an inhibitory structure projecting to the VTA and the lateral hypothalamus (LH), two key brain regions in food intake regulation. Prior research has demonstrated that the RMTg responds to addictive drugs and influences their impact on mesolimbic activity and reward-related behaviors. However, the role of the RMTg in food intake regulation remains largely unexplored. The present study aimed to investigate the role of the RMTg and its projections to the VTA and the LH in regulating food intake in rats. To do so, we examined eating patterns of rats with either bilateral excitotoxic lesions of the RMTg or specific lesions of RMTg-VTA and RMTg-LH pathways. Rats were exposed to a 6-week 'free choice high-fat and high-sugar' diet, followed by a 4-week palatable food forced abstinence and a 24 h re-access period. Our results indicate that an RMTg-VTA pathway lesion increases fat consumption following 6 weeks of diet and at time of re-access. The RMTg-LH pathway lesion produces a milder effect with a decrease in global calorie intake. These findings suggest that the RMTg influences palatable food consumption and relapse through its projections to the VTA.
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Área Tegmental Ventral , Animales , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Ingestión de Alimentos/fisiología , Área Hipotalámica Lateral/fisiología , Área Hipotalámica Lateral/efectos de los fármacos , Grasas de la Dieta , Vías Nerviosas/fisiología , Vías Nerviosas/efectos de los fármacos , Recompensa , Conducta Alimentaria/fisiología , Conducta Alimentaria/efectos de los fármacosRESUMEN
Innate behaviors meet multiple needs adaptively and in a serial order, suggesting the existence of a hitherto elusive brain dynamics that brings together representations of upcoming behaviors during their selection. Here we show that during behavioral transitions, possible upcoming behaviors are encoded by specific signatures of neuronal populations in the lateral hypothalamus (LH) that are active near beta oscillation peaks. Optogenetic recruitment of intrahypothalamic inhibition at this phase eliminates behavioral transitions. We show that transitions are elicited by beta-rhythmic inputs from the prefrontal cortex that spontaneously synchronize with LH 'transition cells' encoding multiple behaviors. Downstream of the LH, dopamine neurons increase firing during beta oscillations and also encode behavioral transitions. Thus, a hypothalamic transition state signals alternative future behaviors, encodes the one most likely to be selected and enables rapid coordination with cognitive and reward-processing circuitries, commanding adaptive social contact and eating behaviors.
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Ritmo beta , Vías Nerviosas , Corteza Prefrontal , Animales , Corteza Prefrontal/fisiología , Vías Nerviosas/fisiología , Masculino , Ritmo beta/fisiología , Ratones , Optogenética , Conducta Animal/fisiología , Área Hipotalámica Lateral/fisiología , Recompensa , Neuronas Dopaminérgicas/fisiología , Hipotálamo/fisiologíaRESUMEN
In alcohol use disorder, the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse but also encoding and expression of alcohol memories. GABAergic neurons in the lateral hypothalamus (LH-GABA) have been shown to be critical for food-cue memories and motivation; however, the extent to which this role extends to alcohol-cue memories and motivations remains unexplored. In this study, we aimed to describe how alcohol-related memories are encoded and expressed in LH GABAergic neurons. Our first step was to monitor LH-GABA calcium transients during acquisition, extinction, and reinstatement of an alcohol-cue memory using fiber photometry. We trained the rats on a Pavlovian conditioning task, where one conditioned stimulus (CS+) predicted alcohol (20% EtOH) and another conditioned stimulus (CS-) had no outcome. We then extinguished this association through non-reinforced presentations of the CS+ and CS- and finally, in two different groups, we measured relapse under non-primed and alcohol-primed induced reinstatement. Our results show that initially both cues caused increased LH-GABA activity, and after learning only the alcohol cue increased LH-GABA activity. After extinction, this activity decreases, and we found no differences in LH-GABA activity during reinstatement in either group. Next, we inhibited LH-GABA neurons with optogenetics to show that activity of these neurons is necessary for the formation of an alcohol-cue association. These findings suggest that LH-GABA might be involved in attentional processes modulated by learning.
Asunto(s)
Área Hipotalámica Lateral , Aprendizaje , Ratas , Animales , Área Hipotalámica Lateral/fisiología , Etanol , Neuronas GABAérgicas , Señales (Psicología) , Recurrencia , Ácido gamma-AminobutíricoRESUMEN
Despite the physiological complexity of the hypothalamus, its role is typically restricted to initiation or cessation of innate behaviors. For example, theories of lateral hypothalamus argue that it is a switch to turn feeding 'on' and 'off' as dictated by higher-order structures that render when feeding is appropriate. However, recent data demonstrate that the lateral hypothalamus is critical for learning about food-related cues. Furthermore, the lateral hypothalamus opposes learning about information that is neutral or distal to food. This reveals the lateral hypothalamus as a unique arbitrator of learning capable of shifting behavior toward or away from important events. This has relevance for disorders characterized by changes in this balance, including addiction and schizophrenia. Generally, this suggests that hypothalamic function is more complex than increasing or decreasing innate behaviors.
Asunto(s)
Área Hipotalámica Lateral , Hipotálamo , Humanos , Área Hipotalámica Lateral/fisiología , Hipotálamo/fisiología , Aprendizaje/fisiología , Señales (Psicología) , Cognición , RecompensaRESUMEN
The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.
Asunto(s)
Hipotálamo , Memoria Espacial , Ratones , Animales , Orexinas/metabolismo , Hipotálamo/metabolismo , Neuronas/fisiología , Área Hipotalámica Lateral/fisiologíaRESUMEN
Psychological stressors, like the nearby presence of a predator, can be strong enough to induce physiological/hormonal alterations, leading to appetite changes. However, little is known about how threats can alter feeding-related hypothalamic circuit functions. Here, we found that proenkephalin (Penk)-expressing lateral hypothalamic (LHPenk) neurons of mice exposed to predator scent stimulus (PSS) show sensitized responses to high-fat diet (HFD) eating, whereas silencing of the same neurons normalizes PSS-induced HFD overconsumption associated with a negative emotional state. Downregulation of endogenous enkephalin peptides in the LH is crucial for inhibiting the neuronal and behavioral changes developed after PSS exposure. Furthermore, elevated corticosterone after PSS contributes to enhance the reactivity of glucocorticoid receptor (GR)-containing LHPenk neurons to HFD, whereas pharmacological inhibition of GR in the LH suppresses PSS-induced maladaptive behavioral responses. We have thus identified the LHPenk neurons as a critical component in the threat-induced neuronal adaptation that leads to emotional overconsumption.
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Área Hipotalámica Lateral , Neuronas , Ratones , Animales , Área Hipotalámica Lateral/fisiología , Neuronas/fisiología , Encefalinas/genética , HiperfagiaRESUMEN
Food cues serve as pivotal triggers for eliciting physiological responses that subsequently influence food consumption. The magnitude of response induced by these cues stands as a critical determinant in the context of obesity risk. Nonetheless, the underlying neural mechanism that underpins how cues associated with edible food potentiate feeding behaviors remains uncertain. In this study, we revealed that corticotropin-releasing hormone (CRH)-expressing neurons in the lateral hypothalamic area played a crucial role in promoting consummatory behaviors in mice, shedding light on this intricate process. By employing an array of diverse assays, we initially established the activation of these neurons during feeding. Manipulations using optogenetic and chemogenetic assays revealed that their activation amplified appetite and promoted feeding behaviors, whereas inhibition decreased them. Additionally, our investigation identified downstream targets, including the ventral tegmental area, and underscored the pivotal involvement of the CRH neuropeptide itself in orchestrating this regulatory network. This research casts a clarifying light on the neural mechanism underlying the augmentation of appetite and the facilitation of feeding behaviors in response to food cues. VIDEO ABSTRACT.
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Hormona Liberadora de Corticotropina , Área Hipotalámica Lateral , Ratones , Animales , Área Hipotalámica Lateral/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Conducta Alimentaria/fisiología , Neuronas/fisiología , ApetitoRESUMEN
Motivated behaviors are often studied in isolation to assess labeled lines of neural connections underlying innate actions. However, in nature, multiple systems compete for expression of goal-directed behaviors via complex neural networks. Here, we examined flexible survival decisions in animals tasked with food seeking under predation threat. We found that predator exposure rapidly induced physiological, neuronal, and behavioral adaptations in mice highlighted by reduced food seeking and consumption contingent on current threat level. Diminishing conflict via internal state or external environment perturbations shifted feeding strategies. Predator introduction and/or selective manipulation of danger-responsive cholecystokinin (Cck) cells of the dorsal premammilary nucleus (PMd) suppressed hunger-sensitive Agouti-related peptide (AgRP) neurons, providing a mechanism for threat-evoked hypophagia. Increased caloric need enhanced food seeking under duress through AgRP pathways to the bed nucleus of the stria terminalis (BNST) and/or lateral hypothalamus (LH). Our results suggest oscillating interactions between systems underlying self-preservation and food seeking to promote optimal behavior.
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Hipotálamo , Neuronas , Ratones , Animales , Proteína Relacionada con Agouti/metabolismo , Hipotálamo/metabolismo , Neuronas/fisiología , Hambre/fisiología , Área Hipotalámica Lateral/fisiologíaRESUMEN
Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABAâVTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABAâVTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABAâVTA projection. Furthermore, repeated activation of the LHGABAâVTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABAâVTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABAâVTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABAâVTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.
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Dopamina , Neuralgia , Ratones , Masculino , Animales , Dopamina/metabolismo , Área Hipotalámica Lateral/fisiología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calcio/metabolismo , Área Tegmental Ventral/fisiología , Neuronas GABAérgicas/fisiología , Ácido gamma-Aminobutírico/metabolismo , Neuralgia/metabolismo , Sensación , Núcleo Accumbens/fisiologíaRESUMEN
To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and lateral hypothalamic area (LHA), since these regions play important yet opposing roles in the sleep-wakefulness regulation. GABA- and galanin (GAL)-producing neurons in the ventrolateral preoptic nucleus (VLPO) of the POA (VLPOGABA and VLPOGAL neurons) are responsible for the maintenance of sleep, while the LHA contains orexin-producing neurons (orexin neurons) that are crucial for maintenance of wakefulness. Through the use of rabies virus-mediated neural tracing combined with in situ hybridization (ISH) in male and female orexin-iCre mice, we revealed that the vesicular GABA transporter (Vgat, Slc32a1)- and galanin (Gal)-expressing neurons in the VLPO directly synapse with orexin neurons in the LHA. A majority (56.3 ± 8.1%) of all VLPO input neurons connecting to orexin neurons were double-positive for Vgat and Gal Using projection-specific rabies virus-mediated tracing in male and female Vgat-ires-Cre and Gal-Cre mice, we discovered that VLPOGABA and VLPOGAL neurons that send projections to the LHA received innervations from similarly distributed input neurons in many brain regions, with the POA and LHA being among the main upstream areas. Additionally, we found that acute optogenetic excitation of axons of VLPOGABA neurons, but not VLPOGAL neurons, in the LHA of male Vgat-ires-Cre mice induced wakefulness. This study deciphers the connectivity between the VLPO and LHA, provides a large-scale map of upstream neuronal populations of VLPOâLHA neurons, and reveals a previously uncovered function of the VLPOGABAâLHA pathway in the regulation of sleep and wakefulness.SIGNIFICANCE STATEMENT We identified neurons in the ventrolateral preoptic nucleus (VLPO) that are positive for vesicular GABA transporter (Vgat) and/or galanin (Gal) and serve as presynaptic partners of orexin-producing neurons in the lateral hypothalamic area (LHA). We depicted monosynaptic input neurons of GABA- and galanin-producing neurons in the VLPO that send projections to the LHA throughout the entire brain. Their input neurons largely overlap, suggesting that they comprise a common neuronal population. However, acute excitatory optogenetic manipulation of the VLPOGABAâLHA pathway, but not the VLPOGALâLHA pathway, evoked wakefulness. This study shows the connectivity of major components of the sleep/wake circuitry in the hypothalamus and unveils a previously unrecognized function of the VLPOGABAâLHA pathway in sleep-wakefulness regulation. Furthermore, we suggest the existence of subpopulations of VLPOGABA neurons that innervate LHA.
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Área Hipotalámica Lateral , Área Preóptica , Ratones , Masculino , Femenino , Animales , Área Preóptica/fisiología , Área Hipotalámica Lateral/fisiología , Orexinas/metabolismo , Galanina/metabolismo , Neuronas/fisiología , Vigilia/fisiología , Sueño/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Animals continuously weigh hunger and thirst against competing needs, such as social contact and mating, according to state and opportunity. Yet neuronal mechanisms of sensing and ranking nutritional needs remain poorly understood. Here, combining calcium imaging in freely behaving mice, optogenetics, and chemogenetics, we show that two neuronal populations of the lateral hypothalamus (LH) guide increasingly hungry animals through behavioral choices between nutritional and social rewards. While increased food consumption was marked by increasing inhibition of a leptin receptor-expressing (LepRLH) subpopulation at a fast timescale, LepRLH neurons limited feeding or drinking and promoted social interaction despite hunger or thirst. Conversely, neurotensin-expressing LH neurons preferentially encoded water despite hunger pressure and promoted water seeking, while relegating social needs. Thus, hunger and thirst gate both LH populations in a complementary manner to enable the flexible fulfillment of multiple essential needs.
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Hambre , Área Hipotalámica Lateral , Ratones , Animales , Área Hipotalámica Lateral/fisiología , Hambre/fisiología , Neuronas/fisiología , NeurotensinaRESUMEN
Pain and anxiety comorbidities are a common health problem, but the neural mechanisms underlying comorbidity remain unclear. We propose that comorbidity implies that similar brain regions and neural circuits, with the lateral septum (LS) as a major candidate, process pain and anxiety. From results of behavioral and neurophysiological experiments combined with selective LS manipulation in mice, we find that LS GABAergic neurons were critical for both pain and anxiety. Selective activation of LS GABAergic neurons induced hyperalgesia and anxiety-like behaviors. In contrast, selective inhibition of LS GABAergic neurons reduced nocifensive withdrawal responses and anxiety-like behaviors. This was found in two mouse models, one for chronic inflammatory pain (induced by complete Freund's adjuvant) and one for anxiety (induced by chronic restraint stress). Additionally, using TetTag chemogenetics to functionally mark LS neurons, we found that activation of LS neurons by acute pain stimulation could induce anxiety-like behaviors and vice versa. Furthermore, we show that LS GABAergic projection to the lateral hypothalamus (LH) plays an important role in the regulation of pain and anxiety comorbidities. Our study revealed that LS GABAergic neurons, and especially the LSGABAergic-LH circuit, are a critical to the modulation of pain and anxiety comorbidities.
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Dolor Crónico , Área Hipotalámica Lateral , Ratones , Animales , Área Hipotalámica Lateral/fisiología , Ansiedad , Comorbilidad , Neuronas GABAérgicas/fisiologíaRESUMEN
BACKGROUND: A greater understanding of how the brain controls appetite is fundamental to developing new approaches for treating diseases characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa. METHODS: By modeling neural network dynamics related to homeostatic state and body mass index, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n = 53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice. RESULTS: In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under nonstressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose seeking in mice. CONCLUSIONS: These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake.
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Conducta Alimentaria , Área Hipotalámica Lateral , Corteza Prefrontal , Estrés Psicológico , Animales , Humanos , Ratones , Conducta Alimentaria/fisiología , Área Hipotalámica Lateral/fisiología , Corteza Prefrontal/fisiología , Estrés Psicológico/fisiopatologíaRESUMEN
It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.