RESUMEN
Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aß mechanoreceptors, with Aß inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aß fibers from activating SOM(+) neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aß mechanoreceptors, together with spinal SOM(+) excitatory and Dyn(+) inhibitory neurons, form a microcircuit that transmits and gates mechanical pain. PAPERCLIP:
Asunto(s)
Neuronas/fisiología , Dolor/metabolismo , Médula Espinal/fisiología , Animales , Dinorfinas/metabolismo , Mecanorreceptores/metabolismo , Ratones , Percepción del Dolor , Somatostatina/metabolismoRESUMEN
Neural regulation of energy expenditure is incompletely understood. By genetically disrupting GABAergic transmission in a cell-specific fashion, and by combining this with selective pharmacogenetic activation and optogenetic mapping techniques, we have uncovered an arcuate-based circuit that selectively drives energy expenditure. Specifically, mice lacking synaptic GABA release from RIP-Cre neurons have reduced energy expenditure, become obese and are extremely sensitive to high-fat diet-induced obesity, the latter due to defective diet-induced thermogenesis. Leptin's ability to stimulate thermogenesis, but not to reduce feeding, is markedly attenuated. Acute, selective activation of arcuate GABAergic RIP-Cre neurons, which monosynaptically innervate PVH neurons projecting to the NTS, rapidly stimulates brown fat and increases energy expenditure but does not affect feeding. Importantly, this response is dependent upon GABA release from RIP-Cre neurons. Thus, GABAergic RIP-Cre neurons in the arcuate selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity.
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Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético , Neuronas GABAérgicas/metabolismo , Vías Nerviosas , Tejido Adiposo Pardo/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/citología , Dieta , Integrasas/metabolismo , Leptina/metabolismo , Ratones , Obesidad/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
Agouti-related peptide (AGRP)-expressing neurons are activated by fasting-this causes hunger1-4, an aversive state that motivates the seeking and consumption of food5,6. Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues6-8, slowly and longer-lasting in response to nutrients in the gut9,10, and even more slowly and permanently with restoration of energy balance9,11. The rapid regulation by food cues is of particular interest as its neurobiological basis and purpose are unknown. Given that AGRP neuron activity is aversive6, the sensory cue-linked reductions in activity could function to guide behaviour. To evaluate this, we first identified the circuit mediating sensory cue inhibition and then selectively perturbed it to determine function. Here, we show that a lateral hypothalamic glutamatergic â dorsomedial hypothalamic GABAergic (γ-aminobutyric acid-producing)12 â AGRP neuron circuit mediates this regulation. Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task. This is specific for food, as learning of an identical water-acquisition task is unaffected. We propose that decreases in aversive AGRP neuron activity6 mediated by this food-specific circuit increases the incentive salience13 of food cues, and thus facilitates the learning of food-acquisition tasks.
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Proteína Relacionada con Agouti/metabolismo , Señales (Psicología) , Alimentos , Hambre/fisiología , Vías Nerviosas , Neuronas/fisiología , Animales , Área Hipotalámica Lateral/fisiología , Aprendizaje , Masculino , Ratones , Ratones Endogámicos C57BL , OptogenéticaRESUMEN
Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.
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Anorexia Nerviosa , Anorexia , Ratones , Humanos , Animales , Anorexia/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Hipotálamo/metabolismo , Anorexia Nerviosa/metabolismo , Neuronas/metabolismo , Ingestión de AlimentosRESUMEN
Behavioral expression of food-associated memory in fruit flies is constrained by satiety and promoted by hunger, suggesting an influence of motivational state. Here, we identify a neural mechanism that integrates the internal state of hunger and appetitive memory. We show that stimulation of neurons that express neuropeptide F (dNPF), an ortholog of mammalian NPY, mimics food deprivation and promotes memory performance in satiated flies. Robust appetitive memory performance requires the dNPF receptor in six dopaminergic neurons that innervate a distinct region of the mushroom bodies. Blocking these dopaminergic neurons releases memory performance in satiated flies, whereas stimulation suppresses memory performance in hungry flies. Therefore, dNPF and dopamine provide a motivational switch in the mushroom body that controls the output of appetitive memory.
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Proteínas de Drosophila/fisiología , Drosophila melanogaster/fisiología , Neuropéptidos/fisiología , Receptores de Neuropéptido/fisiología , Animales , Conducta Apetitiva , Conducta Animal , Condicionamiento Clásico , Dopamina/fisiología , Memoria , Motivación , Cuerpos Pedunculados/fisiologíaRESUMEN
In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.
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Técnicas de Trazados de Vías Neuroanatómicas , Neuronas/fisiología , Área Preóptica/citología , Área Preóptica/fisiología , Sueño/fisiología , Transcriptoma , Animales , Biomarcadores/análisis , Channelrhodopsins , Canales de Cloruro/metabolismo , Canales de Cloruro/efectos de la radiación , Colecistoquinina/análisis , Colecistoquinina/genética , Hormona Liberadora de Corticotropina/análisis , Hormona Liberadora de Corticotropina/genética , Femenino , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de la radiación , Área Hipotalámica Lateral/fisiología , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/efectos de la radiación , Optogenética , Área Preóptica/efectos de los fármacos , Área Preóptica/efectos de la radiación , Proteínas Proto-Oncogénicas c-fos/análisis , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ribosomas/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Sueño/efectos de los fármacos , Sueño/efectos de la radiación , Taquicininas/análisis , Taquicininas/genética , Vigilia/fisiología , Vigilia/efectos de la radiaciónRESUMEN
Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
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Proteína Relacionada con Agouti/metabolismo , Hambre/fisiología , Vías Nerviosas/fisiología , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Proteína Relacionada con Agouti/deficiencia , Animales , Apetito/efectos de los fármacos , Apetito/fisiología , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Mapeo Encefálico , Rastreo Celular , Clozapina/análogos & derivados , Clozapina/farmacología , Dependovirus/genética , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Privación de Alimentos , Hambre/efectos de los fármacos , Integrasas/metabolismo , Masculino , Ratones , Vías Nerviosas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Fragmentos de Péptidos/deficiencia , Fragmentos de Péptidos/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Virus de la Rabia/genética , Respuesta de Saciedad/fisiología , Hormona Liberadora de Tirotropina/metabolismoRESUMEN
Dopamine is synonymous with reward and motivation in mammals. However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies. Instead, octopamine has historically been considered to be the signal for reward in insects. Here we show, using temporal control of neural function in Drosophila, that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the α-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the ß-adrenergic-like OCTß2R receptor reveals that octopamine-dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought.
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Dopamina/metabolismo , Drosophila melanogaster/metabolismo , Octopamina/metabolismo , Recompensa , Transducción de Señal , Animales , Conducta Apetitiva/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Femenino , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Motivación/efectos de los fármacos , Motivación/fisiología , Cuerpos Pedunculados/citología , Cuerpos Pedunculados/efectos de los fármacos , Cuerpos Pedunculados/metabolismo , Octopamina/farmacología , Receptores de Neurotransmisores/deficiencia , Receptores de Neurotransmisores/genética , Receptores de Neurotransmisores/metabolismo , Transducción de Señal/efectos de los fármacos , Gusto/efectos de los fármacos , Gusto/fisiologíaRESUMEN
Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics. In this review we will provide a brief overview of DREADDs, their implementation, and the advantages and disadvantages of their use in animal systems. We also will provide numerous examples of their use across a broad variety of biomedical research fields.
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Conducta/efectos de los fármacos , Drogas de Diseño/farmacología , Diseño de Fármacos , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal/efectos de los fármacos , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Neuronas/efectos de los fármacos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genéticaRESUMEN
The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-CreCeMA-vmPFC) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-CreCeMA-vmPFC circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-CreCeMA-vmPFC projection acts to modulate existing reward-related behaviors. SIGNIFICANCE STATEMENT: Many studies have shown that the interactions between the centromedial nucleus of the amygdala (CeMA) and ventromedial PFC (vmPFC) have critical roles for emotional regulation. However, most studies have associated this circuit with fear and anxiety behaviors and emphasized top-down processing from vmPFC to CeMA. Here, we provide new evidence for bottom-up CeMA to vmPFC influence on reward-related behaviors. Although previous work implicated the CeMA in incentive salience, our results isolate the investigation to a specific CeMA GABAergic projection to the vmPFC. This long-range GABAergic interaction between amygdala and frontal cortex adds a new dimension to the complex regulation of reward-related behaviors.
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Amígdala del Cerebelo/fisiología , Conducta Animal/fisiología , Corteza Prefrontal/fisiología , Recompensa , Ácido gamma-Aminobutírico/fisiología , Animales , Condicionamiento Operante/efectos de los fármacos , Extinción Psicológica , Masculino , Ratones , Actividad Motora , Vías Nerviosas/fisiología , Optogenética , Autoestimulación , Sacarosa/farmacología , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+), located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.
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Conducta Alimentaria , Glutamatos/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Sinapsis/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Peso Corporal , Dependovirus/metabolismo , Metabolismo Energético , Neuronas GABAérgicas/metabolismo , Eliminación de Gen , Inyecciones , Integrasas/metabolismo , Ratones , Neuropéptidos/metabolismo , Proteínas Represoras/metabolismo , Reproducibilidad de los Resultados , Técnicas Estereotáxicas , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
The parabrachial nucleus is important for thermoregulation because it relays skin temperature information from the spinal cord to the hypothalamus. Prior work in rats localized thermosensory relay neurons to its lateral subdivision (LPB), but the genetic and neurochemical identity of these neurons remains unknown. To determine the identity of LPB thermosensory neurons, we exposed mice to a warm (36°C) or cool (4°C) ambient temperature. Each condition activated neurons in distinct LPB subregions that receive input from the spinal cord. Most c-Fos+ neurons in these LPB subregions expressed the transcription factor marker FoxP2. Consistent with prior evidence that LPB thermosensory relay neurons are glutamatergic, all FoxP2+ neurons in these subregions colocalized with green fluorescent protein (GFP) in reporter mice for Vglut2, but not for Vgat. Prodynorphin (Pdyn)-expressing neurons were identified using a GFP reporter mouse and formed a caudal subset of LPB FoxP2+ neurons, primarily in the dorsal lateral subnucleus (PBdL). Warm exposure activated many FoxP2+ neurons within PBdL. Half of the c-Fos+ neurons in PBdL were Pdyn+, and most of these project into the preoptic area. Cool exposure activated a separate FoxP2+ cluster of neurons in the far-rostral LPB, which we named the rostral-to-external lateral subnucleus (PBreL). These findings improve our understanding of LPB organization and reveal that Pdyn-IRES-Cre mice provide genetic access to warm-activated, FoxP2+ glutamatergic neurons in PBdL, many of which project to the hypothalamus.
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Fiebre/metabolismo , Hipotermia/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/metabolismo , Temperatura Cutánea , Sensación Térmica , Animales , Modelos Animales de Enfermedad , Encefalinas/genética , Encefalinas/metabolismo , Fiebre/genética , Fiebre/fisiopatología , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Genes Reporteros , Genotipo , Ácido Glutámico/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipotermia/genética , Hipotermia/fisiopatología , Integrasas/genética , Integrasas/metabolismo , Sitios Internos de Entrada al Ribosoma , Masculino , Ratones Transgénicos , Técnicas de Trazados de Vías Neuroanatómicas , Núcleos Parabraquiales/fisiopatología , Fenotipo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Represoras/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
Mechanisms of energy balance were first examined using very powerful neuroscience techniques such as lesions and electrical stimulation. This early work identified the hypothalamus as a key structure involved in hunger and feeding; however, neural resolution of cell-defined populations contributing to appetite regulation remained elusive. Recent innovations in neuroscience have produced constructs that allow for a high degree of specificity in loss- and gain-of-function manipulations in molecularly circumscribed neural subsets as well as monosynaptic circuit mapping and in vivo neurophysiology. These complimentary techniques have provided researchers an unprecedented amount of empirical agility. As a result, cell populations in two subregions of the hypothalamus have emerged as key players in the physiological control of feeding behavior. The arcuate nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus contain neural populations that have a direct role in the promotion of hunger and satiety. These include neurons that express agouti-related peptide, pro-opiomelanocortin, single-minded homolog 1 protein, and the melanocortin-4 receptor. This review focuses on how these neural subsets communicate with one another, link up to build elaborate networks, and ultimately contribute to alterations in food intake. The continuing advancement of neuroscience tools, as well as a multimodal integration of findings, will be critical in illuminating an exhaustive and clinically relevant hunger circuit.
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Núcleo Arqueado del Hipotálamo/fisiología , Hambre/fisiología , Neuronas/fisiología , Saciedad/fisiología , Proteína Relacionada con Agouti/metabolismo , Animales , Humanos , Vías Nerviosas/fisiología , Proopiomelanocortina/metabolismo , Receptores de Melanocortina/metabolismoRESUMEN
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct timescales.
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Apetito , Ingestión de Alimentos , Apetito/fisiología , Saciedad , Rombencéfalo , NeuronasRESUMEN
OBJECTIVE: Exposure to 60% high fat diet (HFD) leads to a robust consummatory preference over well-balanced chow standard diet (SD) when mice are presented with a choice. This passive HFD-induced SD devaluation following HFD challenge and withdrawal is highlighted by the significant reduction in SD food intake even in states of caloric deprivation. The elements of HFD that lead to this SD depreciation remains unclear. Possibly important factors include the amount and type of fat contained in a diet as well as past eating experiences dependent on sensory properties including taste and post ingestive feedback. We aimed to explore the role of these components to HFD-induced SD devaluation. METHODS: Wildtype mice were longitudinally presented discrete HFDs in conjunction with SD and feeding and metabolic parameters were analyzed. A separate cohort of animals were assessed for acute HFD preference in 3 conditions: 1) ad libitum fed (sated), 2) overnight fasted (physiologically hungry), and 3) ad libitum fed (artificially hungry), elicited through chemogenetic Agouti-related peptide (AgRP) neuron activation. Population dynamics of AgRP neurons were recorded to distinct inaccessible and accessible diets both before and after consummatory experience. Transient receptor potential channel type M5 (TRPM5) knockout mice were used to investigate the role of fat taste perception and preference to HFD-induced SD devaluation. The clinically approved lipase inhibitor orlistat was used to test the contribution of fat absorption to HFD-induced SD devaluation. RESULTS: HFD-induced SD devaluation is dependent on fat content, composition, and preference. This effect scaled both in strength and latency with higher percentages of animal fat. 60% HFD was preferred and almost exclusively consumed in preference to other diets across hours and days, but this was not as evident upon initial introduction over seconds and minutes, suggesting ingestive experience is critical. Optical fiber photometry recordings of AgRP activity supported this notion as neuronal suppression by the different diets was contingent on prior intake. While taste transduced via TRPM5 influenced HFD-evoked weight gain, it failed to impact either HFD preference or HFD-induced SD devaluation. Perturbation of post ingestive feedback through orlistat-mediated diminishment of fat absorption prevented HFD-evoked weight gain and abolished HFD-induced SD devaluation. CONCLUSIONS: Post ingestive feedback via fat digestion is vital for expression of HFD-induced SD devaluation.
RESUMEN
Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.
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Calculating and selecting what sensory and homeostatic requirements to attend to at any given time is vital for animals' survival. Tang et al. uncovered a circuit emanating from excitatory cortical neurons that transmit nociceptive information via the hypothalamus to blunt appetite during periods of chronic pain.
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Apetito , Hambre , Animales , Hambre/fisiología , Dolor , Hipotálamo , Neuronas/fisiologíaRESUMEN
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.