RESUMEN
This year's Nobel Prize in Physiology or Medicine was awarded to David Julius and Ardem Patapoutian for "explaining the molecular basis for sensing heat, cold and mechanical force." Their findings capped off a scientific quest to identify the mechanisms within the somatosensory system mediating the detection of internal and external environments.
Asunto(s)
Canales Iónicos/metabolismo , Sensación/fisiología , Animales , Fenómenos Biomecánicos , Capsaicina/farmacología , Humanos , Premio Nobel , Tacto/fisiologíaRESUMEN
Thriving in times of resource scarcity requires an incredible flexibility of behavioral, physiological, cellular, and molecular functions that must change within a relatively short time. Hibernation is a collection of physiological strategies that allows animals to inhabit inhospitable environments, where they experience extreme thermal challenges and scarcity of food and water. Many different kinds of animals employ hibernation, and there is a spectrum of hibernation phenotypes. Here, we focus on obligatory mammalian hibernators to identify the unique challenges they face and the adaptations that allow hibernators to overcome them. This includes the cellular and molecular strategies used to combat low environmental and body temperatures and lack of food and water. We discuss metabolic, neuronal, and hormonal cues that regulate hibernation and how they are thought to be coordinated by internal clocks. Last, we touch on questions that are left to be addressed in the field of hibernation research. Studies from the last century and more recent work reveal that hibernation is not simply a passive reduction in body temperature and vital parameters but rather an active process seasonally regulated at the molecular, cellular, and organismal levels.
Asunto(s)
Adaptación Fisiológica , Ambiente , Hibernación/fisiología , Animales , Ritmo Circadiano/fisiología , Humanos , Memoria/fisiología , Sueño/fisiologíaRESUMEN
Most available information on endoplasmic reticulum (ER)-plasma membrane (PM) contacts in cells of higher eukaryotes concerns proteins implicated in the regulation of Ca(2+) entry. However, growing evidence suggests that such contacts play more general roles in cell physiology, pointing to the existence of additionally ubiquitously expressed ER-PM tethers. Here, we show that the three extended synaptotagmins (E-Syts) are ER proteins that participate in such tethering function via C2 domain-dependent interactions with the PM that require PI(4,5)P2 in the case of E-Syt2 and E-Syt3 and also elevation of cytosolic Ca(2+) in the case of E-Syt1. As they form heteromeric complexes, the E-Syts confer cytosolic Ca(2+) regulation to ER-PM contact formation. E-Syts-dependent contacts, however, are not required for store-operated Ca(2+) entry. Thus, the ER-PM tethering function of the E-Syts (tricalbins in yeast) mediates the formation of ER-PM contacts sites, which are functionally distinct from those mediated by STIM1 and Orai1.
Asunto(s)
Calcio/metabolismo , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Sinaptotagminas/metabolismo , Secuencia de Aminoácidos , Línea Celular Tumoral , Membrana Celular/química , Membrana Celular/ultraestructura , Retículo Endoplásmico/química , Retículo Endoplásmico/ultraestructura , Células HeLa , Humanos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Alineación de Secuencia , Sinaptotagminas/química , Sinaptotagminas/genética , Levaduras/citología , Levaduras/metabolismoRESUMEN
Hibernators thrive under harsh environmental conditions instead of initiating canonical behavioral and physiological responses to promote survival. Although the physiological changes that occur during hibernation have been comprehensively researched, the role of the nervous system in this process remains relatively underexplored. In this Review, we adopt the perspective that the nervous system plays an active, essential role in facilitating and supporting hibernation. Accumulating evidence strongly suggests that the hypothalamus enters a quiescent state in which powerful drives to thermoregulate, eat and drink are suppressed. Similarly, cardiovascular and pulmonary reflexes originating in the brainstem are altered to permit the profoundly slow heart and breathing rates observed during torpor. The mechanisms underlying these changes to the hypothalamus and brainstem are not currently known, but several neuromodulatory systems have been implicated in the induction and maintenance of hibernation. The intersection of these findings with modern neuroscience approaches, such as optogenetics and in vivo calcium imaging, has opened several exciting avenues for hibernation research.
Asunto(s)
Hibernación , Letargo , Tronco Encefálico , Corazón , Hibernación/fisiología , Letargo/fisiologíaRESUMEN
Tactile information is detected by thermoreceptors and mechanoreceptors in the skin and integrated by the central nervous system to produce the perception of somatosensation. Here we investigate the mechanism by which thermal and mechanical stimuli begin to interact and report that it is achieved by the mechanotransduction apparatus in cutaneous mechanoreceptors. We show that moderate cold potentiates the conversion of mechanical force into excitatory current in all types of mechanoreceptors from mice and tactile-specialist birds. This effect is observed at the level of mechanosensitive Piezo2 channels and can be replicated in heterologous systems using Piezo2 orthologs from different species. The cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the physical properties of the plasma membrane and give rise to a different mechanism of mechanical activation than that of Piezo1. Our data reveal that Piezo2 is an evolutionarily conserved mediator of thermal-tactile integration in cutaneous mechanoreceptors.
Asunto(s)
Señales (Psicología) , Canales Iónicos/metabolismo , Mecanorreceptores/metabolismo , Mecanotransducción Celular , Potenciales de Acción , Animales , Membrana Celular/metabolismo , Humanos , Canales Iónicos/química , Mecanorreceptores/química , Ratones , Especificidad de Órganos , Unión Proteica , Relación Estructura-Actividad , Temperatura , VertebradosRESUMEN
Tactile-foraging ducks are specialist birds known for their touch-dependent feeding behavior. They use dabbling, straining, and filtering to find edible matter in murky water, relying on the sense of touch in their bill. Here, we present the molecular characterization of embryonic duck bill, which we show contains a high density of mechanosensory corpuscles innervated by functional rapidly adapting trigeminal afferents. In contrast to chicken, a visually foraging bird, the majority of duck trigeminal neurons are mechanoreceptors that express the Piezo2 ion channel and produce slowly inactivating mechano-current before hatching. Furthermore, duck neurons have a significantly reduced mechano-activation threshold and elevated mechano-current amplitude. Cloning and electrophysiological characterization of duck Piezo2 in a heterologous expression system shows that duck Piezo2 is functionally similar to the mouse ortholog but with prolonged inactivation kinetics, particularly at positive potentials. Knockdown of Piezo2 in duck trigeminal neurons attenuates mechano current with intermediate and slow inactivation kinetics. This suggests that Piezo2 is capable of contributing to a larger range of mechano-activated currents in duck trigeminal ganglia than in mouse trigeminal ganglia. Our results provide insights into the molecular basis of mechanotransduction in a tactile-specialist vertebrate.
Asunto(s)
Proteínas Aviares/genética , Pico/fisiología , Patos/fisiología , Mecanorreceptores/metabolismo , Percepción del Tacto/fisiología , Tacto/fisiología , Secuencia de Aminoácidos , Animales , Proteínas Aviares/antagonistas & inhibidores , Proteínas Aviares/metabolismo , Pico/citología , Pico/inervación , Pollos , Clonación Molecular , Embrión no Mamífero , Expresión Génica , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Células HEK293 , Humanos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/genética , Canales Iónicos/metabolismo , Cinética , Mecanorreceptores/citología , Mecanotransducción Celular , Ratones , Técnicas de Placa-Clamp , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Ganglio del Trigémino/citología , Ganglio del Trigémino/metabolismoRESUMEN
Mutations in PIEZO1 are the primary cause of hereditary xerocytosis, a clinically heterogeneous, dominantly inherited disorder of erythrocyte dehydration. We used next-generation sequencing-based techniques to identify PIEZO1 mutations in individuals from 9 kindreds referred with suspected hereditary xerocytosis (HX) and/or undiagnosed congenital hemolytic anemia. Mutations were primarily found in the highly conserved, COOH-terminal pore-region domain. Several mutations were novel and demonstrated ethnic specificity. We characterized these mutations using genomic-, bioinformatic-, cell biology-, and physiology-based functional assays. For these studies, we created a novel, cell-based in vivo system for study of wild-type and variant PIEZO1 membrane protein expression, trafficking, and electrophysiology in a rigorous manner. Previous reports have indicated HX-associated PIEZO1 variants exhibit a partial gain-of-function phenotype with generation of mechanically activated currents that inactivate more slowly than wild type, indicating that increased cation permeability may lead to dehydration of PIEZO1-mutant HX erythrocytes. In addition to delayed channel inactivation, we found additional alterations in mutant PIEZO1 channel kinetics, differences in response to osmotic stress, and altered membrane protein trafficking, predicting variant alleles that worsen or ameliorate erythrocyte hydration. These results extend the genetic heterogeneity observed in HX and indicate that various pathophysiologic mechanisms contribute to the HX phenotype.
Asunto(s)
Anemia Hemolítica Congénita/genética , Hidropesía Fetal/genética , Canales Iónicos/genética , Adulto , Anemia Hemolítica Congénita/metabolismo , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Deshidratación/genética , Deshidratación/metabolismo , Eritrocitos/metabolismo , Familia , Femenino , Células HEK293 , Humanos , Hidropesía Fetal/metabolismo , Mutación INDEL , Recién Nacido , Canales Iónicos/metabolismo , Cinética , Masculino , Mutación Missense , Presión Osmótica/fisiologíaRESUMEN
The ability to sense heat is crucial for survival. Increased heat tolerance may prove beneficial by conferring the ability to inhabit otherwise prohibitive ecological niches. This phenomenon is widespread and is found in both large and small animals. For example, ground squirrels and camels can tolerate temperatures more than 40 °C better than many other mammalian species, yet a molecular mechanism subserving this ability is unclear. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal ion channel involved in the detection of noxious thermal and chemical stimuli by primary afferents of the somatosensory system. Here, we show that thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and Bactrian camels (Camelus ferus) express TRPV1 orthologs with dramatically reduced temperature sensitivity. The loss of sensitivity is restricted to temperature and does not affect capsaicin or acid responses, thereby maintaining a role for TRPV1 as a detector of noxious chemical cues. We show that heat sensitivity can be reengineered in both TRPV1 orthologs by a single amino acid substitution in the N-terminal ankyrin-repeat domain. Conversely, reciprocal mutations suppress heat sensitivity of rat TRPV1, supporting functional conservation of the residues. Our studies suggest that squirrels and camels co-opt a common molecular strategy to adapt to hot environments by suppressing the efficiency of TRPV1-mediated heat detection at the level of somatosensory neurons. Such adaptation is possible because of the remarkable functional flexibility of the TRPV1 molecule, which can undergo profound tuning at the minimal cost of a single amino acid change.
Asunto(s)
Camelus/fisiología , Sciuridae/fisiología , Canales Catiónicos TRPV/metabolismo , Termotolerancia , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Repetición de Anquirina , Capsaicina/farmacología , Secuencia Conservada , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Células HEK293 , Calor , Humanos , Concentración de Iones de Hidrógeno , Activación del Canal Iónico/efectos de los fármacos , Mutación/genética , Neuronas/efectos de los fármacos , Neuronas/fisiología , Alineación de Secuencia , Canales Catiónicos TRPV/química , Termotolerancia/efectos de los fármacos , Xenopus/metabolismoRESUMEN
The ability to sense temperature is crucial for the survival of an organism. Temperature influences all biological operations, from rates of metabolic reactions to protein folding, and broad behavioral functions, from feeding to breeding, and other seasonal activities. The evolution of specialized thermosensory adaptations has enabled animals to inhabit extreme temperature niches and to perform specific temperature-dependent behaviors. The function of sensory neurons depends on the participation of various types of ion channels. Each of the channels involved in neuronal excitability, whether through the generation of receptor potential, action potential, or the maintenance of the resting potential have temperature-dependent properties that can tune the neuron's response to temperature stimuli. Since the function of all proteins is affected by temperature, animals need adaptations not only for detecting different temperatures, but also for maintaining sensory ability at different temperatures. A full understanding of the molecular mechanism of thermosensation requires an investigation of all channel types at each step of thermosensory transduction. A fruitful avenue of investigation into how different molecules can contribute to the fine-tuning of temperature sensitivity is to study the specialized adaptations of various species. Given the diversity of molecular participants at each stage of sensory transduction, animals have a toolkit of channels at their disposal to adapt their thermosensitivity to their particular habitats or behavioral circumstances.
Asunto(s)
Regulación de la Temperatura Corporal , Sensación Térmica , Canales de Potencial de Receptor Transitorio/metabolismo , Potenciales de Acción , Animales , Humanos , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiología , Transmisión Sináptica , Canales de Potencial de Receptor Transitorio/química , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
Hibernating mammals possess a unique ability to reduce their body temperature to ambient levels, which can be as low as -2.9 °C, by active down-regulation of metabolism. Despite such a depressed physiologic phenotype, hibernators still maintain activity in their nervous systems, as evidenced by their continued sensitivity to auditory, tactile, and thermal stimulation. The molecular mechanisms that underlie this adaptation remain unknown. We report, using differential transcriptomics alongside immunohistologic and biochemical analyses, that neurons from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) express mitochondrial uncoupling protein 1 (UCP1). The expression changes seasonally, with higher expression during hibernation compared with the summer active state. Functional and pharmacologic analyses show that squirrel UCP1 acts as the typical thermogenic protein in vitro. Accordingly, we found that mitochondria isolated from torpid squirrel brain show a high level of palmitate-induced uncoupling. Furthermore, torpid squirrels during the hibernation season keep their brain temperature significantly elevated above ambient temperature and that of the rest of the body, including brown adipose tissue. Together, our findings suggest that UCP1 contributes to local thermogenesis in the squirrel brain, and thus supports nervous tissue function at low body temperature during hibernation.
Asunto(s)
Hibernación , Canales Iónicos/fisiología , Proteínas Mitocondriales/fisiología , Neuronas/metabolismo , Termogénesis , Animales , Canales Iónicos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Sciuridae , Proteína Desacopladora 1RESUMEN
Relying almost exclusively on their acute sense of touch, tactile-foraging birds can feed in murky water, but the cellular mechanism is unknown. Mechanical stimuli activate specialized cutaneous end organs in the bill, innervated by trigeminal afferents. We report that trigeminal ganglia (TG) of domestic and wild tactile-foraging ducks exhibit numerical expansion of large-diameter mechanoreceptive neurons expressing the mechano-gated ion channel Piezo2. These features are not found in visually foraging birds. Moreover, in the duck, the expansion of mechanoreceptors occurs at the expense of thermosensors. Direct mechanical stimulation of duck TG neurons evokes high-amplitude depolarizing current with a low threshold of activation, high signal amplification gain, and slow kinetics of inactivation. Together, these factors contribute to efficient conversion of light mechanical stimuli into neuronal excitation. Our results reveal an evolutionary strategy to hone tactile perception in vertebrates at the level of primary afferents.
Asunto(s)
Patos/fisiología , Conducta Alimentaria , Mecanotransducción Celular , Neuronas/fisiología , Tacto/fisiología , Animales , Regulación hacia Abajo , Activación del Canal Iónico , Canales Iónicos/metabolismo , Umbral Sensorial , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPV/metabolismo , Termorreceptores/metabolismo , Ganglio del Trigémino/fisiología , Regulación hacia ArribaRESUMEN
K(2P)2.1 (TREK-1) is a polymodal two-pore domain leak potassium channel that responds to external pH, GPCR-mediated phosphorylation signals, and temperature through the action of distinct sensors within the channel. How the various intracellular and extracellular sensory elements control channel function remains unresolved. Here, we show that the K(2P)2.1 (TREK-1) intracellular C-terminal tail (Ct), a major sensory element of the channel, perceives metabolic and thermal commands and relays them to the extracellular C-type gate through transmembrane helix M4 and pore helix 1. By decoupling Ct from the pore-forming core, we further demonstrate that Ct is the primary heat-sensing element of the channel, whereas, in contrast, the pore domain lacks robust temperature sensitivity. Together, our findings outline a mechanism for signal transduction within K(2P)2.1 (TREK-1) in which there is a clear crosstalk between the C-type gate and intracellular Ct domain. In addition, our findings support the general notion of the existence of modular temperature-sensing domains in temperature-sensitive ion channels. This marked distinction between gating and sensory elements suggests a general design principle that may underlie the function of a variety of temperature-sensitive channels.
Asunto(s)
Activación del Canal Iónico , Canales de Potasio de Dominio Poro en Tándem/química , Canales de Potasio de Dominio Poro en Tándem/fisiología , Dominios y Motivos de Interacción de Proteínas/fisiología , Secuencia de Aminoácidos , Animales , Fenómenos Electrofisiológicos , Femenino , Activación del Canal Iónico/genética , Activación del Canal Iónico/fisiología , Metabolismo/fisiología , Ratones , Modelos Biológicos , Modelos Moleculares , Oocitos/química , Oocitos/metabolismo , Estimulación Física , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Dominios y Motivos de Interacción de Proteínas/genética , Temperatura , XenopusRESUMEN
Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a 'choir' of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone.
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Regulación de la Temperatura Corporal/fisiología , Animales , Humanos , Canales Iónicos/fisiologíaRESUMEN
Piezo proteins have recently been identified as ion channels mediating mechanosensory transduction in mammalian cells. Characterization of these channels has yielded important insights into mechanisms of somatosensation, as well as other mechano-associated biologic processes such as sensing of shear stress, particularly in the vasculature, and regulation of urine flow and bladder distention. Other roles for Piezo proteins have emerged, some unexpected, including participation in cellular development, volume regulation, cellular migration, proliferation, and elongation. Mutations in human Piezo proteins have been associated with a variety of disorders including hereditary xerocytosis and several syndromes with muscular contracture as a prominent feature.
Asunto(s)
Canales Iónicos/fisiología , Secuencia de Aminoácidos , Anemia Hemolítica Congénita/genética , Animales , Fenómenos Electrofisiológicos , Eritrocitos/citología , Humanos , Hidropesía Fetal/genética , Canales Iónicos/química , Ratones , Datos de Secuencia Molecular , Mutación , Neuronas Aferentes/metabolismo , Osteoclastos/citología , Filogenia , Estructura Terciaria de Proteína , Homología de Secuencia de AminoácidoRESUMEN
Members of the K(2P) potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K(2P)s are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K(2P), K(2P)2.1 (KCNK2/TREK-1), at a common molecular gate that comprises elements of the pore-forming segments and the N-terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K(2P)s and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K(2P) family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus.
Asunto(s)
Activación del Canal Iónico , Canales de Potasio de Dominio Poro en Tándem/fisiología , Secuencia de Aminoácidos , Animales , Calor , Ratones , Datos de Secuencia Molecular , Canales de Potasio de Dominio Poro en Tándem/genética , Presión , ProtonesRESUMEN
Transient receptor potential ankyrin 1 (TRPA1) is a polymodal excitatory ion channel found in sensory neurons of different organisms, ranging from worms to humans. Since its discovery as an uncharacterized transmembrane protein in human fibroblasts, TRPA1 has become one of the most intensively studied ion channels. Its function has been linked to regulation of heat and cold perception, mechanosensitivity, hearing, inflammation, pain, circadian rhythms, chemoreception, and other processes. Some of these proposed functions remain controversial, while others have gathered considerable experimental support. A truly polymodal ion channel, TRPA1 is activated by various stimuli, including electrophilic chemicals, oxygen, temperature, and mechanical force, yet the molecular mechanism of TRPA1 gating remains obscure. In this review, we discuss recent advances in the understanding of TRPA1 physiology, pharmacology, and molecular function.
Asunto(s)
Sensación Térmica , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Humanos , Canales de Potencial de Receptor Transitorio/químicaRESUMEN
At normal body temperature, the two-pore potassium channels TREK-1 (K2P2.1/KCNK2), TREK-2 (K2P10.1/KCNK10), and TRAAK (K2P4.1/KCNK2) regulate cellular excitability by providing voltage-independent leak of potassium. Heat dramatically potentiates K2P channel activity and further affects excitation. This review focuses on the current understanding of the physiological role of heat-activated K2P current, and discusses the molecular mechanism of temperature gating in TREK-1, TREK-2, and TRAAK.
Asunto(s)
Canales de Potasio/metabolismo , Sensación Térmica , Animales , Activación del Canal Iónico , Fenómenos Mecánicos , Canales de Potasio/químicaRESUMEN
Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) hibernate for several months each winter without access to water,1 but the mechanisms that maintain fluid homeostasis during hibernation are poorly understood. In torpor, when body temperature (TB) reaches 4°C, squirrels decrease metabolism, slow heart rate, and reduce plasma levels of the antidiuretic hormones arginine vasopressin (AVP) and oxytocin (OXT).1 Squirrels spontaneously undergo interbout arousal (IBA) every 2 weeks, temporarily recovering an active-like metabolism and a TB of 37°C for up to 48 h.1,2 Despite the low levels of AVP and OXT during torpor, profound increases in blood pressure and heart rate during the torpor-IBA transition are not associated with massive fluid loss, suggesting the existence of a mechanism that protects against diuresis at a low TB. Here, we demonstrate that the antidiuretic hormone release pathway is activated by hypothalamic supraoptic nucleus (SON) neurons early in the torpor-arousal transition. SON neuron activity, dense-core vesicle release from the posterior pituitary, and plasma hormone levels all begin to increase before TB reaches 10°C. In vivo fiber photometry of SON neurons from hibernating squirrels, together with RNA sequencing and c-FOS immunohistochemistry, confirms that SON is electrically, transcriptionally, and translationally active to monitor blood osmolality throughout the dynamic torpor-arousal transition. Our work emphasizes the importance of the antidiuretic pathway during the torpor-arousal transition and reveals that the neurophysiological mechanism that coordinates the hormonal response to retain fluid is active at an extremely low TB, which is prohibitive for these processes in non-hibernators.
Asunto(s)
Hibernación , Letargo , Animales , Hibernación/fisiología , Letargo/fisiología , Sciuridae/fisiología , Secuencia de BasesRESUMEN
Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.
Asunto(s)
Anorexia , Ghrelina , Hibernación , Hipotálamo , Sciuridae , Animales , Hibernación/fisiología , Sciuridae/fisiología , Anorexia/fisiopatología , Anorexia/metabolismo , Hipotálamo/metabolismo , Ghrelina/metabolismo , Ghrelina/deficiencia , Leptina/deficiencia , Leptina/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Hormonas Tiroideas/metabolismo , Nivel de Alerta/fisiología , Femenino , Estaciones del Año , Conducta Alimentaria/fisiologíaRESUMEN
Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-hour periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.