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1.
J Neurosci ; 44(26)2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38806248

RESUMEN

Coordinated multijoint limb and digit movements-"manual dexterity"-underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that corticostriatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release in both male and female mice as they learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In the dorsolateral striatum, dopamine dynamics are faster than in the dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of the striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.


Asunto(s)
Cuerpo Estriado , Dopamina , Aprendizaje , Destreza Motora , Animales , Dopamina/metabolismo , Masculino , Ratones , Femenino , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Aprendizaje/fisiología , Destreza Motora/fisiología , Ratones Endogámicos C57BL
2.
bioRxiv ; 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38370850

RESUMEN

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

3.
iScience ; 26(9): 107613, 2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37664637

RESUMEN

Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy-the abrupt loss of postural muscle tone during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum and sleep disorders. Recording DA release in the ventral striatum revealed orexin-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low-frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and rapid eye movement (REM) sleep, while phasic high-frequency stimulation increased cataplexy propensity and decreased the latency to REM sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.

4.
J Neurosci ; 43(44): 7376-7392, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37709540

RESUMEN

The survival of an organism is dependent on its ability to respond to cues in the environment. Such cues can attain control over behavior as a function of the value ascribed to them. Some individuals have an inherent tendency to attribute reward-paired cues with incentive motivational value, or incentive salience. For these individuals, termed sign-trackers, a discrete cue that precedes reward delivery becomes attractive and desirable in its own right. Prior work suggests that the behavior of sign-trackers is dopamine-dependent, and cue-elicited dopamine in the NAc is believed to encode the incentive value of reward cues. Here we exploited the temporal resolution of optogenetics to determine whether selective inhibition of ventral tegmental area (VTA) dopamine neurons during cue presentation attenuates the propensity to sign-track. Using male tyrosine hydroxylase (TH)-Cre Long Evans rats, it was found that, under baseline conditions, ∼84% of TH-Cre rats tend to sign-track. Laser-induced inhibition of VTA dopamine neurons during cue presentation prevented the development of sign-tracking behavior, without affecting goal-tracking behavior. When laser inhibition was terminated, these same rats developed a sign-tracking response. Video analysis using DeepLabCutTM revealed that, relative to rats that received laser inhibition, rats in the control group spent more time near the location of the reward cue even when it was not present and were more likely to orient toward and approach the cue during its presentation. These findings demonstrate that cue-elicited dopamine release is critical for the attribution of incentive salience to reward cues.SIGNIFICANCE STATEMENT Activity of dopamine neurons in the ventral tegmental area (VTA) during cue presentation is necessary for the development of a sign-tracking, but not a goal-tracking, conditioned response in a Pavlovian task. We capitalized on the temporal precision of optogenetics to pair cue presentation with inhibition of VTA dopamine neurons. A detailed behavioral analysis with DeepLabCutTM revealed that cue-directed behaviors do not emerge without dopamine neuron activity in the VTA. Importantly, however, when optogenetic inhibition is lifted, cue-directed behaviors increase, and a sign-tracking response develops. These findings confirm the necessity of dopamine neuron activity in the VTA during cue presentation to encode the incentive value of reward cues.


Asunto(s)
Señales (Psicología) , Motivación , Ratas , Masculino , Animales , Neuronas Dopaminérgicas , Ratas Sprague-Dawley , Dopamina , Ratas Long-Evans , Recompensa
5.
bioRxiv ; 2023 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-37397994

RESUMEN

Disruptions to sleep can be debilitating and have a severe effect on daily life. Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy - the abrupt loss of postural muscle tone (atonia) during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum - a major output region of midbrain DA neurons - and sleep disorders. To better characterize the function and pattern of DA release in sleepiness and cataplexy, we combined optogenetics, fiber photometry, and sleep recordings in a murine model of narcolepsy (orexin-/-; OX KO) and in wildtype mice. Recording DA release in the ventral striatum revealed OX-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and REM sleep, while phasic high frequency stimulation increased cataplexy propensity and decreased the latency to rapid eye movement (REM) sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.

6.
bioRxiv ; 2023 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-37205506

RESUMEN

The survival of an organism is dependent on their ability to respond to cues in the environment. Such cues can attain control over behavior as a function of the value ascribed to them. Some individuals have an inherent tendency to attribute reward-paired cues with incentive motivational value, or incentive salience. For these individuals, termed sign-trackers, a discrete cue that precedes reward delivery becomes attractive and desirable in its own right. Prior work suggests that the behavior of sign-trackers is dopamine-dependent, and cue-elicited dopamine in the nucleus accumbens is believed to encode the incentive value of reward cues. Here we exploited the temporal resolution of optogenetics to determine whether selective inhibition of ventral tegmental area (VTA) dopamine neurons during cue presentation attenuates the propensity to sign-track. Using male tyrosine hydroxylase (TH)-Cre Long Evans rats it was found that, under baseline conditions, ∼84% of TH-Cre rats tend to sign-track. Laser-induced inhibition of VTA dopamine neurons during cue presentation prevented the development of sign-tracking behavior, without affecting goal-tracking behavior. When laser inhibition was terminated, these same rats developed a sign-tracking response. Video analysis using DeepLabCut revealed that, relative to rats that received laser inhibition, rats in the control group spent more time near the location of the reward cue even when it was not present and were more likely to orient towards and approach the cue during its presentation. These findings demonstrate that cue-elicited dopamine release is critical for the attribution of incentive salience to reward cues. Significance Statement: Activity of dopamine neurons in the ventral tegmental area (VTA) during cue presentation is necessary for the development of a sign-tracking, but not a goal-tracking, conditioned response in a Pavlovian task. We capitalized on the temporal precision of optogenetics to pair cue presentation with inhibition of VTA dopamine neurons. A detailed behavioral analysis with DeepLabCut revealed that cue-directed behaviors do not emerge without VTA dopamine. Importantly, however, when optogenetic inhibition is lifted, cue-directed behaviors increase, and a sign-tracking response develops. These findings confirm the necessity of VTA dopamine during cue presentation to encode the incentive value of reward cues.

8.
Front Neurosci ; 16: 952275, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36177357

RESUMEN

Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system's role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.

9.
N Engl J Med ; 386(20): 1950-1952, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35584160
10.
Curr Biol ; 32(7): 1563-1576.e8, 2022 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-35245458

RESUMEN

Postrhinal cortex (POR) and neighboring lateral visual association areas are necessary for identifying objects and interpreting them in specific contexts, but how POR neurons encode the same object across contexts remains unclear. Here, we imaged excitatory neurons in mouse POR across tens of days prior to and throughout initial cue-reward learning and reversal learning. We assessed responses to the same cue when it was rewarded or unrewarded, during both locomotor and stationary contexts. Surprisingly, a large class of POR neurons were minimally cue-driven prior to learning. After learning, distinct clusters within this class responded selectively to a given cue when presented in a specific conjunction of reward and locomotion contexts. In addition, another class contained clusters of neurons whose cue responses were more transient, insensitive to reward learning, and adapted over thousands of presentations. These two classes of POR neurons may support context-dependent interpretation and context-independent identification of sensory cues.


Asunto(s)
Señales (Psicología) , Corteza Visual , Animales , Corteza Cerebral/fisiología , Ratones , Neuronas/fisiología , Recompensa , Corteza Visual/fisiología
11.
Neuron ; 110(2): 183-184, 2022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-35051362

RESUMEN

The brain requires a lot of energy to carry out its functions at peak performance. In times of energy deficit, something has to give. In this issue of Neuron, Padamsey et al. (2021) explore how metabolic demands impact cortical coding by demonstrating the effects of food restriction on visual processing.


Asunto(s)
Neuronas , Percepción Visual , Encéfalo , Cognición/fisiología , Percepción Visual/fisiología
12.
Nat Neurosci ; 23(8): 981-991, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32514136

RESUMEN

Salient experiences are often relived in the mind. Human neuroimaging studies suggest that such experiences drive activity patterns in visual association cortex that are subsequently reactivated during quiet waking. Nevertheless, the circuit-level consequences of such reactivations remain unclear. Here, we imaged hundreds of neurons in visual association cortex across days as mice learned a visual discrimination task. Distinct patterns of neurons were activated by different visual cues. These same patterns were subsequently reactivated during quiet waking in darkness, with higher reactivation rates during early learning and for food-predicting versus neutral cues. Reactivations involving ensembles of neurons encoding both the food cue and the reward predicted strengthening of next-day functional connectivity of participating neurons, while the converse was observed for reactivations involving ensembles encoding only the food cue. We propose that task-relevant neurons strengthen while task-irrelevant neurons weaken their dialog with the network via participation in distinct flavors of reactivation.


Asunto(s)
Aprendizaje Discriminativo/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Corteza Visual/fisiología , Percepción Visual/fisiología , Animales , Señales (Psicología) , Alimentos , Privación de Alimentos/fisiología , Ratones , Recompensa
13.
Neuron ; 100(4): 900-915.e9, 2018 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30318413

RESUMEN

The response of a cortical neuron to a motivationally salient visual stimulus can reflect a prediction of the associated outcome, a sensitivity to low-level stimulus features, or a mix of both. To distinguish between these alternatives, we monitored responses to visual stimuli in the same lateral visual association cortex neurons across weeks, both prior to and after reassignment of the outcome associated with each stimulus. We observed correlated ensembles of neurons with visual responses that either tracked the same predicted outcome, the same stimulus orientation, or that emerged only following new learning. Visual responses of outcome-tracking neurons encoded "value," as they demonstrated a response bias to salient, food-predicting cues and sensitivity to reward history and hunger state. Strikingly, these attributes were not evident in neurons that tracked stimulus orientation. Our findings suggest a division of labor between intermingled ensembles in visual association cortex that encode predicted value or stimulus identity.


Asunto(s)
Estimulación Luminosa/métodos , Recompensa , Corteza Visual/fisiología , Percepción Visual/fisiología , Animales , Predicción , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Visual/citología
14.
Curr Opin Neurobiol ; 49: 16-23, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29125986

RESUMEN

Physiological need states and associated motivational drives can bias visual processing of cues that help meet these needs. Human neuroimaging studies consistently show a hunger-dependent, selective enhancement of responses to images of food in association cortex and amygdala. More recently, cellular-resolution imaging combined with circuit mapping experiments in behaving mice have revealed underlying neuronal population dynamics and enabled tracing of pathways by which hunger circuits influence the assignment of value to visual objects in visual association cortex, insular cortex, and amygdala. These experiments begin to provide a mechanistic understanding of motivation-specific neural processing of need-relevant cues in healthy humans and in disease states such as obesity and other eating disorders.


Asunto(s)
Amígdala del Cerebelo/fisiología , Corteza Cerebral/fisiología , Filtrado Sensorial/fisiología , Vías Visuales/fisiología , Amígdala del Cerebelo/diagnóstico por imagen , Animales , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Señales (Psicología) , Humanos , Hambre/fisiología , Ratones , Motivación , Neuroimagen , Estimulación Luminosa , Vías Visuales/diagnóstico por imagen
15.
Nature ; 546(7660): 611-616, 2017 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-28614299

RESUMEN

Physiological needs bias perception and attention to relevant sensory cues. This process is 'hijacked' by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how 'cognitive' cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food-cue-biased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic 'hunger neurons' (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathway-specific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues.


Asunto(s)
Corteza Cerebral/citología , Corteza Cerebral/fisiología , Alimentos , Homeostasis , Vías Nerviosas , Estimulación Luminosa , Proteína Relacionada con Agouti/metabolismo , Animales , Señales (Psicología) , Hambre/fisiología , Hipotálamo/citología , Hipotálamo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Respuesta de Saciedad/fisiología
16.
Neuron ; 93(1): 57-65, 2017 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-27989461

RESUMEN

Ingestion of water and food are major hypo- and hyperosmotic challenges. To protect the body from osmotic stress, posterior pituitary-projecting, vasopressin-secreting neurons (VPpp neurons) counter osmotic perturbations by altering their release of vasopressin, which controls renal water excretion. Vasopressin levels begin to fall within minutes of water consumption, even prior to changes in blood osmolality. To ascertain the precise temporal dynamics by which water or food ingestion affect VPpp neuron activity, we directly recorded the spiking and calcium activity of genetically defined VPpp neurons. In states of elevated osmolality, water availability rapidly decreased VPpp neuron activity within seconds, beginning prior to water ingestion, upon presentation of water-predicting cues. In contrast, food availability following food restriction rapidly increased VPpp neuron activity within seconds, but only following feeding onset. These rapid and distinct changes in activity during drinking and feeding suggest diverse neural mechanisms underlying anticipatory regulation of VPpp neurons.


Asunto(s)
Arginina Vasopresina/metabolismo , Conducta de Ingestión de Líquido/fisiología , Conducta Alimentaria/fisiología , Neuronas/fisiología , Presión Osmótica , Animales , Señales (Psicología) , Ratones , Neuronas/metabolismo , Concentración Osmolar , Núcleo Supraóptico/citología , Vasopresinas/metabolismo
17.
Nat Neurosci ; 19(12): 1628-1635, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27643429

RESUMEN

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues before ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the preconsummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor-expressing GABAergic vDMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, leptin receptor-expressing GABAergic vDMH neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior.


Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas GABAérgicas/metabolismo , Animales , Conducta Alimentaria , Ratones , Neuropéptido Y/metabolismo , Receptores de Leptina/metabolismo , Sensación/fisiología
18.
Neuron ; 91(5): 1154-1169, 2016 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-27523426

RESUMEN

The needs of the body can direct behavioral and neural processing toward motivationally relevant sensory cues. For example, human imaging studies have consistently found specific cortical areas with biased responses to food-associated visual cues in hungry subjects, but not in sated subjects. To obtain a cellular-level understanding of these hunger-dependent cortical response biases, we performed chronic two-photon calcium imaging in postrhinal association cortex (POR) and primary visual cortex (V1) of behaving mice. As in humans, neurons in mouse POR, but not V1, exhibited biases toward food-associated cues that were abolished by satiety. This emergent bias was mirrored by the innervation pattern of amygdalo-cortical feedback axons. Strikingly, these axons exhibited even stronger food cue biases and sensitivity to hunger state and trial history. These findings highlight a direct pathway by which the lateral amygdala may contribute to state-dependent cortical processing of motivationally relevant sensory cues.


Asunto(s)
Amígdala del Cerebelo/fisiología , Señales (Psicología) , Corteza Entorrinal/fisiología , Alimentos , Hambre/fisiología , Respuesta de Saciedad/fisiología , Animales , Masculino , Ratones , Vías Nerviosas/fisiología , Estimulación Luminosa
19.
Elife ; 42015 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-26159614

RESUMEN

Agouti-related-peptide (AgRP) neurons-interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)-are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.


Asunto(s)
Potenciales de Acción , Proteína Relacionada con Agouti/análisis , Núcleo Arqueado del Hipotálamo/fisiología , Conducta Alimentaria , Neuronas/fisiología , Proopiomelanocortina/análisis , Animales , Ratones
20.
Curr Biol ; 23(18): 1719-25, 2013 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-23993842

RESUMEN

BACKGROUND: Appropriate levels of skeletal muscle tone are needed to support routine motor behaviors. But, the brain mechanisms that function to couple muscle tone with waking behaviors are unknown. We addressed this question by studying mice with cataplexy--a condition caused by a decoupling of motor and arousal behaviors. Cataplexy is characterized by involuntary loss of muscle tone during wakefulness, which results in postural collapse during otherwise normal consciousness. Cataplexy is caused by loss of hypocretin (orexin) cells, but it is unknown how this loss triggers motor inactivity during cataplexy. Here, we used hypocretin knockout mice to identify the neurochemical cause of cataplexy and to determine the biochemical mechanisms that normally function to couple arousal and motor systems. RESULTS: Using genetic, behavioral, electrophysiological, and pharmacological approaches, we show that the noradrenergic system acts to synchronize motor and arousal systems. Specifically, we show that an excitatory noradrenergic drive maintains postural muscle tone during wakefulness by activating α1 receptors on skeletal motoneurons. Loss of this normal excitatory drive triggers motor inactivity during cataplexy by reducing motoneuron excitation. However, loss of this drive does not affect arousal since mice remain awake during cataplexy, suggesting the noradrenergic system is not required for maintaining wakefulness. Artificial restoration of noradrenergic drive to motoneurons prevents motor inactivity and rescues cataplexy. CONCLUSIONS: We conclude that hypocretin deficiency causes cataplexy by short-circuiting the noradrenergic drive to skeletal motoneurons. We suggest that the noradrenergic system functions to couple the brain systems that control postural muscle tone and behavioral arousal state.


Asunto(s)
Cataplejía/fisiopatología , Neuronas Motoras/fisiología , Vigilia/fisiología , Animales , Electroencefalografía , Electrofisiología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Noqueados , Músculo Esquelético/fisiopatología , Neuropéptidos/deficiencia , Neuropéptidos/genética , Orexinas , Receptores Adrenérgicos/fisiología , Sueño/fisiología
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