RESUMEN
Rapid phasic activity of midbrain dopamine neurons is thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. However, recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independent from somatic spiking activity. Here we developed experimental paradigms using virtual reality that disambiguate RPEs from values. We examined dopamine circuit activity at various stages, including somatic spiking, calcium signals at somata and axons, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all stages examined. Ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.
Asunto(s)
Dopamina/metabolismo , Transducción de Señal , Potenciales de Acción/fisiología , Animales , Axones/metabolismo , Calcio/metabolismo , Señalización del Calcio , Cuerpo Celular/metabolismo , Señales (Psicología) , Neuronas Dopaminérgicas/fisiología , Fluorometría , Masculino , Ratones Endogámicos C57BL , Modelos Neurológicos , Estimulación Luminosa , Recompensa , Sensación , Factores de Tiempo , Área Tegmental Ventral/metabolismo , Realidad VirtualRESUMEN
Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here, we report the development of genetically encoded GPCR-activation-based-DA (GRABDA) sensors that enable these measurements. In response to extracellular DA, GRABDA sensors exhibit large fluorescence increases (ΔF/F0 â¼90%) with subcellular resolution, subsecond kinetics, nanomolar to submicromolar affinities, and excellent molecular specificity. GRABDA sensors can resolve a single-electrical-stimulus-evoked DA release in mouse brain slices and detect endogenous DA release in living flies, fish, and mice. In freely behaving mice, GRABDA sensors readily report optogenetically elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA signaling during Pavlovian conditioning or during sexual behaviors. Thus, GRABDA sensors enable spatiotemporally precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors.
Asunto(s)
Dopamina/análisis , Drosophila/metabolismo , Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/metabolismo , Conducta Animal , Dopamina/metabolismo , Femenino , Proteínas Fluorescentes Verdes/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Neuronas/citología , Neuronas/metabolismo , Optogenética/métodos , Receptores Acoplados a Proteínas G/genética , Canales Catiónicos TRPV/genética , Proteínas de Pez Cebra/genéticaRESUMEN
The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans1-3. Affiliative social touch, such as allogrooming (grooming behaviour directed towards another individual), is a major type of prosocial behaviour that provides comfort to others1-6. Affiliative touch serves to establish and strengthen social bonds between animals and can help to console distressed conspecifics. However, the neural circuits that promote prosocial affiliative touch have remained unclear. Here we show that mice exhibit affiliative allogrooming behaviour towards distressed partners, providing a consoling effect. The increase in allogrooming occurs in response to different types of stressors and can be elicited by olfactory cues from distressed individuals. Using microendoscopic calcium imaging, we find that neural activity in the medial amygdala (MeA) responds differentially to naive and distressed conspecifics and encodes allogrooming behaviour. Through intersectional functional manipulations, we establish a direct causal role of the MeA in controlling affiliative allogrooming and identify a select, tachykinin-expressing subpopulation of MeA GABAergic (γ-aminobutyric-acid-expressing) neurons that promote this behaviour through their projections to the medial preoptic area. Together, our study demonstrates that mice display prosocial comforting behaviour and reveals a neural circuit mechanism that underlies the encoding and control of affiliative touch during prosocial interactions.
Asunto(s)
Emociones , Conducta Social , Estrés Psicológico , Tacto/fisiología , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/fisiología , Animales , Conducta Cooperativa , Femenino , Masculino , Ratones , Vías Nerviosas , Neuronas/fisiología , Área Preóptica/citología , Área Preóptica/fisiología , Estrés Psicológico/prevención & control , Estrés Psicológico/psicologíaRESUMEN
Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels. We use cell type-specific optogenetics, intra-VTA pharmacology, and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign tracking. We trained male and female rats in a Pavlovian lever autoshaping (PLA) task to determine their tracking groups before testing the effect of VTA â NAc dopamine inhibition. We found that this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRABDA (AAV9-hSyn-DA2m), we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping in female rats. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases in NAc shell, but not core, dopamine levels during reward delivery [unconditioned stimulus (US)]. Our results suggest that CB1R signaling in the VTA influences the balance between the conditioned stimulus-evoked and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats.SIGNIFICANCE STATEMENT Substance use disorder (SUD) is a chronically relapsing psychological disorder that affects a subset of individuals who engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences before drug experience that predict SUD and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug-motivated behaviors.
Asunto(s)
Núcleo Accumbens , Área Tegmental Ventral , Femenino , Ratas , Masculino , Animales , Núcleo Accumbens/fisiología , Área Tegmental Ventral/fisiología , Señales (Psicología) , Dopamina/metabolismo , Endocannabinoides/farmacología , Rimonabant/farmacología , Agonismo Inverso de Drogas , Recompensa , Poliésteres/metabolismo , Poliésteres/farmacologíaRESUMEN
The cultural transmission of behaviour depends on the ability of the pupil to identify and emulate an appropriate tutor1-4. How the brain of the pupil detects a suitable tutor and encodes the behaviour of the tutor is largely unknown. Juvenile zebra finches readily copy the songs of the adult tutors that they interact with, but not the songs that they listen to passively through a speaker5,6, indicating that social cues generated by the tutor facilitate song imitation. Here we show that neurons in the midbrain periaqueductal grey of juvenile finches are selectively excited by a singing tutor and-by releasing dopamine in the cortical song nucleus HVC-help to encode the song representations of the tutor used for vocal copying. Blocking dopamine signalling in the HVC of the pupil during tutoring blocked copying, whereas pairing stimulation of periaqueductal grey terminals in the HVC with a song played through a speaker was sufficient to drive copying. Exposure to a singing tutor triggered the rapid emergence of responses to the tutor song in the HVC of the pupil and a rapid increase in the complexity of the song of the pupil, an early signature of song copying7,8. These findings reveal that a dopaminergic mesocortical circuit detects the presence of a tutor and helps to encode the performance of the tutor, facilitating the cultural transmission of vocal behaviour.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Pinzones/fisiología , Aprendizaje/fisiología , Vías Nerviosas/fisiología , Sustancia Gris Periacueductal/citología , Sustancia Gris Periacueductal/fisiología , Vocalización Animal/fisiología , Animales , Señales (Psicología) , Femenino , Masculino , Optogenética , Terminales Presinápticos/metabolismo , Transducción de Señal , Canto/fisiologíaRESUMEN
Dopamine (DA) plays a critical role in the brain, and the ability to directly measure dopaminergic activity is essential for understanding its physiological functions. We therefore developed red fluorescent G-protein-coupled receptor-activation-based DA (GRABDA) sensors and optimized versions of green fluorescent GRABDA sensors. In response to extracellular DA, both the red and green GRABDA sensors exhibit a large increase in fluorescence, with subcellular resolution, subsecond kinetics and nanomolar-to-submicromolar affinity. Moreover, the GRABDA sensors resolve evoked DA release in mouse brain slices, detect evoked compartmental DA release from a single neuron in live flies and report optogenetically elicited nigrostriatal DA release as well as mesoaccumbens dopaminergic activity during sexual behavior in freely behaving mice. Coexpressing red GRABDA with either green GRABDA or the calcium indicator GCaMP6s allows tracking of dopaminergic signaling and neuronal activity in distinct circuits in vivo.
Asunto(s)
Técnicas Biosensibles/métodos , Encéfalo/metabolismo , Dopamina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Conducta Sexual/fisiología , Animales , Drosophila/genética , Drosophila/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Neuronas/metabolismo , Ratas , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteína Fluorescente RojaRESUMEN
Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit the measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRABDA signals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRABDA signals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRABDA signals decreases immediately following reinforcer-specific satiety. When we deliver unexpected rewards or omit expected rewards, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.
Asunto(s)
Dopamina , Núcleos Septales , Ratas , Animales , Dopamina/metabolismo , Ratas Sprague-Dawley , Señales (Psicología) , Condicionamiento Clásico/fisiología , Recompensa , Motivación , FentaniloRESUMEN
To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward.
Asunto(s)
Dopamina , Recompensa , Ratas , Animales , Área Tegmental Ventral/fisiología , Núcleo Accumbens/fisiología , Aprendizaje/fisiologíaRESUMEN
Social behaviors are among the most important motivated behaviors. How dopamine (DA), a "reward" signal, releases during social behaviors has been a topic of interest for decades. Here, we use a genetically encoded DA sensor, GRABDA2m, to record DA activity in the nucleus accumbens (NAc) core during various social behaviors in male and female mice. We find that DA releases during approach, investigation and consummation phases of social behaviors signal animals' motivation, familiarity of the social target, and valence of the experience, respectively. Positive and negative social experiences evoke opposite DA patterns. Furthermore, DA releases during mating and fighting are sexually dimorphic with a higher level in males than in females. At the functional level, increasing DA in NAc enhances social interest toward a familiar conspecific and alleviates defeat-induced social avoidance. Altogether, our results reveal complex information encoded by NAc DA activity during social behaviors and their multistage functional roles.
Asunto(s)
Dopamina , Núcleo Accumbens , Animales , Femenino , Masculino , Ratones , Motivación , Núcleo Accumbens/fisiología , Recompensa , Conducta SocialRESUMEN
Clues from human movement disorders have long suggested that the neurotransmitter dopamine plays a role in motor control, but how the endogenous dopaminergic system influences movement is unknown. Here, we examined the relationship between dopaminergic signaling and the timing of reward-related movements in mice. Animals were trained to initiate licking after a self-timed interval following a start-timing cue; reward was delivered in response to movements initiated after a criterion time. The movement time was variable from trial-to-trial, as expected from previous studies. Surprisingly, dopaminergic signals ramped-up over seconds between the start-timing cue and the self-timed movement, with variable dynamics that predicted the movement/reward time on single trials. Steeply rising signals preceded early lick-initiation, whereas slowly rising signals preceded later initiation. Higher baseline signals also predicted earlier self-timed movements. Optogenetic activation of dopamine neurons during self-timing did not trigger immediate movements, but rather caused systematic early-shifting of movement initiation, whereas inhibition caused late-shifting, as if modulating the probability of movement. Consistent with this view, the dynamics of the endogenous dopaminergic signals quantitatively predicted the moment-by-moment probability of movement initiation on single trials. We propose that ramping dopaminergic signals, likely encoding dynamic reward expectation, can modulate the decision of when to move.
Asunto(s)
Dopamina/metabolismo , Actividad Motora , Trastornos del Movimiento/metabolismo , Recompensa , Animales , Señales (Psicología) , Neuronas Dopaminérgicas/metabolismo , Femenino , Humanos , Masculino , Ratones , Movimiento , Probabilidad , Factores de TiempoRESUMEN
Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior-predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.
Asunto(s)
Conducta Apetitiva/fisiología , Locomoción/fisiología , Porción Compacta de la Sustancia Negra/fisiología , Conducta Predatoria/fisiología , Colículos Superiores/fisiología , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , Vías Nerviosas/fisiología , Porción Compacta de la Sustancia Negra/citología , Técnicas Estereotáxicas , Colículos Superiores/citología , Transmisión Sináptica/fisiologíaRESUMEN
Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.
Asunto(s)
Prosencéfalo Basal/fisiología , Cocaína/administración & dosificación , Dopamina/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Habénula/fisiología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Receptores de Dopamina D3/fisiología , Animales , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Recompensa , Área Tegmental Ventral/fisiologíaRESUMEN
The brain dopamine (DA) system participates in forming and expressing memory. Despite a well-established role of DA neurons in the ventral tegmental area in memory formation, the exact DA circuits that control memory expression remain unclear. Here, we show that DA neurons in the dorsal raphe nucleus (DRN) and their medulla input control the expression of incentive memory. DRN DA neurons are activated by both rewarding and aversive stimuli in a learning-dependent manner and exhibit elevated activity during memory recall. Disrupting their physiological activity or DA synthesis blocks the expression of natural appetitive and aversive memories as well as drug memories associated with opioids. Moreover, a glutamatergic pathway from the lateral parabrachial nucleus to the DRN selectively regulates the expression of reward memories associated with opioids or foods. Our study reveals a specialized DA subsystem important for memory expression and suggests new targets for interventions against opioid addiction.
Asunto(s)
Neuronas Dopaminérgicas/fisiología , Memoria , Núcleos del Rafe/fisiología , Recompensa , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Femenino , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Narcóticos/farmacología , Núcleos del Rafe/citología , Núcleos del Rafe/metabolismoRESUMEN
BACKGROUND: Dopamine (DA) is hypothesized to modulate anxiety-like behavior, although the precise role of DA in anxiety behaviors and the complete anxiety network in the brain have yet to be elucidated. Recent data indicate that dopaminergic projections from the ventral tegmental area (VTA) innervate the interpeduncular nucleus (IPN), but how the IPN responds to DA and what role this circuit plays in anxiety-like behavior are unknown. METHODS: We expressed a genetically encoded G protein-coupled receptor activation-based DA sensor in mouse midbrain to detect DA in IPN slices using fluorescence imaging combined with pharmacology. Next, we selectively inhibited or activated VTAâIPN DAergic inputs via optogenetics during anxiety-like behavior. We used a biophysical approach to characterize DA effects on neural IPN circuits. Site-directed pharmacology was used to test if DA receptors in the IPN can regulate anxiety-like behavior. RESULTS: DA was detected in mouse IPN slices. Silencing/activating VTAâIPN DAergic inputs oppositely modulated anxiety-like behavior. Two neuronal populations in the ventral IPN (vIPN) responded to DA via D1 receptors (D1Rs). vIPN neurons were controlled by a small population of D1R neurons in the caudal IPN that directly respond to VTA DAergic terminal stimulation and innervate the vIPN. IPN infusion of a D1R agonist and antagonist bidirectionally controlled anxiety-like behavior. CONCLUSIONS: VTA DA engages D1R-expressing neurons in the caudal IPN that innervate vIPN, thereby amplifying the VTA DA signal to modulate anxiety-like behavior. These data identify a DAergic circuit that mediates anxiety-like behavior through unique IPN microcircuitry.
Asunto(s)
Dopamina , Núcleo Interpeduncular , Animales , Ansiedad , Neuronas Dopaminérgicas , Mesencéfalo , Ratones , Área Tegmental VentralRESUMEN
Maintaining healthy body weight is increasingly difficult in our obesogenic environment. Dieting efforts are often overpowered by the internal drive to consume energy-dense foods. Although the selection of calorically rich substrates over healthier options is identifiable across species, the mechanisms behind this choice remain poorly understood. Using a passive devaluation paradigm, we found that exposure to high-fat diet (HFD) suppresses the intake of nutritionally balanced standard chow diet (SD) irrespective of age, sex, body mass accrual and functional leptin or melanocortin-4 receptor signaling. Longitudinal recordings revealed that this SD devaluation and subsequent shift toward HFD consumption is encoded at the level of hypothalamic agouti-related peptide neurons and mesolimbic dopamine signaling. Prior HFD consumption vastly diminished the capacity of SD to alleviate the negative valence associated with hunger and the rewarding properties of food discovery even after periods of HFD abstinence. These data reveal a neural basis behind the hardships of dieting.