RESUMEN
We studied the brain mechanisms underlying action selection in a social dilemma setting in which individuals' effortful gains are unfairly distributed among group members. A stable "worker-parasite" relationship developed when three individually operant-conditioned rats were placed together in a Skinner box equipped with response lever and food dispenser on opposite sides. Specifically, one rat, the "worker," engaged in lever-pressing while the other two "parasitic" rats profited from the worker's effort by crowding the feeder in anticipation of food. Anatomically, c-Fos expression in the anterior cingulate cortex (ACC) was significantly higher in worker rats than in parasite rats. Functionally, ACC inactivation suppressed the worker's lever-press behavior drastically under social, but only mildly under individual, settings. Transcriptionally, GABAA receptor- and potassium channel-related messenger RNA expressions were reliably lower in the worker's, relative to parasite's, ACC. These findings indicate the requirement of ACC activation for the expression of exploitable, effortful behavior, which could be mediated by molecular pathways involving GABAA receptor/potassium channel proteins.
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Conducta de Elección/fisiología , Condicionamiento Operante/fisiología , Giro del Cíngulo/patología , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal , Toma de Decisiones/fisiología , Masculino , Canales de Potasio/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Recompensa , Conducta SocialRESUMEN
To understand how incoming cortical inputs are processed by different types of cortical projection neurons in the medial prefrontal cortex, we compared intrinsic physiological properties of and commissural excitatory/inhibitory influences on layer 5 intratelencephalic (IT), layer 5 pyramidal tract (PT), and layers 2/3 IT projection neurons. We found that intrinsic physiological properties and commissural synaptic transmission varied across the three types of projection neurons. The rank order of intrinsic excitability was layer 5 PT > layer 5 IT > layers 2/3 IT neurons. Commissural connectivity was higher in layers 2/3 than layer 5 projection neurons, but commissural excitatory influence was stronger on layer 5 than layers 2/3 pyramidal neurons. Paired-pulse ratio was also greater in PT than IT neurons. These results indicate that commissural inputs activate deep layer PT neurons most preferentially and superficial layer IT neurons least preferentially. Deep layer PT neurons might faithfully transmit cortical input signals to downstream subcortical structures for reliable control of behavior, whereas superficial layer IT neurons might integrate cortical input signals from diverse sources in support of higher-order cognitive functions.
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Neuronas , Células Piramidales , Interneuronas , Neuronas/fisiología , Células Piramidales/fisiología , Tractos Piramidales/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
To better understand the functional roles of hippocampal forward and reverse replays, we trained rats in a spatial sequence memory task and examined how these replays are modulated by reward and navigation history. We found that reward enhances both forward and reverse replays during the awake state, but in different ways. Reward enhances the rate of reverse replays, but it increases the fidelity of forward replays for recently traveled as well as other alternative trajectories heading toward a rewarding location. This suggests roles for forward and reverse replays in reinforcing representations for all potential rewarding trajectories. We also found more faithful reactivation of upcoming than already rewarded trajectories in forward replays. This suggests a role for forward replays in preferentially reinforcing representations for high-value trajectories. We propose that hippocampal forward and reverse replays might contribute to constructing a map of potential navigation trajectories and their associated values (a "value map") via distinct mechanisms.
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Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Células de Lugar/fisiología , Recompensa , Potenciales de Acción/fisiología , Animales , Conducta Animal/fisiología , Hipocampo/citología , Masculino , RatasRESUMEN
To obtain insights into striatal neural processes underlying reward-based learning and movement control, we examined spatial organizations of striatal neurons related to movement and reward-based learning. For this, we recorded the activity of direct- and indirect-pathway neurons (D1 and A2a receptor-expressing neurons, respectively) in mice engaged in probabilistic classical conditioning and open-field free exploration. We found broadly organized functional clusters of striatal neurons in the direct as well as indirect pathways for both movement- and reward-related variables. Functional clusters for different variables were partially overlapping in both pathways, but the overlap between outcome- and value-related functional clusters was greater in the indirect than direct pathway. Also, value-related spatial clusters were progressively refined during classical conditioning. Our study shows the broad and learning-dependent spatial organization of functional clusters of dorsal striatal neurons in the direct and indirect pathways. These findings further argue against the classic model of the basal ganglia and support the importance of spatiotemporal patterns of striatal neuronal ensemble activity in the control of behavior.
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Cuerpo Estriado/fisiología , Recompensa , Conducta Espacial/fisiología , Animales , Señalización del Calcio , Ratones Transgénicos , MovimientoRESUMEN
Hippocampal mossy fibers have long been proposed to impose new patterns to learn onto CA3 neurons during new memory formation. However, inconsistent with this theory, we found in our previous study that mossy fiber stimulation induces only transient changes in CA3 spatial firing in a familiar environment. Here, we tested whether mossy fiber stimulation affects CA3 spatial firing differently between familiar and novel environments. We compared spatial firing of CA3 neurons before and after optogenetic stimulation of mossy fibers in freely behaving mice in a familiar and three sets of novel environments. We found that CA3 neurons are more responsive to mossy fiber stimulation in the novel than familiar environments. However, we failed to obtain evidence for long-lasting effect of mossy fiber stimulation on spatial firing of CA3 neurons in both the familiar and novel environments. Our results provide further evidence against the view that mossy fibers carry teaching signals.
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Potenciales de Acción/fisiología , Ambiente , Conducta Exploratoria/fisiología , Fibras Musgosas del Hipocampo/fisiología , Reconocimiento en Psicología/fisiología , Animales , Región CA3 Hipocampal/citología , Región CA3 Hipocampal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Ratones , Ratones TransgénicosRESUMEN
Reinforcement learning is an adaptive process in which an animal utilizes its previous experience to improve the outcomes of future choices. Computational theories of reinforcement learning play a central role in the newly emerging areas of neuroeconomics and decision neuroscience. In this framework, actions are chosen according to their value functions, which describe how much future reward is expected from each action. Value functions can be adjusted not only through reward and penalty, but also by the animal's knowledge of its current environment. Studies have revealed that a large proportion of the brain is involved in representing and updating value functions and using them to choose an action. However, how the nature of a behavioral task affects the neural mechanisms of reinforcement learning remains incompletely understood. Future studies should uncover the principles by which different computational elements of reinforcement learning are dynamically coordinated across the entire brain.
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Mapeo Encefálico/psicología , Toma de Decisiones/fisiología , Aprendizaje/fisiología , Refuerzo en Psicología , Animales , Economía del Comportamiento , Humanos , Modelos Neurológicos , Modelos Psicológicos , Redes Neurales de la ComputaciónRESUMEN
Strong hippocampal mossy fiber synapses are thought to function as detonators, imposing "teaching" signals onto CA3 neurons during new memory formation. For an empirical test of this long-standing view, we examined effects of optogenetically stimulating mossy fibers on spatial firing of CA3 neurons in freely-moving mice. We found that spatially restricted mossy fiber stimulation drives novel place-specific firing in some CA3 pyramidal neurons. Such neurons comprise only a minority, however, and many more CA3 neurons showed inhibited spatial firing during mossy fiber stimulation. Also, changes in spatial firing induced by mossy fiber stimulation, both activated and inhibited, reverted immediately upon stimulation termination, leaving CA3 place fields unaltered. Our results do not support the traditional view that mossy fibers impose teaching signals onto CA3 network, and show robustness of established CA3 spatial representations.
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Región CA3 Hipocampal/fisiología , Fibras Musgosas del Hipocampo/fisiología , Potenciales de Acción/fisiología , Animales , Región CA3 Hipocampal/citología , Potenciales Postsinápticos Excitadores/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Transgénicos , Optogenética , Células Piramidales/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Despite tremendous progress, the neural circuit dynamics underlying hippocampal mnemonic processing remain poorly understood. We propose a new model for hippocampal function-the simulation-selection model-based on recent experimental findings and neuroecological considerations. Under this model, the mammalian hippocampus evolved to simulate and evaluate arbitrary navigation sequences. Specifically, we suggest that CA3 simulates unexperienced navigation sequences in addition to remembering experienced ones, and CA1 selects from among these CA3-generated sequences, reinforcing those that are likely to maximize reward during offline idling states. High-value sequences reinforced in CA1 may allow flexible navigation toward a potential rewarding location during subsequent navigation. We argue that the simulation-selection functions of the hippocampus have evolved in mammals mostly because of the unique navigational needs of land mammals. Our model may account for why the mammalian hippocampus has evolved not only to remember, but also to imagine episodes, and how this might be implemented in its neural circuits.
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Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Imaginación/fisiología , Memoria Episódica , Recuerdo Mental/fisiología , Recompensa , Navegación Espacial/fisiología , Potenciales de Acción/fisiología , Animales , Columbidae , Excitabilidad Cortical , Dopamina/fisiología , Sinapsis Eléctricas/fisiología , Memoria , Modelos Neurológicos , Neuronas/fisiología , RatasRESUMEN
A subset of hippocampal neurons, known as "time cells" fire sequentially for circumscribed periods of time within a delay interval. We investigated whether medial prefrontal cortex (mPFC) also contains time cells and whether their qualitative properties differ from those in the hippocampus and striatum. We studied the firing correlates of neurons in the rodent mPFC during a temporal discrimination task. On each trial, the animals waited for a few seconds in the stem of a T-maze. A subpopulation of units fired in a sequence consistently across trials for a circumscribed period during the delay interval. These sequentially activated time cells showed temporal accuracy that decreased as time passed as measured by both the width of their firing fields and the number of cells that fired at a particular part of the interval. The firing dynamics of the time cells was significantly better explained with the elapse of time than with the animals' position and velocity. The findings observed here in the mPFC are consistent with those previously reported in the hippocampus and striatum, suggesting that the sequentially activated time cells are not specific to these areas, but are part of a common representational motif across regions.
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Potenciales de Acción/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Percepción del Tiempo/fisiología , Animales , Discriminación en Psicología/fisiología , Electrodos Implantados , Masculino , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Ratas Sprague-Dawley , Procesamiento de Señales Asistido por ComputadorRESUMEN
UNLABELLED: Although the medial prefrontal cortex (mPFC) is known to play a crucial role in rodent social behavior, little is known about mPFC neural correlates of social behavior. In the present study, we examined single-neuron activity in the mPFC of mice performing a modified version of the three-chamber test. We found that a subset of mPFC neurons elevate discharge rates when approaching a stranger mouse but not when approaching an inanimate object or an empty chamber. Our results reveal mPFC neural activity that is correlated with social approach behavior in a widely used social-interaction paradigm. These findings might be helpful for future investigations of mPFC neural processes underlying social interaction in health and disease. SIGNIFICANCE STATEMENT: Although the prefrontal cortex is known to play a crucial role in rodent social behavior, little is known about prefrontal neural correlates of social behavior. This study shows that the activity of a subset of prefrontal neurons increases in association with social approach behavior during a three-chamber test-a widely used behavioral paradigm. Such responses might be a signature of prefrontal neural processes underlying social approach behavior.
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Relaciones Interpersonales , Neuronas/fisiología , Corteza Prefrontal/citología , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Conducta de Elección , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.
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Potenciales de Acción/fisiología , Relojes Biológicos/fisiología , Encéfalo/fisiología , Modelos Neurológicos , Red Nerviosa/fisiología , Neuronas/fisiología , Animales , Gatos , Simulación por Computador , Femenino , Haplorrinos , Masculino , Ratones , Ratas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Especificidad de la EspecieRESUMEN
The hippocampus is important for contextual behavior, and the striatum plays key roles in decision making. When studying the functional relationships with the hippocampus, prior studies have focused mostly on the dorsolateral striatum (DLS), emphasizing the antagonistic relationships between the hippocampus and DLS in spatial versus response learning. By contrast, the functional relationships between the dorsomedial striatum (DMS) and hippocampus are relatively unknown. The current study reports that lesions to both the hippocampus and DMS profoundly impaired performance of rats in a visual scene-based memory task in which the animals were required to make a choice response by using visual scenes displayed in the background. Analysis of simultaneous recordings of local field potentials revealed that the gamma oscillatory power was higher in the DMS, but not in CA1, when the rat performed the task using familiar scenes than novel ones. In addition, the CA1-DMS networks increased coherence at γ, but not at θ, rhythm as the rat mastered the task. At the single-unit level, the neuronal populations in CA1 and DMS showed differential firing patterns when responses were made using familiar visual scenes than novel ones. Such learning-dependent firing patterns were observed earlier in the DMS than in CA1 before the rat made choice responses. The present findings suggest that both the hippocampus and DMS process memory representations for visual scenes in parallel with different time courses and that flexible choice action using background visual scenes requires coordinated operations of the hippocampus and DMS at γ frequencies.
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Hipocampo/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Neostriado/fisiología , Percepción Visual/fisiología , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Electrodos Implantados , Potenciales Evocados Visuales , Agonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Neostriado/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Ratas Long-Evans , Receptores de GABA-A/efectos de los fármacos , Percepción Visual/efectos de los fármacosRESUMEN
The cortico-basal ganglia network has been proposed to consist of parallel loops serving distinct functions. However, it is still uncertain how the content of processed information varies across different loops and how it is related to the functions of each loop. We investigated this issue by comparing neuronal activity in the dorsolateral (sensorimotor) and dorsomedial (associative) striatum, which have been linked to habitual and goal-directed action selection, respectively, in rats performing a dynamic foraging task. Both regions conveyed significant neural signals for the animal's goal choice and its outcome. Moreover, both regions conveyed similar levels of neural signals for action value before the animal's goal choice and chosen value after the outcome of the animal's choice was revealed. However, a striking difference was found in the persistence of neural signals for the animal's chosen action. Signals for the animal's goal choice persisted in the dorsomedial striatum until the outcome of the animal's next goal choice was revealed, whereas they dissipated rapidly in the dorsolateral striatum. These persistent choice signals might be used for causally linking temporally discontiguous responses and their outcomes in the dorsomedial striatum, thereby contributing to its role in goal-directed action selection.
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Potenciales de Acción/fisiología , Conducta de Elección/fisiología , Cuerpo Estriado/fisiología , Objetivos , Neuronas/fisiología , Animales , Conducta Animal/fisiología , Masculino , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiologíaRESUMEN
Time interval estimation is involved in numerous behavioral processes, but its underlying neural mechanisms remain unclear. In particular, it has been controversial whether time is encoded on a linear or logarithmic scale. Based on our previous finding that inactivation of the medial prefrontal cortex (mPFC) profoundly impairs rat's ability to discriminate time intervals, we investigated how the mPFC processes temporal information by examining activity of mPFC neurons in rats performing a temporal bisection task. Many mPFC neurons conveyed temporal information based on monotonically changing activity profiles over time with negative accelerations, so that their activity profiles were better described by logarithmic than linear functions. Moreover, the precision of time-interval discrimination based on neural activity was lowered in proportion to the elapse of time, but without proportional increase in neural variability, which is well accounted for by logarithmic, but not by linear functions. As a population, mPFC neurons conveyed precise information about the elapse of time with their activity tightly correlated with the animal's choice of target. These results suggest that the mPFC might be part of an internal clock in charge of controlling interval-timing behavior, and that linearly changing neuronal activity on a logarithmic time scale might be one way of representing the elapse of time in the brain.
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Potenciales de Acción/fisiología , Neuronas/fisiología , Corteza Prefrontal/citología , Percepción del Tiempo/fisiología , Animales , Distribución de Chi-Cuadrado , Conducta de Elección/fisiología , Discriminación en Psicología/fisiología , Modelos Lineales , Masculino , Aprendizaje por Laberinto/fisiología , Análisis de Componente Principal , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Many anatomical and physiological features of cortical circuits, ranging from the biophysical properties of synapses to the connectivity patterns among different neuron types, exhibit consistent variation along the hierarchical axis from sensory to association areas. Notably, the scale of temporal correlation of neural activity at rest, known as the intrinsic timescale, increases systematically along this hierarchy in both primates and rodents, analogous to the growing scale and complexity of spatial receptive fields. However, how the timescales for task-related activity vary across brain regions and whether their hierarchical organization appears consistently across different mammalian species remain unexplored. Here, we show that both the intrinsic timescale and the timescales of task-related activity follow a similar hierarchical gradient in the cortices of monkeys, rats, and mice. We also found that these timescales covary similarly in both the cortex and basal ganglia, whereas the timescales of thalamic activity are shorter than cortical timescales and do not conform to the hierarchical order predicted by their cortical projections. These results suggest that the hierarchical gradient of cortical timescales might be a universal feature of intra-cortical circuits in the mammalian brain.
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The role of dentate gyrus in hippocampal mnemonic processing is uncertain. One proposed role of dentate gyrus is binding internally generated spatial representation with sensory information on external landmarks. To test this hypothesis, we compared effects of visual input on spatial firing of CA1 neurons in Bax knock-out mice in which dentate gyrus neural circuitry is selectively disrupted. Whereas spatial selectivity of CA1 neuronal firing was significantly higher under normal illumination than complete darkness in wild-type mice, it was similarly low in both illumination conditions in Bax knock-out mice. Also, whereas the spatial location of neuronal firing was more stably maintained in the light than in the dark condition in wild-type mice, it was similarly unstable in both illumination conditions in Bax knock-out mice. These results show that visual input allows selective and stable spatial firing of CA1 neurons in normal animals, but this effect is lost if dentate gyrus neural circuitry is disrupted. Our results provide empirical support for the proposed role of dentate gyrus in aligning internally generated spatial representation to external landmarks in building a unified representation of external space.
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Potenciales de Acción/fisiología , Región CA1 Hipocampal/citología , Giro Dentado/fisiología , Neuronas/fisiología , Conducta Espacial/fisiología , Vías Visuales/fisiología , Potenciales de Acción/genética , Análisis de Varianza , Animales , Señales (Psicología) , Femenino , Luz , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estimulación Luminosa/métodos , Factores de Tiempo , Proteína X Asociada a bcl-2/deficienciaRESUMEN
In contrast to other techniques utilized in physiological studies, calcium imaging can visualize target neurons located deep in the brain. Here, we present a protocol for one-photon calcium imaging of dorsal and ventral CA1 neurons in head-fixed mice. We describe procedures for injecting GCaMP6f virus, implanting a gradient-index (GRIN) lens, and installing a baseplate for Inscopix microscope mounting. For complete details on the use and execution of this protocol, please refer to Yun et al.1.
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Calcio , Diagnóstico por Imagen , Animales , Ratones , Encéfalo , Neuronas , FotonesRESUMEN
A large body of evidence indicates functional variations along the hippocampal longitudinal axis. To investigate whether and how value and outcome processing vary between the dorsal (DH) and the ventral hippocampus (VH), we examined neuronal activity and inactivation effects of the DH and VH in mice performing probabilistic classical conditioning tasks. Inactivation of either structure disrupts value-dependent anticipatory licking, and value-coding neurons are found in both structures, indicating their involvement in value processing. However, the DH neuronal population increases activity as a function of value, while the VH neuronal population is preferentially responsive to the highest-value sensory cue. Also, signals related to outcome-dependent value learning are stronger in the DH. VH neurons instead show rapid responses to punishment and strongly biased responses to negative prediction error. These findings suggest that the DH faithfully represents the external value landscape, whereas the VH preferentially represents behaviorally relevant, salient features of experienced events.
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Hipocampo , Neuronas , Ratones , Animales , Hipocampo/fisiología , Neuronas/fisiologíaRESUMEN
Social and reward signal processing and their association are critical elements of social motivation. Despite the use of reward learning to improve the social interactions of patients with autism spectrum disorder (ASD), the underlying neural mechanisms are unknown. Here, we found different yet conjunct neuronal representations of social and reward signals in the mouse medial prefrontal cortex (mPFC). We also found that social signal processing is selectively disrupted, whereas reward signal processing is intact in the mPFC of Shank2-knockout mice, a mouse model of ASD. Furthermore, reward learning not only allows Shank2-knockout mice to associate social stimuli with reward availability, but it also rescues the impaired social signal processing. These findings provide insights into the neural basis for the therapeutic use of reward learning in ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Animales , Ratones , Aprendizaje , Recompensa , Ratones Noqueados , Imagen por Resonancia Magnética , Proteínas del Tejido NerviosoRESUMEN
Animals often display choice bias, or a preference for one option over the others, which can significantly impede learning new tasks. Delayed match-to-sample (DMS) tasks with two-alternative choices of lickports on the left and right have been widely used to study sensory processing, working memory, and associative memory in head-fixed animals. However, extensive training time, primarily due to the animals' biased licking responses, limits their practical utility. Here, we present the implementation of an automated side bias correction system in an olfactory DMS task, where the lickport positions and the ratio of left- and right-rewarded trials are dynamically adjusted to counterbalance mouse's biased licking responses during training. The correction algorithm moves the preferred lickport farther away from the mouse's mouth and the non-preferred lickport closer, while also increasing the proportion of non-preferred side trials when biased licking occurs. We found that adjusting lickport distances and the proportions of left- versus right-rewarded trials effectively reduces the mouse's side bias. Further analyses reveal that these adjustments also correlate with subsequent improvements in behavioral performance. Our findings suggest that the automated side bias correction system is a valuable tool for enhancing the applicability of behavioral tasks involving two-alternative lickport choices.