RESUMEN
Anterior cingulate cortex mediates the flexible updating of an animal's choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the terminal projections of cingulate cortical neurons in secondary motor cortex in the rat disrupts choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreases rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that is temporally targeted to error trials immediately after rule switches exacerbates errors in the following trials. These results suggest that cingulate cortex monitors behavioral errors and updates rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.
Asunto(s)
Giro del Cíngulo , Corteza Motora , Animales , Giro del Cíngulo/fisiología , Corteza Motora/fisiología , Neuronas/fisiología , RatasRESUMEN
Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.
Asunto(s)
Mapeo Encefálico , Memoria , Animales , Encéfalo , Miedo/fisiología , Hipocampo/fisiología , Memoria/fisiología , RatonesRESUMEN
There is considerable evidence for hippocampal time cells that briefly activate in succession to represent the temporal structure of memories. Previous studies have shown that time cells can be disrupted while leaving place cells intact, indicating that spatial and temporal information can be coded in parallel. However, the circuits in which spatial and temporal information are coded have not been clearly identified. Here we investigated temporal and spatial coding by dorsal hippocampal CA1 (dCA1) neurons in mice trained on a classic spatial working-memory task. On each trial, the mice approached the same choice point on a maze but were trained to alternate between traversing one of two distinct spatial routes (spatial coding phase). In between trials, there was a 10-s mnemonic delay during which the mouse continuously ran in a fixed location (temporal coding phase). Using cell-type-specific optogenetic methods, we found that inhibiting dorsal CA2 (dCA2) inputs into dCA1 degraded time cell coding during the mnemonic delay and impaired the mouse's subsequent memory-guided choice. Conversely, inhibiting dCA2 inputs during the spatial coding phase had a negligible effect on place cell activity in dCA1 and no effect on behavior. Collectively, our work demonstrates that spatial and temporal coding in dCA1 is largely segregated with respect to the dCA2-dCA1 circuit and suggests that CA2 plays a critical role in representing the flow of time in memory within the hippocampal network.
Asunto(s)
Región CA1 Hipocampal/fisiología , Región CA2 Hipocampal/fisiología , Memoria a Corto Plazo/fisiología , Memoria Espacial/fisiología , Animales , Hipocampo/fisiología , Humanos , Ratones , Neuronas/fisiologíaRESUMEN
The attentional control of behavior is a higher-order cognitive function that operates through attention and response inhibition. The locus coeruleus (LC), the main source of norepinephrine in the brain, is considered to be involved in attentional control by modulating the neuronal activity of the prefrontal cortex (PFC). However, evidence for the causal role of LC activity in attentional control remains elusive. Here, by using behavioral and optogenetic techniques, we investigate the effect of LC neuron activation or inhibition in operant tests measuring attention and response inhibition (i.e., a measure of impulsive behavior). We show that LC neuron stimulation increases goal-directed attention and decreases impulsivity, while its suppression exacerbates distractibility and increases impulsive responding. Remarkably, we found that attention and response inhibition are under the control of two divergent projections emanating from the LC: one to the dorso-medial PFC and the other to the ventro-lateral orbitofrontal cortex, respectively. These findings are especially relevant for those pathological conditions characterized by attention deficits and elevated impulsivity.
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Atención/fisiología , Lóbulo Frontal/metabolismo , Conducta Impulsiva/fisiología , Norepinefrina/metabolismo , Animales , Encéfalo/metabolismo , Cognición/fisiología , Lóbulo Frontal/efectos de los fármacos , Inhibición Psicológica , Locus Coeruleus/fisiología , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Norepinefrina/farmacología , Corteza Prefrontal/fisiologíaRESUMEN
Learning from successes and failures often improves the quality of subsequent decisions. Past outcomes, however, should not influence purely perceptual decisions after task acquisition is complete since these are designed so that only sensory evidence determines the correct choice. Yet, numerous studies report that outcomes can bias perceptual decisions, causing spurious changes in choice behavior without improving accuracy. Here we show that the effects of reward on perceptual decisions are principled: past rewards bias future choices specifically when previous choice was difficult and hence decision confidence was low. We identified this phenomenon in six datasets from four laboratories, across mice, rats, and humans, and sensory modalities from olfaction and audition to vision. We show that this choice-updating strategy can be explained by reinforcement learning models incorporating statistical decision confidence into their teaching signals. Thus, reinforcement learning mechanisms are continually engaged to produce systematic adjustments of choices even in well-learned perceptual decisions in order to optimize behavior in an uncertain world.
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Sesgo , Toma de Decisiones/fisiología , Refuerzo en Psicología , Animales , Conducta de Elección , Audición , Humanos , Ratones , Ratas , Olfato , Visión OcularRESUMEN
The brain codes continuous spatial, temporal and sensory changes in daily experience. Recent studies suggest that the brain also tracks experience as segmented subdivisions (events), but the neural basis for encoding events remains unclear. Here, we designed a maze for mice, composed of four materially indistinguishable lap events, and identify hippocampal CA1 neurons whose activity are modulated not only by spatial location but also lap number. These 'event-specific rate remapping' (ESR) cells remain lap-specific even when the maze length is unpredictably altered within trials, which suggests that ESR cells treat lap events as fundamental units. The activity pattern of ESR cells is reused to represent lap events when the maze geometry is altered from square to circle, which suggests that it helps transfer knowledge between experiences. ESR activity is separately manipulable from spatial activity, and may therefore constitute an independent hippocampal code: an 'event code' dedicated to organizing experience by events as discrete and transferable units.
Asunto(s)
Región CA1 Hipocampal/fisiología , Aprendizaje por Laberinto/fisiología , Neuronas/fisiología , Animales , RatonesRESUMEN
In 1904, Richard Semon introduced the term "engram" to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory retrieval. Although Semon's contributions were largely ignored in his lifetime, new technologies that allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated engram research. We review recent progress in studying engrams, including an evaluation of evidence for the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory.
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Química Encefálica , Encéfalo/citología , Encéfalo/fisiología , Recuerdo Mental/fisiología , Animales , Humanos , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Neuronas/química , Neuronas/fisiologíaRESUMEN
The ability to extinguish conditioned fear memory is critical for adaptive control of fear response, and its impairment is a hallmark of emotional disorders like post-traumatic stress disorder (PTSD). Fear extinction is thought to take place when animals form a new memory that suppresses the original fear memory. However, little is known about the nature and the site of formation and storage of this new extinction memory. Here we demonstrate that a fear extinction memory engram is formed and stored in a genetically distinct basolateral amygdala (BLA) neuronal population that drives reward behaviors and antagonizes the BLA's original fear neurons. Activation of fear extinction engram neurons and natural reward-responsive neurons overlap significantly in the BLA. Furthermore, these two neuronal subsets are mutually interchangeable in driving reward behaviors and fear extinction behaviors. Thus, fear extinction memory is a newly formed reward memory. VIDEO ABSTRACT.
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Amígdala del Cerebelo/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Memoria/fisiología , Neuronas/fisiología , Recompensa , Animales , Condicionamiento Psicológico/fisiología , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neuronas/metabolismo , OptogenéticaRESUMEN
Animals need to optimize the efficacy of memory retrieval to adapt to environmental circumstances for survival. The recent development of memory engram labeling technology allows a precise investigation of the processes associated with the recall of a specific memory. Here, we show that engram cell excitability is transiently increased following memory reactivation. This short-term increase of engram excitability enhances the subsequent retrieval of specific memory content in response to cues and is manifest in the animal's ability to recognize contexts more precisely and more effectively. These results reveal a hitherto unknown transient enhancement of context recognition based on the plasticity of engram cell excitability. They also suggest that recall of a contextual memory is influenced by previous but recent activation of the same engram. The state of excitability of engram cells mediates differential behavioral outcomes upon memory retrieval and may be crucial for survival by promoting adaptive behavior.
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Giro Dentado/citología , Potenciales de la Membrana/fisiología , Recuerdo Mental/fisiología , Neuronas/fisiología , Animales , Anisomicina/farmacología , Proteínas Bacterianas/genética , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Condicionamiento Psicológico/fisiología , Doxiciclina/farmacología , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Imidazoles/farmacología , Proteínas Luminiscentes/genética , Potenciales de la Membrana/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Ratones , Ratones Transgénicos , Microscopía Confocal , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Fenantrolinas/farmacología , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Transducción GenéticaRESUMEN
What happens to memories as days, weeks and years go by has long been a fundamental question in neuroscience and psychology. For decades, researchers have attempted to identify the brain regions in which memory is formed and to follow its changes across time. The theory of systems consolidation of memory (SCM) suggests that changes in circuitry and brain networks are required for the maintenance of a memory with time. Various mechanisms by which such changes may take place have been hypothesized. Recently, several studies have provided insight into the brain networks driving SCM through the characterization of memory engram cells, their biochemical and physiological changes and the circuits in which they operate. In this Review, we place these findings in the context of the field and describe how they have led to a revamped understanding of SCM in the brain.
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Encéfalo/fisiología , Consolidación de la Memoria/fisiología , Neuronas/fisiología , Animales , Hipocampo/fisiología , Humanos , Recuerdo Mental/fisiología , Modelos Neurológicos , Vías Nerviosas/fisiología , Corteza Prefrontal/fisiologíaRESUMEN
The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus.
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Hipocampo/fisiología , Locus Coeruleus/fisiología , Memoria/fisiología , Animales , Conducta Animal , Calcio/metabolismo , Giro Dentado , Masculino , Ratones , Vías Nerviosas/fisiología , Neuronas/fisiología , Lóbulo TemporalRESUMEN
Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.
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Amnesia Retrógrada/fisiopatología , Recuerdo Mental/fisiología , Neuronas/metabolismo , Optogenética/psicología , Animales , Conducta Animal , Espinas Dendríticas/patología , Espinas Dendríticas/fisiología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Aprendizaje , Masculino , Memoria a Largo Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Nucleares/metabolismo , Prótesis e Implantes , Columna Vertebral/patología , Sinapsis/metabolismoRESUMEN
Appropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.
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Conducta de Elección/fisiología , Núcleo Dorsal del Rafe/fisiología , Conducta Impulsiva/fisiología , Recompensa , Neuronas Serotoninérgicas/fisiología , Animales , Masculino , Ratones , Ratones Transgénicos , Factores de TiempoRESUMEN
Hippocampal replays have been demonstrated to play a crucial role in memory. Chains of ripples (ripple bursts) in CA1 have been reported to co-occur with long-range place cell sequence replays during the quiet awake state, but roles of neural inputs to CA1 in ripple bursts and replays are unknown. Here we show that ripple bursts in CA1 and medial entorhinal cortex (MEC) are temporally associated. An inhibition of MECIII input to CA1 during quiet awake reduced ripple bursts in CA1 and restricted the spatial coverage of replays to a shorter distance corresponding to single ripple events. The reduction did not occur with MECIII input inhibition during slow-wave sleep. Inhibition of CA3 activity suppressed ripples and replays in CA1 regardless of behavioral state. Thus, MECIII input to CA1 is crucial for ripple bursts and long-range replays specifically in quiet awake, whereas CA3 input is essential for both, regardless of behavioral state.