RESUMO
Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per â¼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.
Assuntos
Comportamento Animal/fisiologia , Cognição/fisiologia , Tomada de Decisões/fisiologia , Hipocampo/fisiologia , Potenciais de Ação/fisiologia , Animais , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Ratos , Ratos Long-Evans , Ritmo Teta/fisiologiaRESUMO
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
Assuntos
Mapeamento Cromossômico/métodos , Transtornos do Neurodesenvolvimento/genética , Biologia de Sistemas/métodos , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Neurobiologia/métodos , NeuropsiquiatriaRESUMO
The hippocampus is a mammalian brain structure that expresses spatial representations1 and is crucial for navigation2,3. Navigation, in turn, intricately depends on locomotion; however, current accounts suggest a dissociation between hippocampal spatial representations and the details of locomotor processes. Specifically, the hippocampus is thought to represent mainly higher-order cognitive and locomotor variables such as position, speed and direction of movement4-7, whereas the limb movements that propel the animal can be computed and represented primarily in subcortical circuits, including the spinal cord, brainstem and cerebellum8-11. Whether hippocampal representations are actually decoupled from the detailed structure of locomotor processes remains unknown. To address this question, here we simultaneously monitored hippocampal spatial representations and ongoing limb movements underlying locomotion at fast timescales. We found that the forelimb stepping cycle in freely behaving rats is rhythmic and peaks at around 8 Hz during movement, matching the approximately 8 Hz modulation of hippocampal activity and spatial representations during locomotion12. We also discovered precisely timed coordination between the time at which the forelimbs touch the ground ('plant' times of the stepping cycle) and the hippocampal representation of space. Notably, plant times coincide with hippocampal representations that are closest to the actual position of the nose of the rat, whereas between these plant times, the hippocampal representation progresses towards possible future locations. This synchronization was specifically detectable when rats approached spatial decisions. Together, our results reveal a profound and dynamic coordination on a timescale of tens of milliseconds between central cognitive representations and peripheral motor processes. This coordination engages and disengages rapidly in association with cognitive demands and is well suited to support rapid information exchange between cognitive and sensory-motor circuits.
Assuntos
Hipocampo , Locomoção , Navegação Espacial , Animais , Ratos , Membro Anterior/fisiologia , Hipocampo/fisiologia , Locomoção/fisiologia , Navegação Espacial/fisiologia , Tomada de Decisões , Fatores de Tempo , Cognição/fisiologia , Vias EferentesRESUMO
The receptive field of a neuron describes the regions of a stimulus space where the neuron is consistently active. Sparse spiking outside of the receptive field is often considered to be noise, rather than a reflection of information processing. Whether this characterization is accurate remains unclear. We therefore contrasted the sparse, temporally isolated spiking of hippocampal CA1 place cells to the consistent, temporally adjacent spiking seen within their spatial receptive fields ("place fields"). We found that isolated spikes, which occur during locomotion, are strongly phase coupled to hippocampal theta oscillations and transiently express coherent nonlocal spatial representations. Further, prefrontal cortical activity is coordinated with and can predict the occurrence of future isolated spiking events. Rather than local noise within the hippocampus, sparse, isolated place cell spiking reflects a coordinated cortical-hippocampal process consistent with the generation of nonlocal scenario representations during active navigation.
Assuntos
Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Navegação Espacial/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Eletrodos Implantados , Masculino , Ratos Long-Evans , Ritmo TetaRESUMO
Humans have the ability to store and retrieve memories with various degrees of specificity, and recent advances in reinforcement learning have identified benefits to learning when past experience is represented at different levels of temporal abstraction. How this flexibility might be implemented in the brain remains unclear. We analyzed the temporal organization of male rat hippocampal population spiking to identify potential substrates for temporally flexible representations. We examined activity both during locomotion and during memory-associated population events known as sharp-wave ripples (SWRs). We found that spiking during SWRs is rhythmically organized with higher event-to-event variability than spiking during locomotion-associated population events. Decoding analyses using clusterless methods further indicate that a similar spatial experience can be replayed in multiple SWRs, each time with a different rhythmic structure whose periodicity is sampled from a log-normal distribution. This variability increases with experience despite the decline in SWR rates that occurs as environments become more familiar. We hypothesize that the variability in temporal organization of hippocampal spiking provides a mechanism for storing experiences with various degrees of specificity.SIGNIFICANCE STATEMENT One of the most remarkable properties of memory is its flexibility: the brain can retrieve stored representations at varying levels of detail where, for example, we can begin with a memory of an entire extended event and then zoom in on a particular episode. The neural mechanisms that support this flexibility are not understood. Here we show that hippocampal sharp-wave ripples, which mark the times of memory replay and are important for memory storage, have a highly variable temporal structure that is well suited to support the storage of memories at different levels of detail.
Assuntos
Hipocampo , Aprendizagem , Animais , Masculino , RatosRESUMO
Various cognitive functions have long been known to require the hippocampus. Recently, progress has been made in identifying the hippocampal neural activity patterns that implement these functions. One such pattern is the sharp wave-ripple (SWR), an event associated with highly synchronous neural firing in the hippocampus and modulation of neural activity in distributed brain regions. Hippocampal spiking during SWRs can represent past or potential future experience, and SWR-related interventions can alter subsequent memory performance. These findings and others suggest that SWRs support both memory consolidation and memory retrieval for processes such as decision-making. In addition, studies have identified distinct types of SWR based on representational content, behavioural state and physiological features. These various findings regarding SWRs suggest that different SWR types correspond to different cognitive functions, such as retrieval and consolidation. Here, we introduce another possibility - that a single SWR may support more than one cognitive function. Taking into account classic psychological theories and recent molecular results that suggest that retrieval and consolidation share mechanisms, we propose that the SWR mediates the retrieval of stored representations that can be utilized immediately by downstream circuits in decision-making, planning, recollection and/or imagination while simultaneously initiating memory consolidation processes.
Assuntos
Ondas Encefálicas/fisiologia , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Animais , Humanos , Rede Nervosa/fisiologiaRESUMO
Measuring animal behavior in the context of experimental manipulation is critical for modeling, and understanding neuropsychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral phenomenon studied extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this phenomenon remains uncertain. Here, we deconstruct the phenomenon of PPI and confirm several limitations of the methodology traditionally utilized to describe PPI, including that the underlying startle response has a non-Gaussian distribution, and that the traditional PPI metric changes with different stimuli. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound processing. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared with wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In contrast, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.
Assuntos
Síndrome do Cromossomo X Frágil , Inibição Pré-Pulso , Estimulação Acústica , Acústica , Animais , Feminino , Masculino , Camundongos , Ratos , Reflexo de SobressaltoRESUMO
How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.
Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/fisiologia , Orientação/fisiologia , Sono/fisiologia , Percepção Espacial/fisiologia , Potenciais de Ação , Animais , Hipocampo/anatomia & histologia , Masculino , Modelos Neurológicos , Movimento , Ratos , Ratos Long-Evans , Memória Espacial/fisiologiaRESUMO
Animal behavior provides context for understanding disease models and physiology. However, that behavior is often characterized subjectively, creating opportunity for misinterpretation and misunderstanding. For example, spatial alternation tasks are treated as paradigmatic tools for examining memory; however, that link is actually an assumption. To test this assumption, we simulated a reinforcement learning (RL) agent equipped with a perfect memory process. We found that it learns a simple spatial alternation task more slowly and makes different errors than a group of male rats, illustrating that memory alone may not be sufficient to capture the behavior. We demonstrate that incorporating spatial biases permits rapid learning and enables the model to fit rodent behavior accurately. Our results suggest that even simple spatial alternation behaviors reflect multiple cognitive processes that need to be taken into account when studying animal behavior.SIGNIFICANCE STATEMENT Memory is a critical function for cognition whose impairment has significant clinical consequences. Experimental systems aimed at testing various sorts of memory are therefore also central. However, experimental designs to test memory are typically based on intuition about the underlying processes. We tested this using a popular behavioral paradigm: a spatial alternation task. Using behavioral modeling, we show that the straightforward intuition that these tasks just probe spatial memory fails to account for the speed at which rats learn or the types of errors they make. Only when memory-independent dynamic spatial preferences are added can the model learn like the rats. This highlights the importance of respecting the complexity of animal behavior to interpret neural function and validate disease models.
Assuntos
Modelos Neurológicos , Aprendizagem Espacial , Memória Espacial , Animais , Encéfalo/fisiologia , Intuição , Masculino , Ratos , Ratos Long-Evans , RecompensaRESUMO
The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.
Assuntos
Neurociências/métodos , Pesquisa , Tecnologia , HumanosRESUMO
Contemporary brain research seeks to understand how cognition is reducible to neural activity. Crucially, much of this effort is guided by a scientific paradigm that views neural activity as essentially driven by external stimuli. In contrast, recent perspectives argue that this paradigm is by itself inadequate and that understanding patterns of activity intrinsic to the brain is needed to explain cognition. Yet, despite this critique, the stimulus-driven paradigm still dominates-possibly because a convincing alternative has not been clear. Here, we review a series of findings suggesting such an alternative. These findings indicate that neural activity in the hippocampus occurs in one of three brain states that have radically different anatomical, physiological, representational, and behavioral correlates, together implying different functional roles in cognition. This three-state framework also indicates that neural representations in the hippocampus follow a surprising pattern of organization at the timescale of â¼1 s or longer. Lastly, beyond the hippocampus, recent breakthroughs indicate three parallel states in the cortex, suggesting shared principles and brain-wide organization of intrinsic neural activity.
Assuntos
Córtex Cerebral/fisiologia , Cognição/fisiologia , Hipocampo/fisiologia , Modelos Neurológicos , Animais , HumanosRESUMO
Hippocampal sharp-wave ripple (SWR) events occur during both behavior (awake SWRs) and slow-wave sleep (sleep SWRs). Awake and sleep SWRs both contribute to spatial learning and memory, thought to be mediated by the coordinated reactivation of behavioral experiences in hippocampal-cortical circuits seen during SWRs. Current hypotheses suggest that reactivation contributes to memory consolidation processes, but whether awake and sleep reactivation are suited to play similar or different roles remains unclear. Here we addressed that issue by examining the structure of hippocampal (area CA1) and prefrontal (PFC) activity recorded across behavior and sleep stages in male rats learning a spatial alternation task. We found a striking state difference: prefrontal modulation during awake and sleep SWRs was surprisingly distinct, with differing patterns of excitation and inhibition. CA1-PFC synchronization was stronger during awake SWRs, and spatial reactivation, measured using both pairwise and ensemble measures, was more structured for awake SWRs compared with post-task sleep SWRs. Stronger awake reactivation was observed despite the absence of coordination between network oscillations, namely hippocampal SWRs and cortical delta and spindle oscillations, which is prevalent during sleep. Finally, awake CA1-PFC reactivation was enhanced most prominently during initial learning in a novel environment, suggesting a key role in early learning. Our results demonstrate significant differences in awake and sleep reactivation in the hippocampal-prefrontal network. These findings suggest that awake SWRs support accurate memory storage and memory-guided behavior, whereas sleep SWR reactivation is better suited to support integration of memories across experiences during consolidation.SIGNIFICANCE STATEMENT Hippocampal sharp-wave ripples (SWRs) occur both in the awake state during behavior and in the sleep state after behavior. Awake and sleep SWRs are associated with memory reactivation and are important for learning, but their specific memory functions remain unclear. Here, we found profound differences in hippocampal-cortical reactivation during awake and sleep SWRs, with key implications for their roles in memory. Awake reactivation is a higher-fidelity representation of behavioral experiences, and is enhanced during early learning, without requiring coordination of network oscillations that is seen during sleep. Our findings suggest that awake reactivation is ideally suited to support initial memory formation, retrieval and planning, whereas sleep reactivation may play a broader role in integrating memories across experiences during consolidation.
Assuntos
Hipocampo/fisiologia , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Fases do Sono/fisiologia , Aprendizagem Espacial/fisiologia , Vigília/fisiologia , Animais , Masculino , Ratos , Ratos Long-EvansRESUMO
The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.
Assuntos
Comportamento Animal/fisiologia , Motivação/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Núcleos da Rafe/fisiologia , Natação/fisiologia , Potenciais de Ação , Animais , Axônios/fisiologia , Depressão/psicologia , Eletrofisiologia , Locomoção/fisiologia , Masculino , Optogenética , Ratos , Ratos Long-Evans , Sinapses/fisiologia , Fatores de TempoRESUMO
Sharp-wave ripple (SWR) events in the hippocampus replay millisecond-timescale patterns of place cell activity related to the past experience of an animal. Interrupting SWR events leads to learning and memory impairments, but how the specific patterns of place cell spiking seen during SWRs contribute to learning and memory remains unclear. A deeper understanding of this issue will require the ability to manipulate SWR events based on their content. Accurate real-time decoding of SWR replay events requires new algorithms that are able to estimate replay content and the associated uncertainty, along with software and hardware that can execute these algorithms for biological interventions on a millisecond timescale. Here we develop an efficient estimation algorithm to categorize the content of replay from multiunit spiking activity. Specifically, we apply real-time decoding methods to each SWR event and then compute the posterior probability of the replay feature. We illustrate this approach by classifying SWR events from data recorded in the hippocampus of a rat performing a spatial memory task into four categories: whether they represent outbound or inbound trajectories and whether the activity is replayed forward or backward in time. We show that our algorithm can classify the majority of SWR events in a recording epoch within 20 ms of the replay onset with high certainty, which makes the algorithm suitable for a real-time implementation with short latencies to incorporate into content-based feedback experiments.
Assuntos
Potenciais de Ação/fisiologia , Sistemas Computacionais , Hipocampo/fisiologia , Modelos Lineares , Algoritmos , Animais , Masculino , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
When making a decision it is often necessary to consider the available alternatives in order to choose the most appropriate option. This deliberative process, where the pros and cons of each option are considered, relies on memories of past actions and outcomes. The hippocampus and prefrontal cortex are required for memory encoding, memory retrieval and decision making, but it is unclear how these areas support deliberation. Here we examine the potential neural substrates of these processes in the rat. The rat is a powerful model to investigate the network mechanisms underlying deliberation in the mammalian brain given the anatomical and functional conservation of its hippocampus and prefrontal cortex to other mammalian systems. Importantly, it is amenable to large scale neural recording while performing laboratory tasks that exploit its natural decision-making behavior. Focusing on findings in the rat, we discuss how hippocampal-cortical interactions could provide a neural substrate for deliberative decision making.
Assuntos
Córtex Cerebral/fisiologia , Tomada de Decisões/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Animais , Vias Neurais/fisiologia , Ratos , Memória Espacial/fisiologia , Ritmo TetaRESUMO
Point process filters have been applied successfully to decode neural signals and track neural dynamics. Traditionally these methods assume that multiunit spiking activity has already been correctly spike-sorted. As a result, these methods are not appropriate for situations where sorting cannot be performed with high precision, such as real-time decoding for brain-computer interfaces. Because the unsupervised spike-sorting problem remains unsolved, we took an alternative approach that takes advantage of recent insights into clusterless decoding. Here we present a new point process decoding algorithm that does not require multiunit signals to be sorted into individual units. We use the theory of marked point processes to construct a function that characterizes the relationship between a covariate of interest (in this case, the location of a rat on a track) and features of the spike waveforms. In our example, we use tetrode recordings, and the marks represent a four-dimensional vector of the maximum amplitudes of the spike waveform on each of the four electrodes. In general, the marks may represent any features of the spike waveform. We then use Bayes's rule to estimate spatial location from hippocampal neural activity. We validate our approach with a simulation study and experimental data recorded in the hippocampus of a rat moving through a linear environment. Our decoding algorithm accurately reconstructs the rat's position from unsorted multiunit spiking activity. We then compare the quality of our decoding algorithm to that of a traditional spike-sorting and decoding algorithm. Our analyses show that the proposed decoding algorithm performs equivalent to or better than algorithms based on sorted single-unit activity. These results provide a path toward accurate real-time decoding of spiking patterns that could be used to carry out content-specific manipulations of population activity in hippocampus or elsewhere in the brain.
Assuntos
Potenciais de Ação , Algoritmos , Acrilatos , Animais , Teorema de Bayes , Região CA1 Hipocampal/fisiologia , Região CA2 Hipocampal/fisiologia , Simulação por Computador , Eletrofisiologia/instrumentação , Eletrofisiologia/métodos , Modelos Neurológicos , Atividade Motora/fisiologia , Neurônios/fisiologia , Éteres Fenílicos , Ratos Long-Evans , Processamento de Sinais Assistido por Computador , Percepção Espacial/fisiologiaRESUMO
Animals display an innate preference for novelty, spending more time exploring both novel objects and familiar objects in novel locations. This increase in exploration is thought to allow the animal to gather the information necessary to encode new experiences. Despite extensive evidence that increased exploration following spatial change requires the hippocampus, the pattern of hippocampal activity that supports this behavior remains unknown. We examined activity in hippocampal output area CA1 and one synapse upstream in area CA3 while freely behaving rats performed an object-place recognition task. We found that the presence of novelty substantially altered activity in CA1, but not in CA3. During exploration of displaced familiar objects and novel objects in unexpected locations, CA1 place cells showed robust increases in firing rate. These firing rate increases persisted during sharp wave ripples, when place cell representations of previous experiences are replayed. Unexpectedly, increases in CA1 activity were not spatially restricted to regions of the environment that underwent change, indicating a generalized novelty signal. We suggest that hippocampal area CA1 broadcasts the presence of novelty, rather than signaling what is novel, and simultaneously becomes more plastic, allowing the integration of new information into previously stored memories.
Assuntos
Região CA1 Hipocampal/fisiologia , Comportamento Exploratório/fisiologia , Reconhecimento Psicológico/fisiologia , Potenciais de Ação , Animais , Região CA3 Hipocampal/fisiologia , Masculino , Ratos , Ratos Long-Evans , Memória Espacial/fisiologiaRESUMO
Hippocampal replay - the time-compressed, sequential reactivation of ensembles of neurons related to past experience - is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.
Assuntos
Hipocampo , Neurorretroalimentação , Animais , Ratos , Hipocampo/fisiologia , Masculino , Consolidação da Memória/fisiologia , Memória/fisiologia , Neurônios/fisiologiaRESUMO
The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.
RESUMO
Humans can remember specific events without acting on them and can influence which memories are retrieved based on internal goals. However, current animal models of memory typically present sensory cues to trigger retrieval and assess retrieval based on action 1-5 . As a result, it is difficult to determine whether measured patterns of neural activity relate to the cue(s), the retrieved memory, or the behavior. We therefore asked whether we could develop a paradigm to isolate retrieval-related neural activity in animals without retrieval cues or the requirement of a behavioral report. To do this, we focused on hippocampal "place cells." These cells primarily emit spiking patterns that represent the animal's current location (local representations), but they can also generate representations of previously visited locations distant from the animal's current location (remote representations) 6-13 . It is not known whether animals can deliberately engage specific remote representations, and if so, whether this engagement would occur during specific brain states. So, we used a closed-loop neurofeedback system to reward expression of remote representations that corresponded to uncued, experimenter-selected locations, and found that rats could increase the prevalence of these specific remote representations over time; thus, demonstrating memory retrieval modulated by internal goals in an animal model. These representations occurred predominately during periods of immobility but outside of hippocampal sharp-wave ripple (SWR) 13-15 events. This paradigm enables future direct studies of memory retrieval mechanisms in the healthy brain and in models of neurological disorders.