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Memory formation is thought to occur in the brain through dynamic remodeling of the synaptic architecture between neurons. The cellular mechanisms underlying these dynamics remain unclear. In this issue, Nguyen et al. demonstrate a novel role for microglia in regulating synaptic formation by clearing extracellular matrix proteins that embed neurons.
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Microglía , Plasticidad Neuronal , Matriz Extracelular , Neuronas , SinapsisRESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD.SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.
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Enfermedad de Alzheimer , Animales , Masculino , Femenino , Ratones , Enfermedad de Alzheimer/metabolismo , Corteza Entorrinal/patología , Neuronas/fisiología , Hipocampo/patología , Modelos Animales de Enfermedad , Trastornos de la Memoria/patología , Ratones TransgénicosRESUMEN
Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time. According to the memory allocation hypothesis, learning triggers a temporary increase in neuronal excitability that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information.
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Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Memoria/fisiología , Neuronas/fisiología , Animales , Calcio/análisis , Miedo , Masculino , Recuerdo Mental/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Factores de TiempoRESUMEN
Memory is a dynamic process that is continuously regulated by both synaptic and intrinsic neural mechanisms. While numerous studies have shown that synaptic plasticity is important in various types and phases of learning and memory, neuronal intrinsic excitability has received relatively less attention, especially regarding the dynamic nature of memory. In this review, we present evidence demonstrating the importance of intrinsic excitability in memory allocation, consolidation, and updating. We also consider the intricate interaction between intrinsic excitability and synaptic plasticity in shaping memory, supporting both memory stability and flexibility.
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Encéfalo/fisiología , Consolidación de la Memoria/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Animales , Aprendizaje/fisiologíaAsunto(s)
Betacoronavirus , Infecciones por Coronavirus , Laboratorios , Pandemias , Neumonía Viral , Cuarentena , Investigación , Adaptación Psicológica , Actitud , COVID-19 , Movilidad Laboral , Educación a Distancia , Predicción , Humanos , Relaciones Interpersonales , Laboratorios/tendencias , Investigación/tendencias , Investigadores/psicología , Reinserción al Trabajo , SARS-CoV-2 , Estrés Psicológico/psicología , Comunicación por Videoconferencia , Equilibrio entre Vida Personal y LaboralRESUMEN
There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose an integrated view of these processes, such that neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity reflect related aspects of memory allocation mechanisms. Importantly, the properties of these mechanisms suggest a set of rules that profoundly affect how memories are stored and recalled.
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Hipocampo/fisiología , Memoria/fisiología , Modelos Neurológicos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Animales , Espinas Dendríticas/fisiología , Humanos , Red Nerviosa/fisiologíaRESUMEN
Representational drift refers to the dynamic nature of neural representations in the brain despite the behavior being seemingly stable. Although drift has been observed in many different brain regions, the mechanisms underlying it are not known. Since intrinsic neural excitability is suggested to play a key role in regulating memory allocation, fluctuations of excitability could bias the reactivation of previously stored memory ensembles and therefore act as a motor for drift. Here, we propose a rate-based plastic recurrent neural network with slow fluctuations of intrinsic excitability. We first show that subsequent reactivations of a neural ensemble can lead to drift of this ensemble. The model predicts that drift is induced by co-activation of previously active neurons along with neurons with high excitability which leads to remodeling of the recurrent weights. Consistent with previous experimental works, the drifting ensemble is informative about its temporal history. Crucially, we show that the gradual nature of the drift is necessary for decoding temporal information from the activity of the ensemble. Finally, we show that the memory is preserved and can be decoded by an output neuron having plastic synapses with the main region.
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Modelos Neurológicos , Plasticidad Neuronal , Neuronas , Neuronas/fisiología , Plasticidad Neuronal/fisiología , Memoria/fisiología , Encéfalo/fisiología , Red Nerviosa/fisiología , Animales , Humanos , Potenciales de Acción/fisiologíaRESUMEN
BACKGROUND: Economic stress can serve as a second hit for people who have already accumulated a history of adverse life experiences. How one recovers from a setback is a core feature of resilience but is seldom captured in animal studies. METHODS: We challenged mice in a novel 2-hit stress model by first exposing them to chronic social defeat stress and then testing adaptations to increasing reward scarcity on a neuroeconomic task. Mice were tested across months on the Restaurant Row task, during which they foraged daily for their primary source of food while on a limited time budget in a closed-economy system. An abrupt transition into a reward-scarce environment elicits an economic challenge, precipitating a drop in food intake and body weight to which mice must respond to survive. RESULTS: We found that mice with a history of social stress mounted a robust behavioral response to this economic challenge that was achieved through a complex redistribution of time allocation among competing opportunities. Interestingly, we found that mice with a history of social defeat displayed changes in the development of decision-making policies during the recovery process that are important not only for ensuring food security necessary for survival but also prioritizing subjective value and that these changes emerged only for certain types of choices. CONCLUSIONS: These findings indicate that an individual's capacity to recover from economic challenges depends on that person's prior history of stress and can affect multiple decision-making aspects of subjective well-being, thus highlighting a motivational balance that may be altered in stress-related disorders such as depression.
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Toma de Decisiones , Ratones Endogámicos C57BL , Recompensa , Estrés Psicológico , Animales , Toma de Decisiones/fisiología , Masculino , Ratones , Ingestión de Alimentos/psicología , Derrota Social , Peso Corporal , Modelos Animales de EnfermedadRESUMEN
Miniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors into a single Miniscope. To validate our dual-channel Miniscope, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (tdTomato) while mice ran on a linear track. Our results suggest that, even when neurons were registered across days using tdTomato signals, hippocampal spatial coding changes over time. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities. Teaser: Novel open-source dual-channel Miniscope that simultaneously records two wavelengths with minimal crosstalk in freely behaving animals.
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At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence. D1 MSN responses were evoked by stimuli regardless of valence or contingency. D2 MSNs were evoked by both cues and outcomes, were dynamically changed with learning, and tracked valence-free prediction error at the population and individual neuron level. Finally, D2 MSN responses to cues were necessary for associative learning. Thus, D1 and D2 MSNs work in tandem, rather than in opposition, by signaling specific properties of stimuli to control learning.
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Neuronas Espinosas Medianas , Receptores de Dopamina D1 , Ratones , Animales , Ratones Transgénicos , Receptores de Dopamina D1/metabolismo , Núcleo Accumbens/fisiología , Neuronas/fisiología , Ratones Endogámicos C57BLRESUMEN
Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.
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With the prevalence of age-related cognitive deficits on the rise, it is essential to identify cellular and circuit alterations that contribute to age-related memory impairment. Increased intrinsic neuronal excitability after learning is important for memory consolidation, and changes to this process could underlie memory impairment in old age. Some studies find age-related deficits in hippocampal neuronal excitability that correlate with memory impairment but others do not, possibly due to selective changes only in activated neural ensembles. Thus, we tagged CA1 neurons activated during learning and recorded their intrinsic excitability 5 hours or 7 days post-training. Adult mice exhibited increased neuronal excitability 5 hours after learning, specifically in ensemble (learning-activated) CA1 neurons. As expected, ensemble excitability returned to baseline 7 days post-training. In aged mice, there was no ensemble-specific excitability increase after learning, which was associated with impaired hippocampal memory performance. These results suggest that CA1 may be susceptible to age-related impairments in post-learning ensemble excitability and underscore the need to selectively measure ensemble-specific changes in the brain.
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Aprendizaje , Neuronas , Ratones , Animales , Neuronas/fisiología , Aprendizaje/fisiología , Hipocampo/fisiología , Encéfalo , Trastornos de la MemoriaRESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in the hippocampus, but less is known about what happens in the medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured the neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at early (3 months) and late (10 months) time points in the 3xTg mouse model of AD pathology. At 3 months of age, prior to the onset of memory impairments, we found early hyperexcitability in MECII stellate and pyramidal cells' intrinsic properties, but this was balanced by a relative reduction in synaptic excitation (E) compared to inhibition (I), suggesting intact homeostatic mechanisms regulating activity in MECII. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in the synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsically and synaptically generated excitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this post-symptomatic time point. Together, these data suggest that the breakdown in homeostatic excitability mechanisms in MECII stellate cells may contribute to the emergence of memory deficits in AD.
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Severe stress can produce multiple persistent changes in defensive behavior. While much is known about the circuits supporting stress-induced associative fear responses, how circuit plasticity supports the broader changes in defensive behavior observed after severe stress remains unclear. Here, we find that stress-induced plasticity in the ventral hippocampus (vHC) and basolateral amygdala (BLA) support doubly dissociable defensive behavioral changes. Stress-induced protein synthesis in the BLA was found to support lasting enhancements in stress sensitivity but not enhancements in exploratory anxiety-related behaviors, whereas protein synthesis in the vHC was found to support enhancements in anxiety-related behavior but not enhancements in stress sensitivity. Like protein synthesis, neuronal activity of the BLA and vHC were found to differentially support the expression of these same defensive behaviors. Lastly, blockade of associative fear had no impact on stress-induced changes in anxiety-related behavior. These findings highlight that multiple memory-systems support stress-induced defensive behavior changes.
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A core necessity to behavioral neuroscience research is the ability to accurately measure performance on behavioral assays, such as the novel object location and novel object recognition tasks. These tasks are widely used in neuroscience research and measure a rodent's instinct for investigating novel features as a proxy to test their memory of a previous experience. Automated tools for scoring behavioral videos can be cost prohibitive and often have difficulty distinguishing between active investigation of an object and simply being in close proximity to an object. As such, many experimenters continue to rely on hand scoring interactions using stopwatches, which makes it difficult to review scoring after-the-fact and results in the loss of temporal information. Here, we introduce Chronotate, a free, open-source tool to aid in manually scoring novel object behavior videos. The software consists of an interactive video player with keyboard integration for marking timestamps of behavioral events during video playback, making it simple to quickly score and review bouts of rodent-object interaction. In addition, Chronotate outputs detailed interaction bout data, allowing for nuanced behavioral performance analyses. Using this detailed temporal information, we demonstrate that novel object location performance peaks within the first 3 s of interaction time and preference for the novel location becomes reduced across the test session. Thus, Chronotate can be used to determine the temporal structure of interactions on this task and can provide new insight into the memory processes that drive this behavior. Chronotate is available for download at: https://github.com/ShumanLab/Chronotate.
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Memoria , Reconocimiento en Psicología , Animales , Conducta Animal , Percepción VisualRESUMEN
Memories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, linking the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory-linking through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.
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The hypothesized role of rapid eye movement (REM) sleep, which is rich in dreams, in the formation of new associations, has remained anecdotal. We examined the role of REM on creative problem solving, with the Remote Associates Test (RAT). Using a nap paradigm, we manipulated various conditions of prior exposure to elements of a creative problem. Compared with quiet rest and non-REM sleep, REM enhanced the formation of associative networks and the integration of unassociated information. Furthermore, these REM sleep benefits were not the result of an improved memory for the primed items. This study shows that compared with quiet rest and non-REM sleep, REM enhances the integration of unassociated information for creative problem solving, a process, we hypothesize, that is facilitated by cholinergic and noradrenergic neuromodulation during REM sleep.
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Asociación , Creatividad , Solución de Problemas , Sueño REM , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Miniature microscopes have gained considerable traction for in vivo calcium imaging in freely behaving animals. However, extracting calcium signals from raw videos is a computationally complex problem and remains a bottleneck for many researchers utilizing single-photon in vivo calcium imaging. Despite the existence of many powerful analysis packages designed to detect and extract calcium dynamics, most have either key parameters that are hard-coded or insufficient step-by-step guidance and validations to help the users choose the best parameters. This makes it difficult to know whether the output is reliable and meets the assumptions necessary for proper analysis. Moreover, large memory demand is often a constraint for setting up these pipelines since it limits the choice of hardware to specialized computers. Given these difficulties, there is a need for a low memory demand, user-friendly tool offering interactive visualizations of how altering parameters at each step of the analysis affects data output. Our open-source analysis pipeline, Minian (miniscope analysis), facilitates the transparency and accessibility of single-photon calcium imaging analysis, permitting users with little computational experience to extract the location of cells and their corresponding calcium traces and deconvolved neural activities. Minian contains interactive visualization tools for every step of the analysis, as well as detailed documentation and tips on parameter exploration. Furthermore, Minian has relatively small memory demands and can be run on a laptop, making it available to labs that do not have access to specialized computational hardware. Minian has been validated to reliably and robustly extract calcium events across different brain regions and from different cell types. In practice, Minian provides an open-source calcium imaging analysis pipeline with user-friendly interactive visualizations to explore parameters and validate results.
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Encéfalo , Calcio , Animales , Encéfalo/metabolismo , Calcio/metabolismo , Procesamiento de Imagen Asistido por Computador , Microscopía , Fotones , Programas InformáticosRESUMEN
In the century since the notion of the 'engram' was first introduced to describe the physical manifestation of memory, new technologies for identifying cellular activity have enabled us to deepen our understanding of the possible physical substrate of memory. A number of studies have shown that memories are stored in a sparse population of neurons known as a neural ensemble or engram cells. While earlier investigations highlighted that the stability of neural ensembles underlies a memory representation, recent studies have found that neural ensembles are more dynamic and fluid than previously understood. Additionally, a number of studies have begun to dissect the cellular and molecular diversity of functionally distinct subpopulations of cells contained within an engram. We propose that ensemble fluidity and compositional heterogeneity support memory flexibility and functional diversity.
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Memoria , NeuronasRESUMEN
Tracking animal behavior by video is one of the most common tasks in neuroscience. Previously, we have validated ezTrack, a free, flexible, and easy-to-use software for the analysis of animal behavior. ezTrack's Location Tracking Module can be used for the positional analysis of an individual animal and is applicable to a wide range of behavioral tasks. Separately, ezTrack's Freeze Analysis Module is designed for the analysis of defensive freezing behavior. ezTrack supports a range of desirable tools, including options for cropping and masking portions of the field of view, defining regions of interest, producing summary data for specified portions of time, algorithms to remove the influence of electrophysiology cables and other tethers, batch processing of multiple videos, and video down-sampling. Moreover, ezTrack produces a range of interactive plots and visualizations to promote users' confidence in their results. In this protocols paper, we provide step-by-step instructions for the use of ezTrack, from tips for recording behavior to instructions for using the software for video analysis. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Software environment installation Basic Protocol 2: Using the Location Tracking Module Basic Protocol 3: Using the Freeze Analysis Module.