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Increased Attention to Spatial Context Increases Both Place Field Stability and Spatial Memory
Abstract
The hippocampal formation is critical for the acquisition and consolidation of memories. When recorded in freely moving animals, hippocampal pyramidal neurons fire in a location-specific manner: they are "place" cells, comprising a hippocampal representation of the animal's environment. To explore the relationship between place cells and spatial memory, we recorded from mice in several behavioral contexts. We found that long-term stability of place cell firing fields correlates with the degree of attentional demands and that successful spatial task performance was associated with stable place fields. Furthermore, conditions that maximize place field stability greatly increase orientation to novel cues. This suggests that storage and retrieval of place cells is modulated by a top-down cognitive process resembling attention and that place cells are neural correlates of spatial memory. We propose a model whereby attention provides the requisite neuromodulatation to switch short-term homosynaptic plasticity to long-term heterosynaptic plasticity, and we implicate dopamine in this process.
... Not all memories are created equal. Changes in the internal state of the animal have been suggested as an important contributor to drift (Hulse et al., 2017;Kentros et al., 2004;Niell & Stryker, 2010;Sadeh & Clopath, 2022;Vinck et al., 2015). Internal states, such as the expectation of a reward, influence memory formation and retrieval (Krishnan et al., 2022;Schultz et al., 1997). ...
... One of the known roles for hippocampal dopamine is in regulating synaptic transmission and dendritic excitability (Edelmann & Lessmann, 2018;Hansen & Manahan-Vaughan, 2014;Huang & Kandel, 1995;Lisman & Grace, 2005;Tritsch & Sabatini, 2012;Wiescholleck & Manahan-Vaughan, 2014), and high dendritic excitability is associated with higher reliability and long-term stability of place cells (Sheffield et al., 2017;Sheffield & Dombeck, 2015, 2018. Studies have also demonstrated that a decrease in dopamine leads to a reduction in across-day stability of place cells and increased drift (Kentros et al., 2004;Mamad et al., 2017;Martig & Mizumori, 2011;McNamara et al., 2014). Therefore, reduction of dopamine released in the hippocampus from the VTA with lowered reward expectation likely contributes to the observed reduction in lap-to-lap reliability and subsequent instability of place fields across days. ...
Spatial memory in the hippocampus involves dynamic neural patterns that change over days, termed representational drift. While drift may aid memory updating, excessive drift could impede retrieval. Memory retrieval is influenced by reward expectation during encoding, so we hypothesized that diminished reward expectation would exacerbate representational drift. We found that high reward expectation limited drift, with CA1 representations on one day gradually re-emerging over successive trials the following day. Conversely, the absence of reward expectation resulted in increased drift, as the gradual re-emergence of the previous day's representation did not occur. At the single cell level, lowering reward expectation caused an immediate increase in the proportion of place-fields with low trial-to-trial reliability. These place fields were less likely to be reinstated the following day, underlying increased drift in this condition. In conclusion, heightened reward expectation improves memory encoding and retrieval by maintaining reliable place fields that are gradually reinstated across days, thereby minimizing representational drift.
... Catecholamines have a well established role in hippocampal function. Both dopamine and norepinephrine have been shown to impact hippocampal dependent learning and memory [1,2,3,4,5,6,7], alter synaptic plasticity [8,4,9,10,11,12], modulate cell excitability [13,14], and influence the formation and stability of place cells [15,2], hippocampal neurons that selectively fire at specific locations in an environment [16]. Traditionally, the main source of dopamine to the dorsal hippocampus was thought to be sparse inputs from the ventral tegmental area (VTA), while locus coerulues (LC) inputs provided the main source of norepinphrine. ...
... It has been shown that attention and arousal levels impact tuning properties in many cortical areas and this is thought to be mediated through LC activity [55,56,57,58]. Similarly, changes in the animals' brain state, including changes in attention [15] and engagement [59], alter the tuning properties of place cells. This indicates arousal could impact the function of hippocampal neurons through these LC inputs. ...
Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impact of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized 2-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animal's running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, likely contributing to differential modulation of hippocampal activity during behavior and learning.
... Relatedly, multiple lines of evidence have linked the spatially correlated neuronal activity in the hippocampal formation to dopaminergic signaling. For instance, dopaminergic transmission was found to affect both the stability (Kentros et al., 2004) and the flexibility of place cell firing (Tran et al., 2008) as well as the reorganization of place cell activity during the learning of new reward locations or spatial rules (Kaufman et al., 2020, Retailleau andMorris, 2018). ...
... First, a prominent line of research has linked dopaminergic signaling to attention to visuospatial cues as a means to stabilize both hippocampal place representations and spatial memory (Kempadoo et al., 2016, Kentros et al., 2004; for review, see (Muzzio et al., 2009). By this account, our observation of impaired performance in object-location memory could be interpreted as reflecting deficits in attending to distal cues and boundaries which provide location information. ...
Accumulated evidence from animal studies suggests a role for the neuromodulator dopamine in memory processes, particularly under conditions of novelty or reward. Our understanding of how dopaminergic modulation impacts spatial representations and spatial memory in humans remains limited. Recent evidence suggests age-specific regulation effects of dopamine pharmacology on activity in the medial temporal lobe, a key region for spatial memory. To which degree this modulation affects spatially patterned medial temporal representations
remains unclear. We reanalyzed recent data from a pharmacological dopamine challenge during functional brain imaging combined with a virtual object-location memory paradigm to assess the effect of Levodopa, a dopamine
precursor, on grid-like activity in the entorhinal cortex. We found that Levodopa impaired grid cell-like representations in a sample of young adults (n=55, age=26 to 35 years) in a novel environment, accompanied by reduced spatial
memory performance. We observed no such impairment when Levodopa was delivered to participants which had prior experience with the task. These results are consistent with a role of dopamine in modulating the encoding of novel spatial experiences. Our results suggest that dopamine signaling may play a larger role in shaping ongoing spatial representations than previously thought.
... Relatedly, multiple lines of evidence have linked the spatially correlated neuronal activity in the hippocampal formation to dopaminergic signaling. For instance, dopaminergic transmission was found to affect both the stability (Kentros et al. 2004) and the f lexibility of place cell firing (Tran et al. 2008) as well as the reorganization of place cell activity during the learning of new reward locations or spatial rules (Retailleau and Morris 2018;Kaufman et al. 2020). ...
... First, a prominent line of research has linked dopaminergic signaling to attention to visuospatial cues as a means to stabilize both hippocampal place representations and spatial memory (Kempadoo et al. 2016, Kentros et al. 2004; for a review, see Muzzio et al. 2009). By this account, our observation of impaired performance in object-location memory could be interpreted as ref lecting deficits in attending to distal cues and boundaries that provide location information. ...
Accumulated evidence from animal studies suggests a role for the neuromodulator dopamine in memory processes, particularly under conditions of novelty or reward. Our understanding of how dopaminergic modulation impacts spatial representations and spatial memory in humans remains limited. Recent evidence suggests age-specific regulation effects of dopamine pharmacology on activity in the medial temporal lobe, a key region for spatial memory. To which degree this modulation affects spatially patterned medial temporal representations remains unclear. We reanalyzed recent data from a pharmacological dopamine challenge during functional brain imaging combined with a virtual object-location memory paradigm to assess the effect of Levodopa, a dopamine precursor, on grid-like activity in the entorhinal cortex. We found that Levodopa impaired grid cell-like representations in a sample of young adults (n = 55, age = 26–35 years) in a novel environment, accompanied by reduced spatial memory performance. We observed no such impairment when Levodopa was delivered to participants who had prior experience with the task. These results are consistent with a role of dopamine in modulating the encoding of novel spatial experiences. Our results suggest that dopamine signaling may play a larger role in shaping ongoing spatial representations than previously thought.
... Representational instability has been observed in many sensory 1-8 and motor 10,11,47,48 cortices, as well as hippocampus 12,[49][50][51] . Under some conditions, however, sensory cortical 52-54 , motor cortical [55][56][57] , and hippocampal 58 representations can be stable for extended periods at the single neuron level. ...
... Under some conditions, however, sensory cortical 52-54 , motor cortical [55][56][57] , and hippocampal 58 representations can be stable for extended periods at the single neuron level. Factors that contribute to greater response stability include extended periods of task training 6,41,59 , task engagement 49,50,60 , and artificial versus naturalistic stimuli 3 . We observe representational instability in the context of direct cortical stimulation, even in highly trained animals engaged in the task. ...
Sensory cortical representations can be highly dynamic, raising the question of how representational stability impacts learning. We train mice to discriminate the number of photostimulation pulses delivered to opsin-expressing pyramidal neurons in layer 2/3 of primary vibrissal somatosensory cortex. We simultaneously track evoked neural activity across learning using volumetric two-photon calcium imaging. In well-trained animals, trial-to-trial fluctuations in the amount of photostimulus-evoked activity predicted animal choice. Population activity levels declined rapidly across training, with the most active neurons showing the largest declines in responsiveness. Mice learned at varied rates, with some failing to learn the task in the time provided. The photoresponsive population showed greater instability both within and across behavioral sessions among animals that failed to learn. Animals that failed to learn also exhibited a faster deterioration in stimulus decoding. Thus, greater stability in the stimulus response is associated with learning in a sensory cortical microstimulation task.
... Of note, the persistence of environment-specific representations in the hippocampus suggests that the animals did not ignore environmental cues when generalizing task knowledge, as it has been shown that inattentiveness to environmental cues changes spatial coding and reduces hippocampal place-field stability. 40,41 Since the environments shared both the same rules (i.e., remembering correct task sequences) and the same reward configuration, we examined the degree of generalization attributed to coding of reward expectation and task sequences. Previous studies have shown that firing rates of some hippocampal [42][43][44] and prefrontal 45,46 neurons ramp up as the animal moves toward the reward, representing relative proximity of goals and thus reflecting reward expectation. ...
... This idea echoes previous studies, which found that cognitive demands and behavioral engagement can profoundly change hippocampal and prefrontal spatial representations. 29,40,41,[66][67][68] Given that the hippocampus provides a major input to PFC 69,70 and that hippocampal lesions impair the PFC spatial code, 61 we postulate that the spatial responses in PFC may be passively invoked by hippocampal input when not actively engaged in the behavior, such as during spontaneous locomotion, whereas specific task requirements may necessitate further neural computations of generalizable task knowledge in PFC. ...
The ability to abstract information to guide decisions during navigation across changing environments is essential for adaptation and requires the integrity of the hippocampal-prefrontal circuitry. The hippocampus encodes navigational information in a cognitive map, but it remains unclear how cognitive maps are transformed across hippocampal-prefrontal circuits to support abstraction and generalization. Here, we simultaneously record hippocampal-prefrontal ensembles as rats generalize navigational rules across distinct environments. We find that, whereas hippocampal representational maps maintain specificity of separate environments, prefrontal maps generalize across environments. Furthermore, while both maps are structured within a neural manifold of population activity, they have distinct representational geometries. Prefrontal geometry enables abstraction of rule-informative variables, a representational format that generalizes to novel conditions of existing variable classes. Hippocampal geometry lacks such abstraction. Together, these findings elucidate how cognitive maps are structured into distinct geometric representations to support abstraction and generalization while maintaining memory specificity.
... Given that anatomical evidence indicates the presence of D1 and D5 receptors in the hippocampus (Savasta et al., 1986;Wamsley et al., 1992) and the anatomical tracing studies highlighted in the previous section, how does dopaminergic transmission in the hippocampus influence information processing in the hippocampus? Early studies of intact synapses from brain slices provided evidence that D1-type receptors facilitate long-term potentiation (LTP) in the CA1 via activation of protein kinase A (PKA; Huang et al., 1995;Kentros et al., 2004;Muzzio et al., 2009). Because D1/D5 receptors are positively coupled to cAMP-PKA, drugs that enhanced this pathway attenuated age-related deficits in memory and LTP (Bach et al., 1999). ...
... PKA was also shown to be involved in maintaining the stability of place fields in the CA1. Blockade of PKA had the same effect as blockade of protein synthesis: i.e., it impairs the long-term stability of hippocampal place fields (Rotenberg et al., 2000;Agnihotri et al., 2004;Kentros et al., 2004) and also the ability to retain long-term memories. ...
The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.
... Fenton et al. showed that overdispersion of place fields reduced when rats were required to focus on a subset of stimuli in a spatial task (such as selectively using distal features for navigation) (Fenton, et al., 2010). Kentros and colleagues analyzed place field stability in mice and suggested that long-term stability of place fields depend on the behavioral relevance of the spatial context, and attention-like cognitive processes play a role in establishing this link (Kentros, Agnihotri, Streater, Hawkins, & Kandel, 2004;Muzzio, Kentros, & Kandel, 2009). More recently, and in line with the above observations, Scaplen et al. showed that visual cues were processed differently in the hippocampus based on their relevance as navigational landmarks or as context (Scaplen, Gulati, Heimer-McGinn, & Burwell, 2014). ...
... Such a mechanism can be enhanced by the above attentional effects, where certain features of the environment can be selected to drive spatial representations, while others are ignored or suppressed. This idea is consistent with recent observations that spatially relevant objects are processed differently than non-relevant objects (Scaplen, Gulati, Heimer-McGinn, & Burwell, 2014), as well as reports of attentional modulation of hippocampal representations discussed earlier (Fenton, et al., 2010;Kentros, Agnihotri, Streater, Hawkins, & Kandel, 2004;Muzzio, Kentros, & Kandel, 2009). However, attention-based encoding of place memories does not completely solve the stability problem. ...
Animals use sensory information and memory to build internal representations of space. It has been shown that such representations extend beyond the geometry of an environment and also encode rich sensory experiences usually referred to as context. In mammals, contextual inputs from sensory cortices appear to be converging on the hippocampus as a key area for spatial representations and memory. How metric and external sensory inputs (e.g., visual context) are combined into a coherent and stable place representation is not fully understood. Here, I review the evidence of attentional effects along the ventral visual pathway and in the medial temporal lobe and propose an attention-based model for the integration of visual context in spatial representations. I further suggest that attention-based retrieval of spatial memories supports a feedback mechanism that allows consolidation of old memories and new sensory experiences related to the same place, thereby contributing to the stability of spatial representations. The resulting model has the potential to generate new hypotheses to explain complex responses of spatial cells such as place cells in the hippocampus.
... processing, dopamine release in hippocampus has been implicated in stabilizing place 60 fields (Kentros et al., 2004), gating the increase in plasticity in dorsal CA1 synapses by 61 novel experiences (Li et al., 2003), and improving memory retention via increasing 62 ...
Sequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain's reward or novelty signals is unknown. Here we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error, indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent reward prediction error signal that is reliable only in familiar environments.
... This finding was unexpected in light of evidence that the stability of place cells is important for memory maintenance. 83,84 Previous experiments, however, showed that hippocampal cells expressing the early gene c-fos, a prominent genetic marker of neural activity associated with memory formation, 85 are more unstable than other neurons. 86 More recent findings have reinforced the idea that instability of place cells is important for memory updating, particularly upon spatial changes as those taking place in the OPR task. ...
... Such remapping in MEC grid cells is likely complemented by place cells 31 and goal-vector cells 32,33 in the reciprocally connected HPC, which can also exhibit context-dependent remapping. [34][35][36] Collectively, this network of functional cell types across MEC and HPC may provide the necessary neural substrates for an animal to navigate to goals in novel and familiar environments. ...
Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial firing stability. These genes were enriched among interneurons and related to synaptic transmission. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.
... Multiple lines of evidence demonstrate that the hippocampus also prioritizes coding for aspects of experience that are particularly salient or that can affect the animal's behavior 27,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][57][58][59][60][61][62][63][64][65] . The presence of food or water reward is one such highly salient event that is consistently prioritized, as demonstrated by prior work finding that place cells tend to cluster near (i.e. ...
Hippocampal place cells fire in sequences that span spatial environments, and remap, or change their preferred firing locations, across different environments. This sequential firing is common to multiple modalities beyond space, suggesting that hippocampal activity can anchor to the most behaviorally relevant or salient aspects of experience. As reward is a highly salient event, we hypothesized that broad sequences of hippocampal activity can likewise become anchored relative to reward. To test this hypothesis, we performed two-photon imaging of calcium activity in hippocampal area CA1 as mice navigated virtual linear environments with multiple changing hidden reward locations. We found that when the reward moved, a subpopulation of cells remapped to the same relative position with respect to reward, including previously undescribed cells with fields distant from reward. These reward-relative cells constructed sequences that spanned the task structure irrespective of spatial stimuli. The density of the reward-relative sequences increased with task experience as additional neurons were recruited to the reward-relative population. In contrast, a largely separate subpopulation of cells maintained a place code relative to the spatial environment. These findings provide insight into how separate hippocampal ensembles may flexibly encode multiple behaviorally salient reference frames, reflecting the structure of the experience.
... Populations of cortical neurons representing specific sensory 1-4 , cognitive [5][6][7][8] , or motor 9 features exhibit a baseline level of change even in the context of behavioral stability. This 'representational drift' typically involves changing responses of individual neurons as well as the addition and removal of neurons to and from the responsive population 10 . ...
Cortical populations often exhibit changes in activity even when behavior is stable. How behavioral stability is maintained in the face of such ‘representational drift’ remains unclear. One possibility is that some neurons are stable despite broader instability. We examine whisker touch responses in superficial layers of primary vibrissal somatosensory cortex (vS1) over several weeks in mice stably performing an object detection task with two whiskers. While the number of touch neurons remained constant, individual neurons changed with time. Touch-responsive neurons with broad receptive fields were more stable than narrowly tuned neurons. Transitions between functional types were non-random: before becoming broadly tuned neurons, unresponsive neurons first pass through a period of narrower tuning. Broadly tuned neurons with higher pairwise correlations to other touch neurons were more stable than neurons with lower correlations. Thus, a small population of broadly tuned and synchronously active touch neurons exhibit elevated stability and may be particularly important for downstream readout.
... Representational drift is the gradual weakening and shifting of stimulus-responsive cells ( Fig. 2; Driscoll, Duncker, & Harvey, 2022;Rule, O'Leary, & Harvey, 2019). Drift, a type of functional neural plasticity, had previously been demonstrated in the hippocampus (Kentros, Agnihotri, Streater, Hawkins, & Kandel, 2004;Lee, Briguglio, Cohen, Romani, & Lee, 2020;Rubin, Geva, Sheintuch, & Ziv, 2015) and posterior parietal cortex, but initially not in any primary sensory cortex (Driscoll et al., 2017). Another study shortly after Schoonhover et al. found representational drift in multiple visual areas of the mouse cortex, including V1 (Deitch, Rubin, & Ziv, 2021), reinforcing our view that the piriform findings apply to general sensory modeling and go beyond "just olfaction." ...
Representational drift is a phenomenon of increasing interest in the cognitive and neural sciences. While investigations are ongoing for other sensory cortices, recent research has demonstrated the pervasiveness in which it occurs in the piriform cortex for olfaction. This gradual weakening and shifting of stimulus-responsive cells has critical implications for sensory stimulus-response models and perceptual decision-making. While representational drift may complicate traditional sensory processing models, it could be seen as an advantage in olfaction, as animals live in environments with constantly changing and unpredictable chemical information. Non-topographical encoding in the olfactory system may aid in contextualizing reactions to promiscuous odor stimuli, facilitating adaptive animal behavior and survival. This article suggests that traditional models of stimulus-(neural) response mapping in olfaction may need to be reevaluated and instead motivates the use of dynamical systems theory as a methodology and conceptual framework.
... In both studies, manipulating theta physiology led to memory defects, yet the tuning of hippocampal neurons to spatiotemporal features remained unaltered, providing a clear example of a dissociation between theta, memory, and spatial tuning. Spatiotemporal coding has long been proposed to serve as a substrate for memory (Kentros et al., 2004;Eichenbaum, 2014;Moser et al., 2015;Lisman et al., 2017), making this dissociation between hippocampal representations and memory performance perplexing. In the following sections, we will explore potential explanations for this phenomenon and in particular why sequential activities of hippocampal neurons can be uncoupled from theta oscillations. ...
Oscillations in neural activity are widespread throughout the brain and can be observed at the population level through the local field potential. These rhythmic patterns are associated with cycles of excitability and are thought to coordinate networks of neurons, in turn facilitating effective communication both within local circuits and across brain regions. In the hippocampus, theta rhythms (4–12 Hz) could contribute to several key physiological mechanisms including long-range synchrony, plasticity, and at the behavioral scale, support memory encoding and retrieval. While neurons in the hippocampus appear to be temporally coordinated by theta oscillations, they also tend to fire in sequences that are developmentally preconfigured. Although loss of theta rhythmicity impairs memory, these sequences of spatiotemporal representations persist in conditions of altered hippocampal oscillations. The focus of this review is to disentangle the relative contribution of hippocampal oscillations from single-neuron activity in learning and memory. We first review cellular, anatomical, and physiological mechanisms underlying the generation and maintenance of hippocampal rhythms and how they contribute to memory function. We propose candidate hypotheses for how septohippocampal oscillations could support memory function while not contributing directly to hippocampal sequences. In particular, we explore how theta rhythms could coordinate the integration of upstream signals in the hippocampus to form future decisions, the relevance of such integration to downstream regions, as well as setting the stage for behavioral timescale synaptic plasticity. Finally, we leverage stimulation-based treatment in Alzheimer's disease conditions as an opportunity to assess the sufficiency of hippocampal oscillations for memory function.
... Neural circuit computations throughout the brain, from the primary sensory cortex (Bennett et al., 2013;Niell and Stryker, 2010;Vinck et al., 2015;Zhou et al., 2014) to higher cognitive areas, (Boccara et al., 2019;Butler et al., 2019;Hardcastle et al., 2017b;Hulse et al., 2017;Pettit et al., 2022) are shaped by combinations of internal and external factors. Internal state changes, such as shifts in attention (Fenton et al., 2010;Kentros et al., 2004;Pettit et al., 2022), thirst (Allen et al., 2019), arousal (Stringer et al., 2019), and impulsivity (Cowley et al., 2020), can profoundly alter neural activity across multiple brain areas. This raises a question: how can individual brain regions with specialized functions integrate global state changes without compromising their local processing dynamics? ...
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
... Neural circuit computations throughout the brain, from primary sensory cortex (Bennett et al., 2013 ;Niell and Stryker, 2010 ;Vinck et al., 2015 ;Zhou et al., 2014 ) to higher cognitive areas, (Boccara et al., 2019 ;Butler et al., 2019 ;Hardcastle et al., 2017b ;Hulse et al., 2017 ;Pettit et al., 2022 ) are shaped by combinations of internal and external factors. Internal state changes, such as shifts in attention (Fenton et al., 2010 ;Kentros et al., 2004 ;Pettit et al., 2022 ), thirst (Allen et al., 2019 ), arousal (Stringer et al., 2019 ), and impulsivity (Cowley et al., 2020 ), can profoundly alter neural activity across multiple brain areas. This raises a question: how can individual brain regions with specialized functions integrate global state changes without compromising their local processing dynamics? ...
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (“remap”) in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
... We contend that two behavioral states described by different patterns of reward acquisition in a plus-maze are more comparable to each other than are the period following a shock and periods of free exploration before and after the threat of physical harm. Navigation tasks also allow for a longer window for observing activity when the hippocampus is known to be engaged than can be assumed during the window following a shock (Kentros et al., 2004;Pettit et al., 2022). However, as this study primarily concerns the degree of remapping observed across two behavioral epochs depending on whether an intervening behavior was performed in the same spatial environment, the results are consistent with the above-mentioned fear conditioning studies in that they demonstrate remapping following an intervening event, and additionally can be seen as expanding such findings to a novel combination of behaviors. ...
The hippocampus plays a central role in episodic memory and spatial navigation. Hippocampal neurons form unique representational codes in different spatial environments, which may provide a neural substrate for context that can trigger memory recall or enable performance of context-guided memory tasks. However, new learning often occurs in a familiar location, requiring that location’s representation to be updated without erasing the previously existing memory representations that may be adaptive again in the future. To study how new learning affects a previously acquired spatial memory representation, we trained mice to perform two plus maze tasks across nine days in the sequence Turn Right 1 – Go East – Turn Right 2 (three days each), while we used single-photon calcium imaging to record the activity of hundreds of neurons in dorsal CA1. One cohort of mice performed the entire experiment on the same maze (One-Maze), while the second cohort performed the Go East task on a unique maze (Two-Maze). We hypothesized that CA1 representations in One-Maze mice would exhibit more change in the spatial patterns of neuronal activity on the maze from Turn Right 1 to Turn Right 2 than would be seen in Two-Maze mice. Indeed, changes in single unit activity and in the population code were larger in the One-Maze group. We further show evidence that Two-Maze mice utilize a separate neural representation for each maze environment. Finally, we found that remapping across the two Turn Right epochs did not involve an erasure of the representation for the first Turn Right experience, as many neurons in mice from both groups maintained Turn Right-associated patterns of activity even after performing the Go East rule. These results demonstrate that hippocampal activity patterns remap in response to new learning, that remapping is greater when experiences occur in the same spatial context, and that throughout remapping information from each experience is preserved.
The hippocampus plays a central role in self-localization and the consolidation of new experiences into long term memory. The activity of hippocampal place cells tracks an animal’s spatial location and upcoming navigational decisions, providing, at the ensemble level, unique patterns of activity for experiences that occur in the same physical location. Many studies have demonstrated the existence of divergent patterns at short time scales and how remapping can orthogonalize distinct experiences learned simultaneously. Here, we expand on this knowledge using the power of single-photon calcium imaging to track how new learning affects previously existing spatial memories either in the same or different environments over long periods of time. We observe patterns of hippocampal neural activity in mice during performance of two different rules either in the same environment or in different environments. We find that performing a new behavioral rule in the same environment as a previous rule causes significantly more remapping of hippocampal activity associated with the first rule than observed in mice that perform the two rules in separate environments. However, this remapping does not wholly destabilize memory for the first rule, as many neurons in both groups of mice maintain spatial activity patterns specific to the first rule. These results provide an important step forward in understanding the function of the hippocampus in memory by dramatically expanding the temporal scale over which changes to memory are measured.
... Still, in that experiment, mice were simply running back and forth along a linear track, which arguably does not require detailed spatial knowledge. Place fields appear to be more stable under conditions that produce or require increased attention to spatial cues (Kentros et al., 2004). Additionally, in rats, some place fields have been shown to be stable for as long as 6 months (Thompson and Best, 1990). ...
Spatial navigation has received much attention from neuroscientists, leading to the identification of key brain areas and the discovery of numerous spatially selective cells. Despite this progress, our understanding of how the pieces fit together to drive behavior is generally lacking. We argue that this is partly caused by insufficient communication between behavioral and neuroscientific researchers. This has led the latter to under-appreciate the relevance and complexity of spatial behavior, and to focus too narrowly on characterizing neural representations of space-disconnected from the computations these representations are meant to enable. We therefore propose a taxonomy of navigation processes in mammals that can serve as a common framework for structuring and facilitating interdisciplinary research in the field. Using the taxonomy as a guide, we review behavioral and neural studies of spatial navigation. In doing so, we validate the taxonomy and showcase its usefulness in identifying potential issues with common experimental approaches, designing experiments that adequately target particular behaviors, correctly interpreting neural activity, and pointing to new avenues of research.
... Neural circuit computations throughout the brain, from the primary sensory cortex (Bennett et al., 2013;Niell and Stryker, 2010;Vinck et al., 2015;Zhou et al., 2014) to higher cognitive areas, (Boccara et al., 2019;Butler et al., 2019;Hardcastle et al., 2017b;Hulse et al., 2017;Pettit et al., 2022) are shaped by combinations of internal and external factors. Internal state changes, such as shifts in attention (Fenton et al., 2010;Kentros et al., 2004;Pettit et al., 2022), thirst (Allen et al., 2019), arousal (Stringer et al., 2019), and impulsivity (Cowley et al., 2020), can profoundly alter neural activity across multiple brain areas. This raises a question: how can individual brain regions with specialized functions integrate global state changes without compromising their local processing dynamics? ...
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (“remap”) in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
... While remapping may contribute to discrimination among different environments, the reproducibility of spatial maps during repeated exposures to a single environment can support the recognition of familiar contexts, which is also critical for the formation of episodic and associative memory. 3,41 Compared with place cells in rats, place cells in mice have been shown to be unstable in specific tasks [42][43][44][45][46][47] and the stability of spatially modulated activity also varies among hippocampal subregions. 19,46,48,49 To measure stability of DG spatial representations in mice in our study, we evaluated activity patterns in both granule cells and mossy cells upon re-exposure to one environment at the end of the recording day. ...
Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.
... Our analysis of stability across context reveals that FI cells are stable, whereas FS cells are not. It has been previously suggested that place cell stability is a correlate of memory because the ability of a cell to fire in the same location over time requires some of the same molecular cascades and modulatory factors as memory consolidation Kentros et al., 2004;Muzzio et al., 2009). However, a recent study looking at cells expressing cFos, a marker of cellular activity associated with memory formation (Kitamura et al., 2017), showed that the hippocampus contains subpopulations of cells with distinct stability patterns that differentially express this early gene (Pettit et al., 2022;. ...
Reorientation, the process of regaining one’s bearings after becoming lost, requires identification of a spatial context (context recognition) and recovery of heading direction within that context (heading retrieval). We previously showed that these processes rely on the use of features and geometry, respectively. Here, we examine reorientation behavior in a task that creates contextual ambiguity over a long timescale to demonstrate that mice learn to combine both featural and geometric cues to recover heading with experience. At the neural level, most CA1 neurons persistently align to geometry, and this alignment predicts heading behavior. However, a small subset of cells shows feature-sensitive place field remapping, which serves to predict context. Efficient heading retrieval and context recognition require integration of featural and geometric information in the active network through rate changes. These data illustrate how context recognition and heading retrieval are coded in CA1 and how these processes change with experience.
... One reason for this is that most studies have only controlled the observable properties of the environment but did not analyze behavioral outputs that could give some insight into the inferences the animal is making about a particular environment or experience. In other words, the variability of circuit activation in the same physical environment has been overlooked, variability that could be influenced by motivation [31,32], attention [33] and experience [34]. Moreover, it is not clear how this individual mnemonic variability (i.e. ...
In a constantly changing environment, organisms face the challenge of adapting their behavior by retrieving previous experiences or acquiring new information. Previous research has postulated that this balance between memory generalization and differentiation manifests in a dichotomic manner. When environmental information exceeds a given threshold, activation of a stored representation could initiate retrieval, but below this threshold, a novel event could be encoded with a concomitant remapping of the internal representation in the hippocampus. Here, we examined the hippocampal molecular and neuronal mechanisms underlying retrieval in a cue-degraded environment by combining in vivo electrophysiological recordings and pharmacological manipulations. We developed a memory recognition task that allows a graded decrease in the contextual cues present during retrieval. We found that the manipulation of the number of visual cues was consistent with the activation or not of the contextual memory trace. Retrieval of a specific context memory was reflected by the level of CA3 remapping, demonstrating a clear relationship between remapping and contextual recognition. Also, manipulation of NMDAR activity in the DG-CA3 circuit bidirectionally modulated contextual memory retrieval. The blockade of NMDAR in CA3 impaired recognition in a cue-degraded, but not in a full-cue context, while their activation has the opposite effect. Conversely, blockade of NMDAR in the DG promoted retrieval under an even more cue-degraded environment, while activation had the opposite effect. Our results provide evidence for a flexible interaction between environmental cues and information stored in the hippocampus and give new insights into the biological mechanisms that balance memory encoding and retrieval.
... We proposed that the dynamic difference might be due to the different task requirements. According to the limited research available thus far, relatively higher stability was reported in more sensation-or action-associated areas, while lower stability in the hippocampus was reported [63][64][65][66][67]. In our VPL task, the mouse mPFC may play a part in improving the ability to read out sensory information. ...
Background
Perceptual learning refers to an augmentation of an organism’s ability to respond to external stimuli, which has been described in most sensory modalities. Visual perceptual learning (VPL) is a manifestation of plasticity in visual information processing that occurs in the adult brain, and can be used to ameliorate the ability of patients with visual defects mainly based on an improvement of detection or discrimination of features in visual tasks. While some brain regions such as the primary visual cortex have been described to participate in VPL, the way more general high-level cognitive brain areas are involved in this process remains unclear. Here, we showed that the medial prefrontal cortex (mPFC) was essential for both the training and maintenance processes of VPL in mouse models.
Results
We built a new VPL model in a custom-designed training chamber to enable the utilization of miniScopes when mice freely executed the VPL task. We found that pyramidal neurons in the mPFC participate in both the training process and maintenance of VPL. By recording the calcium activity of mPFC pyramidal neurons while mice freely executed the task, distinct ON and OFF neural ensembles tuned to different behaviors were identified, which might encode different cognitive information. Decoding analysis showed that mouse behaviors could be well predicted using the activity of each ON ensemble. Furthermore, VPL recruited more reward-related components in the mPFC.
Conclusion
We revealed the neural mechanism underlying vision improvement following VPL and identify distinct ON and OFF neural ensembles in the mPFC that tuned to different information during visual perceptual training. These results uncover an important role of the mPFC in VPL, with more reward-related components being also involved, and pave the way for future clarification of the reward signal coding rules in VPL.
... The mean correlation values reported by Hales et al. (2014) were also higher than in this study, so this effect could depend on the type of environment used, or familiarity of the environment. There is some evidence to suggest that there may also be a species difference, as mice show lower levels of place field stability than rats when freely exploring an environment, only showing comparable levels when spatial memory is required for a task (Kentros et al., 2004). Therefore, the lack of task demand in the current experiment may have resulted in relatively low place field stability in both groups of mice, and any effects of MEC lesion may not have been observed for this reason. ...
A fundamental property of place cells in the hippocampus is the anchoring of their firing fields to salient landmarks within the environment. However, it is unclear how such information reaches the hippocampus. In the current experiment, we tested the hypothesis that the stimulus control exerted by distal visual landmarks requires input from the medial entorhinal cortex (MEC). Place cells were recorded from mice with ibotenic acid lesions of the MEC (n = 7) and from sham‐lesioned mice (n = 6) following 90° rotations of either distal landmarks or proximal cues in a cue‐ controlled environment. We found that lesions of the MEC impaired the anchoring of place fields to distal landmarks, but not proximal cues. We also observed that, relative to sham‐lesioned mice, place cells in animals with MEC lesions exhibited significantly reduced spatial information and increased sparsity. These results support the view that distal landmark information reaches the hippocampus via the MEC, but that proximal cue information can do so via an alternative neural pathway.
... Still, in that experiment, mice were simply running back and forth along a linear track, which arguably does not require detailed spatial knowledge. Place fields appear to be more stable under conditions that produce or require increased attention to spatial cues (Kentros et al., 2004). Additionally, in rats, some place fields have been shown to be stable for as long as 6 months (Thompson and Best, 1990). ...
An animal's ability to navigate space is crucial to its survival. It is also cognitively demanding, and relatively easy to probe. For these reasons, spatial navigation has received a great deal of attention from neuroscientists, leading to the identification of key brain areas and the ongoing discovery of a ``zoo'' of cell types responding to different aspects of spatial tasks. Despite this progress, our understanding of how the pieces fit together to drive behavior is generally lacking. We argue that this is partly caused by insufficient communication between researchers focusing on spatial behavior and those attempting to study its neural basis. This has led the latter to under-appreciate the relevance and complexity of spatial behavior, and to focus too narrowly on characterizing neural representations of space—disconnected from the computations these representations are meant to enable. We therefore propose a taxonomy of navigation processes in mammals that can serve as a common framework for structuring and facilitating interdisciplinary research in the field. Using the taxonomy as a guide, we review behavioral and neural studies of spatial navigation. In doing so, we both validate the taxonomy and showcase its usefulness in identifying potential issues with common experimental approaches, designing experiments that adequately target particular behaviors, correctly interpreting neural activity, and pointing to new avenues of research.
... Neural circuit computations throughout the brain, from primary sensory cortex [1][2][3][4] to higher cognitive areas, [5][6][7][8][9] are shaped by combinations of internal and external factors. Internal state changes, such as shifts in attention, [9][10][11] thirst, 12 arousal, 13 and impulsivity, 14 can profoundly alter neural activity across multiple brain areas. This raises a question: how can individual brain regions with specialized functions integrate global state changes without compromising their local processing dynamics? ...
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns ("remap") in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local roles while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
... Our analysis of stability across context reveals that FI cells are stable, whereas FS cells are not. It has been previously suggested that place cell stability is a correlate of memory because the ability of a cell to fire in the same location over time requires some of the same molecular cascades and modulatory factors as memory consolidation Kentros et al., 2004;Muzzio et al., 2009). However, a recent study looking at cells expressing cFos, a marker of cellular activity associated with memory formation (Kitamura et al., 2017), showed that the hippocampus contains subpopulations of cells with distinct stability patterns that differentially express this early gene (Pettit et al., 2022;. ...
The representation of distinct spaces by hippocampal place cells has been linked to changes in their place fields (the locations in the environment where the place cells discharge strongly), a phenomenon that has been termed 'remapping'. Remapping has been assumed to be accompanied by the reorganization of subsecond cofiring relationships among the place cells, potentially maximizing hippocampal information coding capacity. However, several observations challenge this standard view. For example, place cells exhibit mixed selectivity, encode non-positional variables, can have multiple place fields and exhibit unreliable discharge in fixed environments. Furthermore, recent evidence suggests that, when measured at subsecond timescales, the moment-to-moment cofiring of a pair of cells in one environment is remarkably similar in another environment, despite remapping. Here, I propose that remapping is a misnomer for the changes in place fields across environments and suggest instead that internally organized manifold representations of hippocampal activity are actively registered to different environments to enable navigation, promote memory and organize knowledge.
Overview: The basic ideas presented here are: 1.that cognition is continuous with navigation (which means navigation itself can be understood as pre-reflective cognition); 2. that taking this seriously changes our understanding of landscape in ways that require non-binary vocabularies (i.e. using terms like 'mental' and 'physical' as dichotomies is no longer a productive strategy); and 3. the orientation and methods of cognitive neuroscience could be optimised by an ecological approach which looks at scales of complexity rather than stimulus-response and metricizes the experiment itself so it becomes part of the data and analysis.
Dopamine is a neurotransmitter that plays a crucial role in regulating diverse functions, such as motor control, mood, sleep, attention, reward systems, reinforcing behavior, and certain higher cognitive functions. Physiological and behavioral evidence indicates that dopamine receptor signaling has been shown to modulate hippocampus-dependent synaptic plasticity and learning and memory. Although the role of dopamine in regulating the hippocampus is well-established, the precise molecular and cellular mechanisms by which dopamine coordinates these processes in the hippocampus are not yet fully understood. This chapter presents a concise overview of dopaminergic neuromodulation required for the establishment of hippocampal late LTP (L-LTP) and its late-associative processes such as synaptic tagging and capture (STC) in CA1 pyramidal neurons. Additionally, the source of dopaminergic signals in the hippocampus and the mechanism by which dopamine neuromodulation induces the synthesis of plasticity-related proteins (PRPs) is detailed, along with its involvement in establishing STC.
Most everyday memories, including numerous episodic memories formed automatically in the hippocampus, are forgotten. However, some memories are retained for extended periods through a memory stabilization process known as cellular or initial memory consolidation. Notably, in both animals and humans, the retention of everyday memories is enhanced during novel experiences occurring shortly before or after memory encoding, a process known as synaptic tagging and capture (STC). A growing body of evidence suggests that dopamine signaling via D1/D5 receptors in the hippocampus is crucial for the persistence of synaptic plasticity and memory, highlighting its significant role in novelty-associated memory enhancement. This chapter presents an overview of key findings related to the persistence of synaptic plasticity and memory in the hippocampus through hippocampal D1/D5 receptor dependency, with special emphasis on the emerging role of the locus coeruleus (LC) in novelty-associated dopamine-dependent memory consolidation. Furthermore, two distinct dopaminergic systems are explored (the ventral tegmental area (VTA)-hippocampal and LC-hippocampal systems), and the specialization mechanisms of each system in different memory consolidation processes are discussed. Additionally, the anatomical and molecular foundations of D1/D5 receptor-mediated signaling in the LC-hippocampal system are examined. Finally, the molecular mechanisms possibly underlying distinct novelty-associated memory enhancement are discussed, including the involvement of plasticity-related proteins (PRPs) in the stabilization of structural and functional changes at potentiated synapses, culminating in initial memory consolidation in the hippocampus.
The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal’s exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals’ investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems.
Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neurons. However, it remains highly challenging to map the functional properties of transcriptionally heterogeneous neuronal subtypes in mammalian cortical circuits in vivo. Here, we introduce a high-throughput two-photon nuclear phototagging (2P-NucTag) approach optimized for on-demand and indelible labeling of single neurons via a photoactivatable red fluorescent protein following in vivo functional characterization in behaving mice. We demonstrate the utility of this function-forward pipeline by selectively labeling and transcriptionally profiling previously inaccessible place and silent cells in the mouse hippocampus. Our results reveal unexpected differences in gene expression between these hippocampal pyramidal neurons with distinct spatial coding properties. Thus, 2P-NucTag opens a new way to uncover the molecular principles that govern the functional organization of neural circuits.
The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.
We present computer simulations illustrating how the plastic integration of spatially stable inputs could contribute to the dynamic character of hippocampal spatial representations. In novel environments of slightly larger size than typical apparatus, the emergence of well-defined place fields in real place cells seems to rely on inputs from normally functioning grid cells. Theoretically, the grid-to-place transformation is possible if a place cell is able to respond selectively to a combination of suitably aligned grids. We previously identified the functional characteristics that allow a synaptic plasticity rule to accomplish this selection by synaptic competition during rat foraging behavior. Here, we show that the synaptic competition can outlast the formation of place fields, contributing to their spatial reorganization over time, when the model is run in larger environments and the topographical/modular organization of grid inputs is taken into account. Co-simulated cells that differ only by their randomly assigned grid inputs display different degrees and kinds of spatial reorganization—ranging from place-field remapping to more subtle in-field changes or lapses in firing. The model predicts a greater number of place fields and propensity for remapping in place cells recorded from more septal regions of the hippocampus and/or in larger environments, motivating future experimental standardization across studies and animal models. In sum, spontaneous remapping could arise from rapid synaptic learning involving inputs that are functionally homogeneous, spatially stable, and minimally stochastic.
Head direction (HD) cells, which fire persistently when an animal's head is pointed in a particular direction, are widely thought to underlie an animal's sense of spatial orientation and have been identified in several limbic brain regions. Robust HD cell firing is observed throughout the thalamo‐parahippocampal system, although recent studies report that parahippocampal HD cells exhibit distinct firing properties, including conjunctive aspects with other spatial parameters, which suggest they play a specialized role in spatial processing. Few studies, however, have quantified these apparent differences. Here, we performed a comparative assessment of HD cell firing characteristics across the anterior dorsal thalamus (ADN), postsubiculum (PoS), parasubiculum (PaS), medial entorhinal (MEC), and postrhinal (POR) cortices. We report that HD cells with a high degree of directional specificity were observed in all five brain regions, but ADN HD cells display greater sharpness and stability in their preferred directions, and greater anticipation of future headings compared to parahippocampal regions. Additional analysis indicated that POR HD cells were more coarsely modulated by other spatial parameters compared to PoS, PaS, and MEC. Finally, our analyses indicated that the sharpness of HD tuning decreased as a function of laminar position and conjunctive coding within the PoS, PaS, and MEC, with cells in the superficial layers along with conjunctive firing properties showing less robust directional tuning. The results are discussed in relation to theories of functional organization of HD cell tuning in thalamo‐parahippocampal circuitry.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (‘remap’) in response to changing contextual factors such as environmental cues, task conditions, and behavioral states, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Large-scale recordings of neural activity over days and weeks have revealed that neural representations of familiar tasks, precepts and actions continually evolve without obvious changes in behaviour. We hypothesise that this steady drift in neural activity and accompanying physiological changes is due in part to the continuous application of a learning rule at the cellular and population level. Explicit predictions of this drift can be found in neural network models that use iterative learning to optimise weights. Drift therefore provides a measurable signal that can reveal systems-level properties of biological plasticity mechanisms, such as their precision and effective learning rates.
Episodic memory, or memory of experienced events, is a critical function of the hippocampus. It is therefore important to understand how hippocampal activity represents specific events in an animal's life. We addressed this question in chickadees — specialist food-caching birds that hide food at scattered locations and use memory to find their caches later in time. We performed high-density neural recordings in the hippocampus of chickadees as they cached and retrieved seeds in a laboratory arena. We found that each caching event was represented by a burst of firing in a unique set of hippocampal neurons. These 'barcode-like' patterns of activity were sparse (<10% of neurons active), uncorrelated even for immediately adjacent caches, and different even for separate caches at the same location. The barcode representing a specific caching event was transiently reactivated whenever a bird later interacted with the same cache — for example, to retrieve food. Barcodes co-occurred with the conventional activity of place cells, as well as with responses to cached seeds. We propose that barcodes are signatures of episodic memories evoked during memory recall. These patterns assign a unique identifier to each event and may be a mechanism for rapid formation and storage of many non-interfering memories.
Neurons in navigational brain regions provide information about position, orientation, and speed relative to environmental landmarks. These cells also change their firing patterns (“remap”) in response to changing contextual factors such as environmental cues, task conditions, and behavioral state, which influence neural activity throughout the brain. How can navigational circuits preserve their local computations while responding to global context changes? To investigate this question, we trained recurrent neural network models to track position in simple environments while at the same time reporting transiently-cued context changes. We show that these combined task constraints (navigation and context inference) produce activity patterns that are qualitatively similar to population-wide remapping in the entorhinal cortex, a navigational brain region. Furthermore, the models identify a solution that generalizes to more complex navigation and inference tasks. We thus provide a simple, general, and experimentally-grounded model of remapping as one neural circuit performing both navigation and context inference.
Objects and landmarks are crucial for guiding navigation and must be integrated into the cognitive map of space. Studies of object coding in the hippocampus have primarily focused on activity of single cells. Here, we record simultaneously from large numbers of hippocampal CA1 neurons to determine how the presence of a salient object in the environment alters single-neuron and neural-population activity of the area. The majority of the cells showed some change in their spatial firing patterns when the object was introduced. At the neural-population level, these changes were systematically organized according to the animal's distance from the object. This organization was widely distributed across the cell sample, suggesting that some features of cognitive maps-including object representation-are best understood as emergent properties of neural populations.
The authors thank Eric Kandel, Richard Morris, Peter Rapp, and Larry Squire for their thoughtful comments and criticisms on versions of this manuscript. This research is supported by grants from NIMH and NIA.
: The concept of attention as central to human performance extends back to the start of experimental psychology, yet even a few years ago, it would not have been possible to outline in even a preliminary form a functional anatomy of the human attentional system. New developments in neuroscience have opened the study of higher cognition to physiological analysis, and have revealed a system of anatomical areas that appear to be basic to the selection of information for focal (conscious) processing. The importance of attention is its unique role in connecting the mental level of description of processes used in cognitive science with the anatomical level common in neuroscience. Sperry describes the central role that mental concepts play in understanding brain function. As is the case for sensory and motor systems of the brain, our knowledge of the anatomy of attention is incomplete. Nevertheless, we can now begin to identify some principles of organization that allow attention to function as a unified system for the control of mental processing. Although many of our points are still speculative and controversial, we believe they constitute a basis for more detailed studies of attention from a cognitive-neuroscience viewpoint. Perhaps even more important for furthering future studies, multiple methods of mental chronometry, brain lesions, electrophysiology, and several types of neuro-imaging have converged on common findings.
Priming is a nonconscious form of human memory, which is concerned with perceptual identification of words and objects and
which has only recently been recognized as separate from other forms of memory or memory systems. It is currently under intense
experimental scrutiny. Evidence is converging for the proposition that priming is an expression of a perceptual representation
system that operates at a pre-semantic level; it emerges early in development, and access to it lacks the kind of flexibility
characteristic of other cognitive memory systems. Conceptual priming, however, seems to be based on the operations of semantic
memory.
Over 90% of all spontaneously active hippocampal pyramidal cells in freely moving rats signal the animal's spatial position by reliably changing their firing rate each time the animal enters a given place within an environment. This place-field activity exhibits plasticity when specific environmental variables are manipulated. Indeed, the hippocampus is perhaps best known as a system that serves as a model of neuronal plasticity. Although place-field activity has previously been examined only over relatively short experimental sessions, this behavioral correlate of hippocampal functional activity has been assumed to exhibit stability rather than plasticity in the absence of environmental changes. The present study shows that hippocampal neurons have stable place-field correlates that persist over very long periods of time. Single-unit activity was chronically recorded from the dorsal hippocampus of rats foraging repeatedly in a stable spatial environment. The location of the place fields of all units were stable over all time periods tested, for intervals up to 153 days in duration. The consistency of the information conveyed by this single-unit activity in a fixed spatial environment indicates that stability of neuronal activity may be as important as plasticity in the integrated processing of information that occurs in the hippocampus and throughout the nervous system.
When rats forage for randomly dispersed food in a high walled cylinder the firing of their hippocampal "place" cells exhibits little dependence on the direction faced by the rat. On radial arm mazes and similar tasks, place cells are strongly directionally selective within their fields. These tasks differ in several respects, including the visual environment, configuration of the traversable space, motor behavior (e.g., linear and angular velocities), and behavioral context (e.g., presence of specific, consistent goal locations within the environment). The contributions of these factors to spatial and directional tuning of hippocampal neurons was systematically examined in rats performing several tasks in either an enriched or a sparse visual environment, and on different apparati. Place fields were more spatially and directionally selective on a radial maze than on an open, circular platform, regardless of the visual environment. On the platform, fields were more directional when the rat searched for food at fixed locations, in a stereotypic and directed manner, than when the food was scattered randomly. Thus, it seems that place fields are more directional when the animal is planning or following a route between points of special significance. This might be related to the spatial focus of the rat's attention (e.g., a particular reference point). Changing the behavioral task was also accompanied by a change in firing location in about one-third of the cells. Thus, hippocampal neuronal activity appears to encode a complex interaction between locations, their significance and the behaviors the rat is called upon to execute.
Agonists of the dopamine D1/D5 receptors that are positively coupled to adenylyl cyclase specifically induce a slowly developing long-lasting potentiation of the field excitatory postsynaptic potential in the CA1 region of the hippocampus that lasts for > 6 hr. This potentiation is blocked by the specific D1/D5 receptor antagonist SCH 23390 and is occluded by the potentiation induced by cAMP agonists. An agonist of the D2 receptor, which is negatively coupled to adenylyl cyclase through G alpha i, did not induce potentiation. Although this slow D1/D5 agonist-induced potentiation is partially independent of N-methyl-D-aspartate receptors, it seems to share some steps with and is occluded by the late phase of long-term potentiation (LTP) produced by three repeated trains of nerve stimuli applied to the Schaffer collateral pathway. Similarly, the D1/D5 antagonist SCH 23390 attenuates the late phase of the LTP induced by repeated trains, and the D1/D5 agonist-induced potentiation is blocked by the protein synthesis inhibitor anisomycin. These results suggest that the D1/D5 receptor may be involved in the late, protein synthesis-dependent component of LTP in the hippocampal CA1 region, either as an ancillary component or as a mediator directly contributing to the late phase.
Previous studies have shown that hippocampal place fields are controlled by the salient sensory cues in the environment, in that rotation of the cues causes an equal rotation of the place fields. We trained rats to forage for food pellets in a gray cylinder with a single salient directional cue, a white card covering 90 degrees of the cylinder wall. Half of the rats were disoriented before being placed in the cylinder, in order to disrupt their internal sense of direction. The other half were not disoriented before being placed in the cylinder; for these rats, there was presumably a consistent relationship between the cue card and their internal direction sense. We subsequently recorded hippocampal place cells and thalamic head direction cells from both groups of rats as they moved in the cylinder; between some sessions the cylinder and cue card were rotated to a new direction. All rats were disoriented before recording. Under these conditions, the cue card had much weaker control over the place fields and head direction cells in the rats that had been disoriented during training than in the rats that had not been disoriented. For the former group, the place fields often rotated relative to the cue card or completely changed their firing properties between sessions. In all recording sessions, the head direction cells and place cells were strongly coupled. It appears that the strength of cue control over place cells and head direction cells depends on the rat's learned perception of the stability of the cues.
The behavioral correlates of rat hippocampal CA1 cells were examined in a spatial navigation task in which two cylindrical landmarks predicted the location of food. The landmarks were maintained at a constant distance from each other but were moved from trial to trial within a large arena surrounded by static background cues. On each trial, the rats were released from a box to which they returned for additional food after locating the goal. The box also was located variably from trial to trial and was moved to a new location while the animals were searching for the goal site. The discharge characteristics of multiple, simultaneously recorded cells were examined with respect to the landmarks, the static background cues, and the box in which each trial started and ended. Three clear categories of cells were observed: (1) cells with location-specific firing (place cells); (2) goal/landmark-related cells that fired in the vicinity of the goal or landmarks, regardless of their location in the arena; and (3) box-related cells that fired either when the rat was in the box or as it was leaving or entering the box, regardless of its location in the arena. Disjunctive cells with separate firing fields in more than one reference frame also were observed. These results suggest that in this task a subpopulation of hippocampal cells encodes location in the fixed spatial frame, whereas other subpopulations encode location with respect to different reference frames associated with the task-relevant, mobile objects.
A key feature of perception is that the interpretation of a single, continuously available stimulus can change from time to time. This aspect of perception is well illustrated by the use of ambiguous figures that can be seen in two different ways. When people view such a stimulus they almost universally describe what they are seeing as jumping between two states. If it is agreed that this perceptual phenemonon is causally linked to the activity of nerve cells, the state jumps would have to occur in conjunction with changes in neural activity somewhere in the nervous system.
The experiments described in this paper suggest that hippocampal place cells are part of a perceptual system. Variations were made of a ‘cue–card rotation’ experiment on rats in which the angular position of a prominent visual stimulus on the wall of cylinder is changed in the rat's presence. The three main results are as follows. (i) Place–cell firing fields remain stationary if the cue is rotated by 180° so that the relation between the cue and the field is altered. (ii) Firing fields rotate by 45° when the cue is rotated by 45°and the relation between the field and the card is maintained. (iii) If the cue is first rotated by 180°and then rotated in a series of 45° steps, the field finishes at a different angular position relative to the card when the card is back in its original position. Thus, place cells can fire in two different ways in reponse to a continuously viewed stimulus. It is concluded that place cells reveal that the hippocampal mapping system also has properties expected of a perceptual system.
Allocentric spatial learning can sometimes occur in one trial. The incorporation of information into a spatial representation may, therefore, obey a one-trial correlational learning rule rather than a multi-trial error-correcting rule. It has been suggested that physiological implementation of such a rule could be mediated by N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) in the hippocampus, as its induction obeys a correlational type of synaptic learning rule. Support for this idea came originally from the finding that intracerebral infusion of the NMDA antagonist AP5 impairs spatial learning, but studies summarized in the first part of this paper have called it into question. First, rats previously given experience of spatial learning in a watermaze can learn a new spatial reference memory task at a normal rate despite an appreciable NMDA receptor blockade. Second, the classical phenomenon of 'blocking' occurs in spatial learning. The latter finding implies that spatial learning can also be sensitive to an animal's expectations about reward and so depend on more than the detection of simple spatial correlations. In this paper a new hypothesis is proposed about the function of hippocampal LTP. This hypothesis retains the idea that LTP subserves rapid one-trial memory, but abandons the notion that it serves any specific role in the geometric aspects of spatial learning. It is suggested that LTP participates in the automatic recording of attended experience': a subsystem of episodic memory in which events are temporarily remembered in association with the contexts in which they occur. An automatic correlational form of synaptic plasticity is ideally suited to the online registration of context event associations. In support, it is reported that the ability of rats to remember the most recent place they have visited in a familiar environment is exquisitely sensitive to AP5 in a delay-dependent manner. Moreover, new studies of the lasting persistence of NMDA-dependent LTP, known to require protein synthesis, point to intracellular mechanisms that enable transient synaptic changes to be stabilized if they occur in close temporal proximity to important events. This new property of hippocampal LTP is a desirable characteristic of an event memory system.
Hippocampal "place cells" fire selectively when an animal is in a specific location. The fine-tuning and stability of place cell firing was compared in two types of mutant mice with different long-term potentiation (LTP) and place learning impairments. Place cells from both mutants showed decreased spatial selectivity. Place cell stability was also deficient in both mutants and, consistent with the severities in their LTP and spatial learning deficits, was more affected in mice with a point mutation [threonine (T) at position 286 mutated to alanine (A)] in the alpha calmodulin kinase II (alphaCaMKIIT286A) than in mice deficient for the alpha and Delta isoforms of adenosine 3'5'-monophosphate-responsive element binding proteins (CREBalphaDelta-). Thus, LTP appears to be important for the fine tuning and stabilization of place cells, and these place cell properties may be necessary for spatial learning.
Hippocampal pyramidal cells are called place cells because each cell tends to fire only when the animal is in a particular part of the environment-the cell's firing field. Acute pharmacological blockade of N-methyl-D-aspartate (NMDA) glutamate receptors was used to investigate how NMDA-based synaptic plasticity participates in the formation and maintenance of the firing fields. The results suggest that the formation and short-term stability of firing fields in a new environment involve plasticity that is independent of NMDA receptor activation. By contrast, the long-term stabilization of newly established firing fields required normal NMDA receptor function and, therefore, may be related to other NMDA-dependent processes such as long-term potentiation and spatial learning.
The space around us is represented not once but many times in parietal cortex. These multiple representations encode locations and objects of interest in several egocentric reference frames. Stimulus representations are transformed from the coordinates of receptor surfaces, such as the retina or the cochlea, into the coordinates of effectors, such as the eye, head, or hand. The transformation is accomplished by dynamic updating of spatial representations in conjunction with voluntary movements. This direct sensory-to-motor coordinate transformation obviates the need for a single representation of space in environmental coordinates. In addition to representing object locations in motoric coordinates, parietal neurons exhibit strong modulation by attention. Both top-down and bottom-up mechanisms of attention contribute to the enhancement of visual responses. The saliance of a stimulus is the primary factor in determining the neural response to it. Although parietal neurons represent objects in motor coordinates, visual responses are independent of the intention to perform specific motor acts.
To further elucidate the links among synaptic plasticity, hippocampal place cells, and spatial memory, place cells were recorded from wild-type mice and transgenic "R(AB)" mice with reduced forebrain protein kinase A (PKA) activity after introduction into a novel environment. Place cells in both strains were similar during the first exposure and were equally stable for recording sessions separated by 1 hr. Place cell stability in wild-type mice was unchanged for sessions separated by 24 hr but was reduced in R(AB) mice over the longer interval. This stability pattern parallels both the reduced late-phase long-term potentiation in hippocampal slices from R(AB) mice and the amnesia for context fear conditioning seen in R(AB) mice 24 but not 1 hr after training. The similar time courses of synaptic, network, and behavioral instability suggest that the genetic reduction of PKA activity is responsible for the defects at each level and support the idea that hippocampal synaptic plasticity is important in spatial memory.
In 1894, Ramón y Cajal first proposed that memory is stored as an anatomical change in the strength of neuronal connections. For the following 60 years, little evidence was recruited in support of this idea. This situation changed in the middle of the twentieth century with the development of cellular techniques for the study of synaptic connections and the emergence of new formulations of synaptic plasticity that redefined Ramón y Cajal's idea, making it more suitable for testing. These formulations defined two categories of plasticity, referred to as homosynaptic or Hebbian activity-dependent, and heterosynaptic or modulatory input-dependent. Here we suggest that Hebbian mechanisms are used primarily for learning and for short-term memory but often cannot, by themselves, recruit the events required to maintain a long-term memory. In contrast, heterosynaptic plasticity commonly recruits long-term memory mechanisms that lead to transcription and to synpatic growth. When jointly recruited, homosynaptic mechanisms assure that learning is effectively established and heterosynaptic mechanisms ensure that memory is maintained.
The startling discovery by O'Keefe & Dostrovsky (Brain Res. 1971; 34: 171-75) that hippocampal neurons fire selectively in different regions or "place fields" of an environment and the subsequent development of the comprehensive theory by O'Keefe & Nadel (The Hippocampus as a Cognitive Map. Oxford, UK: Clarendon, 1978) that the hippocampus serves as a cognitive map have stimulated a substantial body of literature on the characteristics of hippocampal "place cells" and their relevance for our understanding of the mechanisms by which the brain processes spatial information. This paper reviews the major dimensions of the empirical research on place-cell activity and the development of computational models to explain various characteristics of place fields.
The processing of visual information combines bottom-up sensory aspects with top-down influences, most notably attentional processes. Attentional influences have now been demonstrated throughout visual cortex, and their influence on the processing of visual information is profound. Neuronal responses to attended locations or stimulus features are enhanced, whereas those from unattended locations or features are suppressed. This influence of attention increases as one ascends the hierarchy of visual areas in primate cortex, ultimately resulting in a neural representation of the visual world that is dominated by the behavioral relevance of the information, rather than designed to provide an accurate and complete description of it. This realization has led to a rethinking of the role of areas that have previously been considered to be "purely sensory".
The importance of the hippocampus in spatial representation is well established. It is suggested that the rodent hippocampal network should provide an optimal substrate for the study of unsupervised Hebbian learning. We focus on the firing characteristics of hippocampal place cells in morphologically different environments. A hard-wired quantitative geometric model of individual place fields is reviewed and presented as the framework in which to understand the additional effects of synaptic plasticity. Existent models employing Hebbian learning are also reviewed. New information is presented regarding the dynamics of place field plasticity over short and long time scales in experiments using barriers and differently shaped walled environments. It is argued that aspects of the temporal dynamics of stability and plasticity in the hippocampal place cell representation both indicate modifications to, and inform the nature of, the synaptic plasticity in place cell models. Our results identify a potential neural basis for long-term incidental learning of environments and provide strong constraints for the way the unsupervised learning in cell assemblies envisaged by Hebb might occur within the hippocampus.
We recorded neurons from the hippocampus of freely behaving rats during an auditory fear conditioning task. Rats received either paired or unpaired presentations of an auditory conditioned stimulus (CS) and an electric shock unconditioned stimulus (US). Hippocampal neurons (place and theta cells) acquired responses to the auditory CS in the paired but not in the unpaired group. After CS-US pairing, rhythmic firing of theta cells became synchronized to the onset of the CS. Conditioned responses of place cells were gated by their location-specific firing, so that after CS-US pairing, place cells responded to the CS only when the rat was within the cell's place field. These findings may help to elucidate how the hippocampus contributes to context-specific memory formation during associative learning.
Place cells of the rodent hippocampus constitute one of the most striking examples of a correlation between neuronal activity and complex behaviour in mammals. These cells increase their firing rates when the animal traverses specific regions of its surroundings, providing a context-dependent map of the environment. Neuroimaging studies implicate the hippocampus and the parahippocampal region in human navigation. However, these regions also respond selectively to visual stimuli. It thus remains unclear whether rodent place coding has a homologue in humans or whether human navigation is driven by a different, visually based neural mechanism. We directly recorded from 317 neurons in the human medial temporal and frontal lobes while subjects explored and navigated a virtual town. Here we present evidence for a neural code of human spatial navigation based on cells that respond at specific spatial locations and cells that respond to views of landmarks. The former are present primarily in the hippocampus, and the latter in the parahippocampal region. Cells throughout the frontal and temporal lobes responded to the subjects' navigational goals and to conjunctions of place, goal and view.
This study examined the performance of spatial problems by rats when purely behavioral manipulations disturb the relationship between the place cell representation and the cues used to solve the problems. Place cells were recorded while rats performed a task in which they had to locate a goal in a gray cylinder. In the "far" task, the unmarked goal was displaced by a large fixed distance from a white card on the cylinder wall. In the "near" task, the unmarked goal was directly in front of the card. Finally, in the "cue" task the goal was marked by a black disk on the cylinder floor. Relationships between visible stimuli and place cell activity were manipulated by conducting either "hidden" (with the rat in its home cage) or "visible" (with the rat in the recording apparatus) rotations of the wall card and, when present, independent rotations of the black disk. Hidden card rotations generally caused equal firing field rotations, whereas visible card rotations often did not cause fields to move. In the far task, visible card rotations were associated with a strong decrease of correct responses in the card-referred goal area. Most rats tended to search the goal in the field-referred area. In the near task, visible card rotations were associated with a moderate decrease of performance, with rats searching the goal at the wall card. Finally, field placements had no effect on performance in the cue task. Thus, visible rotations tended to disrupt the relationship between firing fields and cues in all tasks but impaired performance only in the task that required map-based navigation. These results provide strong new evidence in favor of the spatial mapping theory of hippocampal function.
SAS PROC MIXED is a flexible program suitable for fitting multilevel models, hierarchical linear models, and individual growth models. Its position as an integrated program within the SAS statistical package makes it an ideal choice for empirical researchers and applied statisticians seeking to do data reduction, management, and analysis within a single statistical package. Because the program was developed from the perspective of a "mixed" statistical model with both random and fixed effects, its syntax and programming logic may appear unfamiliar to users in education and the social and behavioral sciences who tend to express these models as multilevel or hierarchical models. The purpose of this paper is to help users familiar with fitting multilevel models using other statistical packages (e.g., HLM, MLwiN, MIXREG) add SAS PROC MIXED to their array of analytic options. The paper is written as a step-by-step tutorial that shows how to fit the two most common multilevel models: (a) school effects models, designed for data on individuals nested within naturally occurring hierarchies (e.g., students within classes); and (b) individual growth models, designed for exploring longitudinal data (on individuals) over time. The conclusion discusses how these ideas can be extended straighforwardly to the case of three level models. An appendix presents general strategies for working with multilevel data in SAS and for creating data sets at several levels.
Hippocampal “place cells” fire selectively when an animal is in a specific location. The fine-tuning and stability of place
cell firing was compared in two types of mutant mice with different long-term potentiation (LTP) and place learning impairments.
Place cells from both mutants showed decreased spatial selectivity. Place cell stability was also deficient in both mutants
and, consistent with the severities in their LTP and spatial learning deficits, was more affected in mice with a point mutation
[threonine (T) at position 286 mutated to alanine (A)] in the α calmodulin kinase II (αCaMKIIT286A) than in mice deficient for the α and Δ isoforms of adenosine 3′5′-monophosphate–responsive element binding proteins (CREBαΔ
−). Thus, LTP appears to be important for the fine tuning and stabilization of place cells, and these place cell properties
may be necessary for spatial learning.
SAS PROC MIXED is a flexible program suitable for fitting multilevel models, hierarchical linear models, and individual growth models. Its position as an integrated program within the SAS statistical package makes it an ideal choice for empirical researchers and applied statisticians seeking to do data reduction, management, and analysis within a single statistical package. Because the program was developed from the perspective of a "mixed" statistical model with both random and fixed effects, its syntax and programming logic may appear unfamiliar to users in education and the social and behavioral sciences who tend to express these models as multilevel or hierarchical models. The purpose of this paper is to help users familiar with fitting multilevel models using other statistical packages (e.g., HLM, MLwiN, MIXREG) add SAS PROC MIXED to their array of analytic options. The paper is written as a step-by-step tutorial that shows how to fit the two most common multilevel models: (a) school effects models, designed for data on individuals nested within naturally occurring hierarchies (e.g., students within classes); and (b) individual growth models, designed for exploring longitudinal data (on individuals) over time. The conclusion discusses how these ideas can be extended straighforwardly to the case of three level models. An appendix presents general strategies for working with multilevel data in SAS and for creating data sets at several levels.
Hippocampal principal neurons—‘place cells’–exhibit location-specific firing. Recent work addresses the link between place cell activity and hippocampal memory function. New tasks that challenge spatial memory allow recording from single neurons, as well as ensembles of neurons, during memory computations, and insights into the cellular mechanisms of spatial memory are beginning to emerge.
Dry arenas are a convenient tool for assessing the spatial navigation abilities of rodents. In this paper, mice must avoid a punished sector of a dry arena from which they are expelled by a puff of compressed air. The position of the punished sector is defined relative to the coordinate system of the room. In a stable environment the mice can use both extramaze and intramaze landmarks to orient themselves accurately. However, when the shock area is defined by extramaze landmarks, continuous rotation of the arena at 1 rpm makes it impossible to solve the avoidance task using arena-based cues or idiothesis. The avoidance can only be solved by paying attention to extramaze cues. Our protocol tested spatial abilities on stable and rotating arenas. The acquisition of the task was manifested under both conditions by a significant improvement of performance within the first session (short-term memory component) and at the beginning of the 24-h delayed second session (long-term memory component).
Microelectrodes were passed through the dorsal hippocampal formation of unrestrained rats, recording for at least 5 min each 35.3 μm. At each site the amplitude and duration of action potential spikes, frequency of firing, relation to slow wave theta rhythm, and presence of complex spikes or theta cells was recorded. One thousand and fourteen neurons were recorded from. (When recording from many neurons simultaneously, the “number” of the neurons was “counted” in an arbitrary and approximate way.) Of 949 nontheta cells greater than 80 μV amplitude, only one was not in the hilus of fascia dentata or in a layer of cells which overlapped stratum pyramidale and stratum granulosum. These are the locations of the cell bodies of projection cells (pyramidal cells and granule cells). However, this layer is, up to 400 μm thicker than stratum pyramidale. Theta cells were seen in sites of cell bodies of projection cells and also in stratum oriens of CA1, suprapyramidal layers of CA3, and dorsal part of the hilus of fascia dentata. The frequency of occurrence in these locations corresponded to the distribution of cell bodies of interneurons. We conclude that the class of projection cells and the class of nontheta cells have a very large overlap, and that the class of interneurons and the class of theta cells have a very large overlap.
Understanding the empirical rules that regulate alterations of hippocampal firing fields will enhance our understanding of hippocampal function. The current study sought to extend previous research in this area by examining the effect of substituting a new stimulus for a familiar stimulus in a familiar environment. Hippocampal place cells were recorded while rats chased food pellets scattered onto the floor of a cylindrical apparatus with a white cue card affixed to the apparatus wall. Once a place cell had been recorded in the presence of the white card, the white card was replaced by a black card of the same size and shape. The place cell was then recorded in the presence of the black card. Thirty-six cells were recorded using this procedure. All cells had stable firing fields in the presence of the white card. Both the white and black cards had stimulus control over place cell firing; generally, rotation of either card caused an equal rotation of the firing fields present. When the black card was substituted for the white card, place cells showed time-variant changes in their spatial firing patterns. The change was such that the spatial firing patterns of the majority of place cells were similar in the presence of the white and black cards during initial black card exposures. During subsequent presentations of the black card, the spatial firing patterns associated with the 2 cards became distinct from each other. Once the differentiation of firing patterns had occurred in a given rat, all place cells subsequently recorded from that rat had different firing patterns in the presence of the white and black cards. The findings are discussed relative to sensory-, motor-, attentional-, and learning-related interpretations of hippocampal function. It is argued that the time-variant alteration of place cell firing fields observed following exposure to a novel stimulus in this study reflects an experience-dependent modification of place cell firing patterns.
Amnesic patients acquired a mirror-reading skill at a rate equivalent to that of matched control subjects and retained it
for at least 3 months. The results indicate that the class of preserved learning skills in amnesia is broader than previously
reported. Amnesia seems to spare information that is based on rules or procedures, as contrasted with information that is
data-based or declarative--"knowing how rather than "knowing that." The results support the hypothesis that such a distinction
is honored by the nervous system.
The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 “complex spike” (CS) cells were studied in young and old Fischer-344 rats during food-motivated performance of a randomized, forced-choice task on an eight-arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms.
In the dark, a lower proportion of CS cells had “place fields,” and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields.
Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness.
While the task was simple and errors rare, rats that made fewer errors (i.e., re-entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention.
An ecological niche that requires competency in water has prepared rats for the swimming pool spatial tasks that they are administered in the laboratory. Their ability to eventually solve spatial tasks in a single trial makes them ideal subjects for evaluating neural contributions to spatial behavior and for addressing many other neuroscience problems. Swimming pool place tasks are also given to mice, but the spatial abilities of the animal has not been evaluated as extensively as have those of rats. In the present paper, place learning in a single place task and a matching to place task is comparatively assessed in groups of rats and mice. The rats were superior to the mice on both problems. Although the mice could learn a single place problem, their acquisition was slower and their asymptotic performance was inferior to that of rats. Mice also did not display one trial learning on the matching to place task as did rats. These species differences in swimming pool place learning are discussed with respect to both methodological considerations and to species differences in preparedness to learn. It is suggested that given the variability of the performance of mice across both strains and laboratories, rat performance could be used to provide a baseline for comparative purposes.
Place cells in the rat hippocampus fire whenever the animal is in a particular location. In a symmetrical environment, their receptive fields (place fields) are oriented by visual cues, and if these are unavailable they are oriented by movement-generated (idiothetic) cues. The present study tested the hypothesis that the cells would learn not to 'trust' a visual cue if the rat experienced it to be unstable (Knierim et al., 1995. Place cells, head direction cells and the learning of landmark stability. J. Neurosci. 15, 1648-1659). In an otherwise symmetrical environment, a visual cue was moved with respect to the idiothetic cues, either in sight or out-of-sight of the rat. When the visual cue was moved out-of-sight of the rat, place fields were initially oriented by this cue in preference to the idiothetic cues. However, if the cue was seen by the rat to be mobile, place fields ceased following the visual cue and became oriented by the idiothetic cues instead. If the cue was not seen to be mobile until the rat had had several days of experience in the environment, then the fields continued to be oriented by the (now visibly mobile) visual cue. It thus appears that the orienting influence of a visual cue on place fields can be either strengthened or weakened relative to the idiothetic cues, depending on the experience of the rat.
In this study, hippocampal place cells were recorded in a behavioral paradigm previously not employed in place-cell research. Rats were exposed to the same fixed environment for as long as 8-24 h without interruption, while the firing of CA1 and CA3 place cells was monitored continuously. The first finding was that all place cells that were detected at the beginning of the recording sessions ceased to produce location-specific firing in their original firing fields within 2-12 h. This was observed despite the fact that the animals kept visiting the original firing fields, the hippocampal EEG was virtually unchanged, and the discriminated action potentials of the cells could be clearly recorded. The second finding was that some complex-spike cells that produced no spatially selective firing pattern at the beginning of the recording sessions developed location-specific discharges within 3-12 h. Thus, place cells can flexibly terminate and develop their spatial firing. even in a fixed environment and during similar behaviors, if that environment is explored continuously for a prolonged period. To explain this phenomenon, a new place-cell theory is outlined. Accordingly, the high-frequency discharges of these neurons may serve to create, under multiple extrahippocampal control and within limited periods, stable engrams for specific spatial sites in the association cortex where the cognitive map probably resides. After the creation of a stable engram, or in the absence of favorable extrahippocampal inputs, place cells may suspend their location-specific firing in the original field, and initiate the processing of another spatial site.
Access to novel objects, similar to drugs of abuse, can enhance a place preference in rats. In the present experiments, the dopamine D1 receptor antagonist SCH-23390 blocked an increase in place preference conditioned by access to novel objects at doses that did not interfere with object interaction (0.01 and 0.03 mg/kg) or produce a place aversion in controls. However, eticlopride, a D2/D3 dopamine receptor antagonist, only blocked the conditioned increase in place preference at a dose (0.3 mg/kg) that impaired object interaction. In contrast, neither SCH-23390 nor eticlopride blocked preference for the novel object in an object recognition task at doses that did not interfere with object interaction. These experiments provide further evidence that the neural processes controlling learned associations between novel stimuli and the environment overlap with drugs of abuse.
Trace eyeblink classical conditioning is a non-spatial learning paradigm that requires an intact hippocampus. This task is hippocampus-dependent because the auditory tone conditioned stimulus (CS) is temporally separated from the corneal airpuff unconditioned stimulus (US) by a 500-ms trace interval. Our laboratory has performed a series of neurophysiological experiments that have examined the activity of pyramidal cells in the CA1 area of the hippocampus during trace eyeblink conditioning. We have found that the non-spatial stimuli involved in this paradigm are encoded in the hippocampus in a logical order that is necessary for their association and the subsequent expression of behavioral learning. Although there were many profiles of single neurons responding to the CS-US trial during training, the majority of the neurons showed an increase in activity to the airpuff-US. Prior to learning, it appears that hippocampal cells and ensembles of cells were preferentially attending to the stimulus with immediate behavioral importance, the US. Hippocampal cells then began to respond to the associated neutral stimulus, the CS. Shortly thereafter, animals began to show increases in the behavioral expression of CRs. In some experiments, hippocampal neurons from aged animals exhibited impairments in the encoding of CS and US information. These aged animals were not able to associate these stimuli and acquire trace eyeblink CRs. Our findings along with the findings of other spatial learning studies, suggest that the hippocampus is involved in encoding information about discontiguous sets of stimuli, either spatial or nonspatial, especially early in the learning process.
Continuous rotation of an arena in a cue-rich room dissociates the stationary room-bound information from the rotating arena-bound information. This disrupted spatial discharge in the majority of place cells from rats trained to collect randomly scattered food. In contrast, most place cell firing patterns recorded from rats trained to solve a navigation task on the rotating arena were preserved during the rotation. Spatial discharge was preserved in both the task-relevant stationary and the task-irrelevant rotating reference frames, but firing was more organized in the task-relevant frame. It is concluded that, (i) the effects of environmental manipulations can be understood with confidence only when the rat's purposeful behavior is used to formulate interpretations of the data, and (ii) hippocampal place cell activity is organized in multiple overlapping spatial reference frames.
When attention is directed to a location in the visual field, sensitivity to stimuli at that location is increased. At the neuronal level, this could arise either through a multiplicative increase in firing rate or through an increase in the effective strength of the stimulus. To test conflicting predictions of these alternative models, we recorded responses of V4 neurons to stimuli across a range of luminance contrasts and measured the change in response when monkeys attended to them in order to discriminate a target stimulus from nontargets. Attention caused greater increases in response at low contrast than at high contrast, consistent with an increase in effective stimulus strength. On average, attention increased the effective contrast of the attended stimulus by a factor of 1.51, an increase of 51% of its physical contrast.
For years, the debate has been: "Is the hippocampus the cognitive map?" or "Is the hippocampus the core of memory?" These two hypotheses derived their original power from two key experiments--the cognitive map theory from the remarkable spatial correlates seen in recordings of hippocampal pyramidal cells and the memory theory from the profound amnesias seen in the patient H.M. Both of these key experiments have been reinterpreted over the years: hippocampal cells are correlated with much more than place and H.M. is missing much more than just his hippocampus. However, both theories are still debated today. The hippocampus clearly plays a role in both navigation and memory processing. The question that must be addressed is rather: "What is the role played by the hippocampus in the navigation and memory systems?" By looking at the navigation system as a whole, one can identify the major role played by the hippocampus as correcting for accumulation errors that occur within idiothetic navigation systems. This is most clearly experimentally evident as reorientation when an animal is lost. Carrying this over to a more general process, this becomes a role of recalling a context, bridging a contextual gap, or, in other words, it becomes a form of recognition memory. I will review recent experimental data which seems to support this theory over the more general spatial or memory theories traditionally applied to hippocampus.
Theta oscillations represent the "on-line" state of the hippocampus. The extracellular currents underlying theta waves are generated mainly by the entorhinal input, CA3 (Schaffer) collaterals, and voltage-dependent Ca(2+) currents in pyramidal cell dendrites. The rhythm is believed to be critical for temporal coding/decoding of active neuronal ensembles and the modification of synaptic weights. Nevertheless, numerous critical issues regarding both the generation of theta oscillations and their functional significance remain challenges for future research.
There is a good deal of evidence that in the rodent, an internal model of the external world is encoded by hippocampal pyramidal cells, called 'place cells'. During free exploration, the activity of place cells is higher within a small part of the space, called the firing field, and virtually silent elsewhere. We have previously shown that the spiking activity during passes through the firing field is characterized not only by the high firing rate, but also by its very high variability ('overdispersion'). This overdispersion indicates that place cells carry information in addition to position. Here we demonstrate by simulations of an integrate-and-fire neuronal model that while a rat is foraging in an open space this additional information may arise from a process that alternatingly modulates the inputs to place cells by about 10% with a mean period of about 1 s. We propose that the overdispersion reflects switches of the rats attention between different spatial reference frames of the environment. This predicts that the overdispersion will not be observed in rats that use only room-based cues for navigation. We show that while place cell firing is overdispersed in rats during foraging in an open arena, the firing is less overdispersed during the same behavior in the same environment, when the rats have been trained to use only room-based and not arena-based cues to navigate.
The spatially localized firing of hippocampal place cells is thought to underlie the navigational function of the hippocampus. Performance on a spatial task learned using a particular place cell map should therefore deteriorate if the map is disrupted. To test this prediction, we trained rats on a hippocampal-dependent spatial task in a black box and tested them in a white box. Although the change from black to white induced remapping of most place cells, navigational performance remained essentially intact. Furthermore, place cell activity was also unrelated to specific aspects of the task such as tone onset, response, or goal location. Together, these results imply that the spatial information needed to solve this navigation task is represented outside the hippocampus and suggest that the place cells encode some other aspect, such as the spatial context.
In addition to its role in memory formation, the hippocampus may act as a novelty detector. Here we investigated whether attention to novel events can promote the associative synaptic plasticity mechanisms believed to be necessary for storing those events in memory. We therefore examined whether exposure to a novel spatial environment promoted the induction of activity-dependent persistent increases in glutamatergic transmission (long-term potentiation, LTP) at CA1 synapses in the rat hippocampus. We found that brief exposure to a novel environment lowered the threshold for the induction of LTP. This facilitatory effect was present for a short period following novelty exposure but was absent in animals that explored a familiar environment. Furthermore, the facilitation was dependent on activation of D1/D5 receptors. These findings support an important role for dopamine-regulated synaptic plasticity in the storage of unpredicted information in the CA1 area.
Long-term stability of the Pre-place-field activity of single units recorded from the dorsal hippo-served performance in a hippocampal-dependent spatial task de-campus of freely behaving rats
- L T Thompson
- P J Best
- K J Jeffery
- A Gilbert
- S Burton
- A Strudwick
Thompson, L.T., and Best, P.J. (1990). Long-term stability of the Jeffery, K.J., Gilbert, A., Burton, S., and Strudwick, A. (2003). Pre-place-field activity of single units recorded from the dorsal hippo-served performance in a hippocampal-dependent spatial task de-campus of freely behaving rats. Brain Res. 509, 299–308.
Binding of hippocampal CA1 neural activity to multiple refer Parallel instabilities of long-term potentiation, place ence frames in a landmark-based navigation task
- A Abel
- T Hawkins
- R D Kandel
- E R Muller
(1996). Binding of hippocampal CA1 neural activity to multiple refer-Rotenberg, A., Abel, T., Hawkins, R.D., Kandel, E.R., and Muller, R.U. (2000). Parallel instabilities of long-term potentiation, place ence frames in a landmark-based navigation task. J. Neurosci. 16, 823–835.
Inbred C57 black mice Learning of landmark stability and instability by cropthalmia and ocular infections. JAX Notes Fall 463. hippocampal place cells
- R S Smith
- J P Sundberg
Smith, R.S., and Sundberg, J.P. (1995). Inbred C57 black mice: mi-Jeffery, K.J. (1998). Learning of landmark stability and instability by cropthalmia and ocular infections. JAX Notes Fall 463. hippocampal place cells. Neuropharmacology 37, 677–687.
Neural correlates of attention in primate visual Kentros
- S C Treue
- E Hargreaves
- R D Hawkins
- E R Kandel
- Shapiro
Treue, S. (2001). Neural correlates of attention in primate visual Kentros, C., Hargreaves, E., Hawkins, R.D., Kandel, E.R., Shapiro, cortex. Trends Neurosci. 24, 295–300.
Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade Priming and human memory 280
- M Muller
- R V E Schacter
M., and Muller, R.V. (1998). Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science Tulving, E., and Schacter, D.L. (1990). Priming and human memory 280, 2121–2126.
A comparison of rats and mice in a swimming Place cells, head direction cells, and the learning of landmark stability. J. pool place task and matching to place task: some surprising differ-ences
- I Q Whishaw
- J J Knierim
- H S Kudrimoti
- B L Mcnaughton
Whishaw, I.Q. (1995). A comparison of rats and mice in a swimming Knierim, J.J., Kudrimoti, H.S., and McNaughton, B.L. (1995). Place cells, head direction cells, and the learning of landmark stability. J. pool place task and matching to place task: some surprising differ-ences. Physiol. Behav. 58, 687–693.