Showing papers in "Hippocampus in 2020"

The content of hippocampal "replay".

Abstract: One of the most striking features of the hippocampal network is its ability to self-generate neuronal sequences representing temporally compressed, spatially coherent paths. These brief events, often termed "replay" in the scientific literature, are largely confined to non-exploratory states such as sleep or quiet rest. Early studies examining the content of replay noted a strong correlation between the encoded spatial information and the animal's prior behavior; thus, replay was initially hypothesized to play a role in memory formation and/or systems-level consolidation via "off-line" reactivation of previous experiences. However, recent findings indicate that replay may also serve as a memory retrieval mechanism to guide future behavior or may be an incidental reflection of pre-existing network assemblies. Here, I will review what is known regarding the content of replay events and their correlation with past and future actions, and I will discuss how this knowledge might inform or constrain models which seek to explain the circuit-level mechanisms underlying these events and their role in mnemonic processes.

Meta‐analytic and functional connectivity evidence from functional magnetic resonance imaging for an anterior to posterior gradient of function along the hippocampal axis

Abstract: There is considerable evidence from non-human animal studies that the anterior and posterior regions of the hippocampus have different anatomical connections and support different behavioural functions. Although there are some recent human studies using functional magnetic resonance imaging (fMRI) that have addressed this idea directly in the memory and spatial processing domains and provided support for it, there has been no broader meta-analysis of the fMRI literature to determine if there is consistent evidence for functional dissociations in anterior and posterior hippocampus across all of the different cognitive domains in which the hippocampus participates. The purpose of this review is to address this gap in our knowledge using three approaches. One approach involved PubMed searches to identify relevant fMRI papers reporting hippocampal activation during episodic encoding and retrieval, semantic retrieval, working memory, spatial navigation, simulation/scene construction, transitive inference, and social cognition tasks. The second was to use a large meta-analytic database (neurosynth) to find text terms and coactivation maps associated with the anterior and posterior hippocampal regions identified in the literature search. The third approach was to contrast the resting-state functional connectivity of the anterior and posterior hippocampal regions using a publicly available database that includes a large sample of adults. These three approaches provided converging evidence that not only are cognitive processes differently distributed along the hippocampal axis, but there also are distinct areas coactivated and functionally connected with the anterior and posterior segments. This anterior/posterior distinction involving multiple cognitive domains is consistent with the animal literature and provides strong support from fMRI for the idea of functional dissociations across the long axis of the hippocampus.

Flexible spatial learning requires both the dorsal and ventral hippocampus and their functional interactions with the prefrontal cortex

Abstract: When faced with changing contingencies, animals can use memory to flexibly guide actions, engaging both frontal and temporal lobe brain structures. Damage to the hippocampus (HPC) impairs episodic memory, and damage to the prefrontal cortex (PFC) impairs cognitive flexibility, but the circuit mechanisms by which these areas support flexible memory processing remain unclear. The present study investigated these mechanisms by temporarily inactivating the medial PFC (mPFC), the dorsal HPC (dHPC), and the ventral HPC (vHPC), individually and in combination, as rats learned spatial discriminations and reversals in a plus maze. Bilateral inactivation of either the dHPC or vHPC profoundly impaired spatial learning and memory, whereas bilateral mPFC inactivation primarily impaired reversal versus discrimination learning. Inactivation of unilateral mPFC together with the contralateral dHPC or vHPC impaired spatial discrimination and reversal learning, whereas ipsilateral inactivation did not. Flexible spatial learning thus depends on both the dHPC and vHPC and their functional interactions with the mPFC.

Navigating with grid and place cells in cluttered environments.

Abstract: Hippocampal formation contains several classes of neurons thought to be involved in navigational processes, in particular place cells and grid cells. Place cells have been associated with a topological strategy for navigation, while grid cells have been suggested to support metric vector navigation. Grid cell-based vector navigation can support novel shortcuts across unexplored territory by providing the direction toward the goal. However, this strategy is insufficient in natural environments cluttered with obstacles. Here, we show how navigation in complex environments can be supported by integrating a grid cell-based vector navigation mechanism with local obstacle avoidance mediated by border cells and place cells whose interconnections form an experience-dependent topological graph of the environment. When vector navigation and object avoidance fail (i.e., the agent gets stuck), place cell replay events set closer subgoals for vector navigation. We demonstrate that this combined navigation model can successfully traverse environments cluttered by obstacles and is particularly useful where the environment is underexplored. Finally, we show that the model enables the simulated agent to successfully navigate experimental maze environments from the animal literature on cognitive mapping. The proposed model is sufficiently flexible to support navigation in different environments, and may inform the design of experiments to relate different navigational abilities to place, grid, and border cell firing.

The role of replay and theta sequences in mediating hippocampal‐prefrontal interactions for memory and cognition

Abstract: Sequential activity is seen in the hippocampus during multiple network patterns, prominently as replay activity during both awake and sleep sharp-wave ripples (SWRs), and as theta sequences during active exploration. Although various mnemonic and cognitive functions have been ascribed to these hippocampal sequences, evidence for these proposed functions remains primarily phenomenological. Here, we briefly review current knowledge about replay events and theta sequences in spatial memory tasks. We reason that in order to gain a mechanistic and causal understanding of how these patterns influence memory and cognitive processing, it is important to consider how these sequences influence activity in other regions, and in particular, the prefrontal cortex, which is crucial for memory-guided behavior. For spatial memory tasks, we posit that hippocampal-prefrontal interactions mediated by replay and theta sequences play complementary and overlapping roles at different stages in learning, supporting memory encoding and retrieval, deliberative decision making, planning, and guiding future actions. This framework offers testable predictions for future physiology and closed-loop feedback inactivation experiments for specifically targeting hippocampal sequences as well as coordinated prefrontal activity in different network states, with the potential to reveal their causal roles in memory-guided behavior.

Anterior and posterior hippocampus macro- and microstructure across the lifespan in relation to memory-A longitudinal study.

Abstract: There is evidence for a hippocampal long axis anterior-posterior (AP) differentiation in memory processing, which may have implications for the changes in episodic memory performance seen across development and aging. The hippocampus shows substantial structural changes with age, but the lifespan trajectories of hippocampal sub-regions along the AP axis are not established. The aim of the present study was to test whether the micro- and macro-structural age-trajectories of the anterior (aHC) and posterior (pHC) hippocampus are different. In a single-center longitudinal study, 1,790 cognitively healthy participants, 4.1-93.4 years of age, underwent a total of 3,367 MRI examinations and 3,033 memory tests sessions over 1-6 time points, spanning an interval up to 11.1 years. T1-weighted scans were used to estimate the volume of aHC and pHC (macrostructure), and diffusion tensor imaging to measure mean diffusion (MD, microstructure) within each region. We found that the macro- and microstructural lifespan-trajectories of aHC and pHC were clearly distinguishable, with partly common and partly unique variance shared with age. aHC showed a protracted period of microstructural development, while pHC microstructural development as indexed by MD was more or less completed in early childhood. In contrast, pHC showed larger unique aging-related changes. An aHC-pHC difference was also observed for volume, with pHC changing relatively more with higher age. All regions showed age-dependent relationships with episodic memory. aHC micro- and macrostructure was significantly related to verbal memory independently of age, but the relationships were still strongest among the older participants. We suggest that memory processes supported by each sub-region improve or decline in concert with volumetric and microstructural changes in the same age-period. Future research should disentangle the lifespan relationship between changes in these structural properties and different memory processes, encoding versus retrieval in particular, as well as other cognitive functions depending on the hippocampal long-axis specialization.

Learning, memory and consolidation mechanisms for behavioral control in hierarchically organized cortico-basal ganglia systems.

Abstract: This article aims to provide a synthesis on the question how brain structures cooperate to accomplish hierarchically organized behaviors, characterized by low-level, habitual routines nested in larger sequences of planned, goal-directed behavior. The functioning of a connected set of brain structures-prefrontal cortex, hippocampus, striatum, and dopaminergic mesencephalon-is reviewed in relation to two important distinctions: (a) goal-directed as opposed to habitual behavior and (b) model-based and model-free learning. Recent evidence indicates that the orbitomedial prefrontal cortices not only subserve goal-directed behavior and model-based learning, but also code the "landscape" (task space) of behaviorally relevant variables. While the hippocampus stands out for its role in coding and memorizing world state representations, it is argued to function in model-based learning but is not required for coding of action-outcome contingencies, illustrating that goal-directed behavior is not congruent with model-based learning. While the dorsolateral and dorsomedial striatum largely conform to the dichotomy between habitual versus goal-directed behavior, ventral striatal functions go beyond this distinction. Next, we contextualize findings on coding of reward-prediction errors by ventral tegmental dopamine neurons to suggest a broader role of mesencephalic dopamine cells, viz. in behavioral reactivity and signaling unexpected sensory changes. We hypothesize that goal-directed behavior is hierarchically organized in interconnected cortico-basal ganglia loops, where a limbic-affective prefrontal-ventral striatal loop controls action selection in a dorsomedial prefrontal-striatal loop, which in turn regulates activity in sensorimotor-dorsolateral striatal circuits. This structure for behavioral organization requires alignment with mechanisms for memory formation and consolidation. We propose that frontal corticothalamic circuits form a high-level loop for memory processing that initiates and temporally organizes nested activities in lower-level loops, including the hippocampus and the ripple-associated replay it generates. The evidence on hierarchically organized behavior converges with that on consolidation mechanisms in suggesting a frontal-to-caudal directionality in processing control.

Is hippocampal remapping the physiological basis for context

Abstract: In 1980, Nadel and Wilner extended Richard Hirsh's notion that the hippocampus creates environmental representations, called "contexts," suggesting that the fundamental structure of context was the spatial representation proposed by O'Keefe and Nadel's landmark book, The Hippocampus as a Cognitive Map (1978). This book, in turn, derives from the discovery that individual hippocampal neurons act as place cells, with the complete set of place cells tiling an enclosure, forming a type of spatial map. It was found that unique environments had unique place cell representations. That is, if one takes the hippocampal map of a specific environment, this representation scrambles, or "remaps" when the animal is placed in a different environment. Several authors have speculated that "maps" and "remapping" form the physiological substrates for context and context shifting. One difficulty with this definition is that it is exclusively spatial; it can only be inferred when an animal locomotes in an enclosure. There are five aims for this article. The first is to give an historical overview of context as a variable that controls behavior. The second aim is to give an historical overview of concepts of place cell maps and remapping. The third aim is to propose an updated definition of a place cell map, based on temporal rather than spatial overlaps, which adds flexibility. The fourth aim is to address the issue of whether the biological phenomenon of hippocampal remapping, is, in fact, the substrate for shifts in the psychological phenomenon of context. The final aim is speculation of how contextual representations may contribute to effective behavior.

Place cell firing cannot support navigation without intact septal circuits.

Abstract: Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location-specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA-A agonist; and gabazine, a GABA-A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location-specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location-specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.

Improving fitness increases dentate gyrus/CA3 volume in the hippocampal head and enhances memory in young adults

Abstract: Converging evidence suggests a relationship between aerobic exercise and hippocampal neuroplasticity that interactively impacts hippocampally-dependent memory. The majority of human studies have focused on the potential for exercise to reduce brain atrophy and attenuate cognitive decline in older adults, whereas animal studies often center on exercise-induced neurogenesis and hippocampal plasticity in the dentate gyrus of young adult animals. In the present study, initially sedentary young adults (18–35 years) participated in a moderate-intensity randomized controlled exercise intervention trial (ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT02057354","term_id":"NCT02057354"}}NCT02057354) for a duration of twelve weeks. The aims of the study were to investigate the relationship between change in cardiorespiratory fitness (CRF) as determined by estimated V˙O2MAX, hippocampally-dependent mnemonic discrimination, and change in hippocampal subfield volume. Results show that improving CRF after exercise training is associated with an increased volume in the left dentate gyrus/CA3 subregion in young adults. Consistent with previous studies that found exercise-induced increases in anterior hippocampus in older adults, this result was specific to the hippocampal head, or most anterior portion, of the subregion. Our results also demonstrate a positive relationship between change in CRF and change in corrected accuracy for trials requiring the highest level of discrimination on a putative behavioral pattern separation task. This relationship was observed in individuals who were initially lower-fit, suggesting that individuals who show greater improvement in their CRF may receive greater cognitive benefit. This work extends animal models by providing evidence for exercise-induced neuroplasticity specific to the neurogenic zone of the human hippocampus.

The rodent hippocampus as a bilateral structure: A review of hemispheric lateralization

Abstract: The left and right rodent hippocampi exhibit striking lateralization in some of the very neural substrates considered to be critical for hippocampal cognitive function. Despite this, there is an overwhelming lack of consideration for hemispheric differences in studies of the rodent hippocampus. Asymmetries identified so far suggest that a bilateral model of the hippocampus will be essential for an understanding of this brain region, and perhaps of the brain more widely. Although hypotheses have been proposed to explain how the left and right hippocampi contribute to behavior and cognition, these hypotheses have either been refuted by more recent studies or have been limited in the scope of data they explain. Here, I will first review data on human and rodent hippocampal lateralization. The implications of these data suggest that considering the hippocampus as a bilateral structure with functional lateralization will be critical moving forward in understanding the function and mechanisms of this brain region. In exploring these implications, I will then propose a hypothesis of the hippocampus as a bilateral structure. This discrete-continuous hypothesis proposes that the left and right hippocampi contribute to spatial memory and navigation in a complementary manner. Specifically, the left hemisphere stores spatial information as discrete, salient locations, and the right hemisphere represents space continuously, contributing to route computation and flexible spatial navigation. Consideration of hippocampal lateralization in designing future studies may provide insight into the function of the hippocampus and resolve debates concerning its function.

Data-driven integration of hippocampal CA1 synaptic physiology in silico.

Abstract: The anatomy and physiology of monosynaptic connections in rodent hippocampal CA1 have been extensively studied in recent decades. Yet, the resulting knowledge remains disparate and difficult to reconcile. Here, we present a data-driven approach to integrate the current state-of-the-art knowledge on the synaptic anatomy and physiology of rodent hippocampal CA1, including axo-dendritic innervation patterns, number of synapses per connection, quantal conductances, neurotransmitter release probability, and short-term plasticity into a single coherent resource. First, we undertook an extensive literature review of paired recordings of hippocampal neurons and compiled experimental data on their synaptic anatomy and physiology. The data collected in this manner is sparse and inhomogeneous due to the diversity of experimental techniques used by different groups, which necessitates the need for an integrative framework to unify these data. To this end, we extended a previously developed workflow for the neocortex to constrain a unifying in silico reconstruction of the synaptic physiology of CA1 connections. Our work identifies gaps in the existing knowledge and provides a complementary resource toward a more complete quantification of synaptic anatomy and physiology in the rodent hippocampal CA1 region.

Neurobiological successor features for spatial navigation.

Abstract: The hippocampus has long been observed to encode a representation of an animal's position in space. Recent evidence suggests that the nature of this representation is somewhat predictive and can be modeled by learning a successor representation (SR) between distinct positions in an environment. However, this discretization of space is subjective making it difficult to formulate predictions about how some environmental manipulations should impact the hippocampal representation. Here, we present a model of place and grid cell firing as a consequence of learning a SR from a basis set of known neurobiological features-boundary vector cells (BVCs). The model describes place cell firing as the successor features of the SR, with grid cells forming a low-dimensional representation of these successor features. We show that the place and grid cells generated using the BVC-SR model provide a good account of biological data for a variety of environmental manipulations, including dimensional stretches, barrier insertions, and the influence of environmental geometry on the hippocampal representation of space.

Hippocampal ripples as a mode of communication with cortical and subcortical areas.

Abstract: Hippocampal sharp wave-ripple complexes are transient events of highly synchronous neuronal activity that typically occur during "offline" brain states. This endogenous surge of activity consists of behaviorally relevant spiking patterns, describing spatial trajectories. They have been shown to play a critical role in memory consolidation during sleep and in navigational planning during wakefulness. Beyond their local impact on the hippocampal formation, ripples also exert direct and indirect effects on target cortical and subcortical areas, which are thought to play a key role in information processing and semantic network reconfiguration. We review research into the function of hippocampal sharp waves-ripples, with a special focus on information flow between the hippocampus and its cortical and subcortical targets. First, we briefly review seminal work establishing a causal role of ripple-related activity in cognitive processes. We then review evidence for a functional interplay between hippocampal ripples and specific patterns of cortical and subcortical activity. Finally, we discuss the critical role of the functional coupling between ripples and other sleep rhythms, including the cortical slow oscillation and thalamocortical sleep spindles.

Interactive effects of stress reactivity and rapid eye movement sleep theta activity on emotional memory formation.

Abstract: Sleep and stress independently enhance emotional memory consolidation. In particular, theta oscillations (4-7 Hz) during rapid eye movement (REM) sleep increase coherence in an emotional memory network (i.e., hippocampus, amygdala, and prefrontal cortex) and enhance emotional memory. However, little is known about how stress during learning might interact with subsequent REM theta activity to affect emotional memory. In the current study, we examined whether the relationship between REM theta activity and emotional memory differs as a function of pre-encoding stress exposure and reactivity. Participants underwent a psychosocial stressor (the Trier Social Stress Task; n = 32) or a comparable control task (n = 32) prior to encoding. Task-evoked cortisol reactivity was assessed by salivary cortisol rise from pre- to post-stressor, and participants in the stress condition were additionally categorized as high or low cortisol responders via a median split. During incidental encoding, participants studied 150 line drawings of negative, neutral, and positive images, followed by the complete color photo. All participants then slept overnight in the lab with polysomnographic recording. The next day, they were given a surprise recognition memory task. Results showed that memory was better for emotional relative to neutral information. Critically, these findings were observed only in the stress condition. No emotional memory benefit was observed in the control condition. In stressed participants, REM theta power significantly predicted memory for emotional information, specifically for positive items. This relationship was observed only in high cortisol responders. For low responders and controls, there was no relationship between REM theta and memory of any valence. These findings provide evidence that elevated stress at encoding, and accompanying changes in neuromodulators such as cortisol, may interact with theta activity during REM sleep to promote selective consolidation of emotional information.

Characterization of hippocampal subfields using ex vivo MRI and histology data: Lessons for in vivo segmentation.

Abstract: Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2-weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA-stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body-like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.

Spatial coordinate transforms linking the allocentric hippocampal and egocentric parietal primate brain systems for memory, action in space, and navigation

Abstract: A theory and model of spatial coordinate transforms in the dorsal visual system through the parietal cortex that enable an interface via posterior cingulate and related retrosplenial cortex to allocentric spatial representations in the primate hippocampus is described. First, a new approach to coordinate transform learning in the brain is proposed, in which the traditional gain modulation is complemented by temporal trace rule competitive network learning. It is shown in a computational model that the new approach works much more precisely than gain modulation alone, by enabling neurons to represent the different combinations of signal and gain modulator more accurately. This understanding may have application to many brain areas where coordinate transforms are learned. Second, a set of coordinate transforms is proposed for the dorsal visual system/parietal areas that enables a representation to be formed in allocentric spatial view coordinates. The input stimulus is merely a stimulus at a given position in retinal space, and the gain modulation signals needed are eye position, head direction, and place, all of which are present in the primate brain. Neurons that encode the bearing to a landmark are involved in the coordinate transforms. Part of the importance here is that the coordinates of the allocentric view produced in this model are the same as those of spatial view cells that respond to allocentric view recorded in the primate hippocampus and parahippocampal cortex. The result is that information from the dorsal visual system can be used to update the spatial input to the hippocampus in the appropriate allocentric coordinate frame, including providing for idiothetic update to allow for self-motion. It is further shown how hippocampal spatial view cells could be useful for the transform from hippocampal allocentric coordinates to egocentric coordinates useful for actions in space and for navigation.

The history of long-term potentiation as a memory mechanism: Controversies, confirmation, and some lessons to remember.

Abstract: The discovery of long-term potentiation (LTP) provided the first, direct evidence for long-lasting synaptic plasticity in the living brain. Consequently, LTP was proposed to serve as a mechanism for information storage among neurons, thus providing the basis for the behavioral and psychological phenomena of learning and long-term memory formation. However, for several decades, the LTP-memory hypothesis remained highly controversial, with inconsistent and contradictory evidence providing a barrier to its general acceptance. This review summarizes the history of these early debates, challenges, and experimental strategies (successful and unsuccessful) to establish a link between LTP and memory. Together, the empirical evidence, gathered over a period of about four decades, strongly suggests that LTP serves as one of the mechanisms affording learning and memory storage in neuronal circuits. Notably, this body of work also offers some important lessons that apply to the broader fields of behavioral and cognitive neuroscience. As such, the history of LTP as a learning mechanism provides valuable insights to neuroscientists exploring the relations between brain and psychological states.

Event conjunction: How the hippocampus integrates episodic memories across event boundaries.

Abstract: Our lives are a continuous stream of experience. Our episodic memories on the other hand have a definitive beginning, middle, and end. Theories of event segmentation suggest that salient changes in our environment produce event boundaries which partition the past from the present and, as a result, produce discretized memories. However, event boundaries cannot completely discretize two memories; any shared conceptual link will lead to the rapid integration of these memories. Here, we present a new framework inspired by electrophysiological research that resolves this apparent contradiction. At its heart, the framework proposes that hippocampal theta-gamma coupling maintains a highly abstract model of an ongoing event and serves to encode this model as an episodic memory. When a second but related event begins, this theta-gamma model is rapidly reconstructed within the hippocampus where new details of the second event can be appended to the existing event model. The event conjunction framework is the first electrophysiological explanation of how event memories can be formed at, and integrated across, event boundaries.

Recalling Lashley and reconsolidating Hebb.

Abstract: Many of the foundational theoretical ideas in the field of learning and memory are traced to Donald Hebb. Examination of these ideas and their evolution suggest that Karl Lashley might have significantly influenced their development. Here, we discuss the relationship between Hebb and Lashley, and the parallels between them. Many now investigating the neurobiological basis of memory may be unaware both of Hebb's original descriptions, and the likely substantial contributions of Lashley. Many of their concerns remain with us today, and by clarifying the history we hope to strengthen the foundations of our field.

Conjunctive representation of what and when in monkey hippocampus and lateral prefrontal cortex during an associative memory task

Abstract: Adaptive memory requires the organism to form associations that bridge between events separated in time. Many studies show interactions between hippocampus (HPC) and prefrontal cortex (PFC) during formation of such associations. We analyze neural recording from monkey HPC and PFC during a memory task that requires the monkey to associate stimuli separated by about a second in time. After the first stimulus was presented, large numbers of units in both HPC and PFC fired in sequence. Many units fired only when a particular stimulus was presented at a particular time in the past. These results indicate that both HPC and PFC maintain a temporal record of events that could be used to form associations across time. This temporal record of the past is a key component of the temporal coding hypothesis, a hypothesis in psychology that memory not only encodes what happened, but when it happened.

Advantages and detection of phase coding in the absence of rhythmicity

Abstract: The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes. One notable example is provided by place and grid cells in the rodent hippocampal formation, which exhibit phase precession-firing at progressively earlier phases of the 6-12 Hz movement-related theta rhythm as their spatial firing fields are traversed. It is often assumed that such phase coding relies on a high amplitude baseline oscillation with relatively constant frequency. However, sustained oscillations with fixed frequency are generally absent in LFP and spike train recordings from the human brain. Hence, we examine phase coding relative to LFP signals with broadband low-frequency (2-20 Hz) power but without regular rhythmicity. We simulate a population of grid cells that exhibit phase precession against a baseline oscillation recorded from depth electrodes in human hippocampus. We show that this allows grid cell firing patterns to multiplex information about location, running speed and movement direction, alongside an arbitrary fourth variable encoded in LFP frequency. This is of particular importance given recent demonstrations that movement direction, which is essential for path integration, cannot be recovered from head direction cell firing rates. In addition, we investigate how firing phase might reduce errors in decoded location, including those arising from differences in firing rate across grid fields. Finally, we describe analytical methods that can identify phase coding in the absence of high amplitude LFP oscillations with approximately constant frequency, as in single unit recordings from the human brain and consistent with recent data from the flying bat. We note that these methods could also be used to detect phase coding outside of the spatial domain, and that multi-unit activity can substitute for the LFP signal. In summary, we demonstrate that the computational advantages offered by phase coding are not contingent on, and can be detected without, regular rhythmicity in neural activity.

Age‐associated changes in waking hippocampal sharp‐wave ripples

Abstract: Hippocampal sharp-wave ripples are brief high-frequency (120-250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate-of-occurrence of ripples during sleep that may contribute to age-associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age-dependent changes. Sharp-wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place-dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track-running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task-relevant information and compensate for age-related declines in ripple rate during task performance.

Optogenetic "low-theta" pacing of the septohippocampal circuit is sufficient for spatial goal finding and is influenced by behavioral state and cognitive demand.

Abstract: Hippocampal theta oscillations show prominent changes in frequency and amplitude depending on behavioral state or cognitive demands. How these dynamic changes in theta oscillations contribute to the spatial and temporal organization of hippocampal cells, and ultimately behavior, remain unclear. We used low-theta frequency optogenetic stimulation to pace coordination of cellular and network activity between the medial septum (MS) and hippocampus during baseline and MS stimulation while rats were at rest or performing a spatial accuracy task with a visible or hidden goal zone. Hippocampal receptivity to pan-neuronal septal stimulation at low-theta frequency was primarily determined by speed and secondarily by task demands. Competition between artificial and endogenous field potentials at theta frequency attenuated hippocampal phase preference relative to local theta, but the spike-timing activity of hippocampal pyramidal cells was effectively driven by artificial septal output, particularly during the hidden goal task. Notwithstanding temporal reorganization by artificial theta stimulation, place field properties were unchanged and alterations to spatial behavior were limited to goal zone approximation. Our results indicate that even a low-theta frequency timing signal in the septohippocampal circuit is sufficient for spatial goal finding behavior. The results also advance a mechanistic understanding of how endogenous or artificial somatodendritic timing signals relate to displacement computations during navigation and spatial memory.

Double dissociation of learned approach-avoidance conflict processing and spatial pattern separation along the dorsoventral axis of the dentate gyrus.

Abstract: The ventral portion of the rodent hippocampus (HPC; anterior in primates) has been implicated in the detection and resolution of approach-avoidance conflict, which arises when an organism encounters a stimulus that predicts both positive and negative outcomes. Previous work has found differential regulation of approach-avoidance conflict behavior by the CA3 and CA1 subfields, with inhibition of ventral CA3 increasing approach toward conflicting stimuli and inhibition of the ventral CA1 potentiating avoidance. Here, we sought to extend these findings by investigating the role of the dentate gyrus (DG), the input region of the HPC, in learned approach-avoidance conflict processing in rats. Animals were first trained to acquire three different visuotactile cue-outcome associations in separate arms of a Y-maze (appetitive, aversive, and neutral). Postacquisition, they were administered a "conflict test," in which they were presented with a choice between exploring an arm in which the appetitive and aversive cues were concurrently presented (conflict stimulus), and another arm containing the neutral stimulus. GABAR-mediated inactivation of the ventral DG, but not dorsal DG, potentiated approach behavior toward the conflict stimulus, similar to the effects of ventral CA3 inactivation. In contrast, dorsal DG, but not ventral DG, inactivation was found to impair performance on a metric spatial discrimination task, which is commonly used as a test of pattern separation. The findings of this study demonstrate a robust double dissociation between the ventral and dorsal aspects of the DG, in line with previous reports of functional differences along the longitudinal axis of the HPC.

Longitudinal development of hippocampal subregions from early- to mid-childhood.

Abstract: Early childhood is characterized by vast changes in behaviors supported by the hippocampus and an increased susceptibility of the hippocampus to environmental influences. Thus, it is an important time to investigate the development of the hippocampus. Existing research suggests subregions of the hippocampus (i.e., head, body, tail) have dissociable functions and that the relations between subregions and cognitive abilities vary across development. However, longitudinal research examining age-related changes in subregions in humans, particularly during early childhood (i.e., 4-6 years), is limited. Using a large sample of 184 healthy 4- to 8-year-old children, the present study is the first to characterize developmental changes in hippocampal subregion volume from early- to mid-childhood. Results reveal differential developmental trajectories in hippocampal head, body, and tail during this period. Specifically, head volume showed a quadratic pattern of change, and both body and tail showed linear increases, resulting in a pattern of cubic change for total hippocampal volume. Further, main effects of sex on hippocampal volume (males > females) and hemispheric differences in developmental trajectories were observed. These findings provide an improved understanding of the development of the hippocampus and have important implications for research investigating a range of cognitive abilities and behaviors.

Spatial encoding in dorsomedial prefrontal cortex and hippocampus is related during deliberation.

Abstract: Deliberation is thought to involve the internal simulation of the outcomes of candidate actions, the valuation of those outcomes, and the selection of the actions with the highest expected value While it is known that deliberation involves prefrontal cortical areas, specifically the dorsomedial prefrontal cortex (dmPFC), as well as the hippocampus (HPC) and other brain regions, how these areas process prospective information and select actions is not well understood We recorded simultaneously from ensembles in dmPFC and CA1 of dorsal HPC in rats during performance of a spatial contingency switching task, and examined the relationships between spatial and reward encoding in these two areas during deliberation at the choice point We found that CA1 and dmPFC represented either goal locations or the current position simultaneously, but that when goal locations were encoded, HPC and dmPFC did not always represent the same goal location Ensemble activity in dmPFC predicted when HPC would represent goal locations, but on a broad timescale on the order of seconds Also, reward encoding in dmPFC increased during hippocampal theta cycles where CA1 ensembles represented the goal location These results suggest that dmPFC and HPC share prospective information during deliberation, that dmPFC may influence whether HPC represents prospective information, and that information recalled about goal locations by HPC may be integrated into dmPFC reward representations on fast timescales

Modulation of local field potentials and neuronal activity in primate hippocampus during saccades.

Abstract: Primates use saccades to gather information about objects and their relative spatial arrangement, a process essential for visual perception and memory. It has been proposed that signals linked to saccades reset the phase of local field potential (LFP) oscillations in the hippocampus, providing a temporal window for visual signals to activate neurons in this region and influence memory formation. We investigated this issue by measuring hippocampal LFPs and spikes in two macaques performing different tasks with unconstrained eye movements. We found that LFP phase clustering (PC) in the alpha/beta (8-16 Hz) frequencies followed foveation onsets, while PC in frequencies lower than 8 Hz followed spontaneous saccades, even on a homogeneous background. Saccades to a solid grey background were not followed by increases in local neuronal firing, whereas saccades toward appearing visual stimuli were. Finally, saccade parameters correlated with LFPs phase and amplitude: saccade direction correlated with delta (≤4 Hz) phase, and saccade amplitude with theta (4-8 Hz) power. Our results suggest that signals linked to saccades reach the hippocampus, producing synchronization of delta/theta LFPs without a general activation of local neurons. Moreover, some visual inputs co-occurring with saccades produce LFP synchronization in the alpha/beta bands and elevated neuronal firing. Our findings support the hypothesis that saccade-related signals enact sensory input-dependent plasticity and therefore memory formation in the primate hippocampus.

Grid coding, spatial representation, and navigation: Should we assume an isomorphism?

Abstract: Grid cells provide a compelling example of a link between cellular activity and an abstract and difficult to define concept like space. Accordingly, a representational perspective on grid coding argues that neural grid coding underlies a fundamentally spatial metric. Recently, some theoretical proposals have suggested extending such a framework to nonspatial cognition as well, such as category learning. Here, we provide a critique of the frequently employed assumption of an isomorphism between patterns of neural activity (e.g., grid cells), mental representation, and behavior (e.g., navigation). Specifically, we question the strict isomorphism between these three levels and suggest that human spatial navigation is perhaps best characterized by a wide variety of both metric and nonmetric strategies. We offer an alternative perspective on how grid coding might relate to human spatial navigation, arguing that grid coding is part of a much larger conglomeration of neural activity patterns that dynamically tune to accomplish specific behavioral outputs.

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval, and combining them attenuates the acquisition rate of spatial reference memory.

Abstract: The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over-generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.