Showing papers in "Hippocampus in 2022"

Hippocampal spatial view cells for memory and navigation, and their underlying connectivity in humans

Abstract: Hippocampal and parahippocampal gyrus spatial view neurons in primates respond to the spatial location being looked at. The representation is allocentric, in that the responses are to locations “out there” in the world, and are relatively invariant with respect to retinal position, eye position, head direction, and the place where the individual is located. The underlying connectivity in humans is from ventromedial visual cortical regions to the parahippocampal scene area, leading to the theory that spatial view cells are formed by combinations of overlapping feature inputs self‐organized based on their closeness in space. Thus, although spatial view cells represent “where” for episodic memory and navigation, they are formed by ventral visual stream feature inputs in the parahippocampal gyrus in what is the parahippocampal scene area. A second “where” driver of spatial view cells are parietal inputs, which it is proposed provide the idiothetic update for spatial view cells, used for memory recall and navigation when the spatial view details are obscured. Inferior temporal object “what” inputs and orbitofrontal cortex reward inputs connect to the human hippocampal system, and in macaques can be associated in the hippocampus with spatial view cell “where” representations to implement episodic memory. Hippocampal spatial view cells also provide a basis for navigation to a series of viewed landmarks, with the orbitofrontal cortex reward inputs to the hippocampus providing the goals for navigation, which can then be implemented by hippocampal connectivity in humans to parietal cortex regions involved in visuomotor actions in space. The presence of foveate vision and the highly developed temporal lobe for object and scene processing in primates including humans provide a basis for hippocampal spatial view cells to be key to understanding episodic memory in the primate and human hippocampus, and the roles of this system in primate including human navigation.

Complementary representations of time in the prefrontal cortex and hippocampus

Abstract: Episodic memory binds the spatial and temporal relationships between the elements of experience. The hippocampus encodes space through place cells that fire at specific spatial locations. Similarly, time cells fire sequentially at specific time points within a temporally organized experience. Recent studies in rodents, monkeys, and humans have identified time cells with discrete firing fields and cells with monotonically changing activity in supporting the temporal organization of events across multiple timescales. Using in vivo electrophysiological tetrode recordings, we simultaneously recorded neurons from the prefrontal cortex and dorsal CA1 of the hippocampus while rats performed a delayed match to sample task. During the treadmill mnemonic delay, hippocampal time cells exhibited sparser firing fields with decreasing resolution over time, consistent with previous results. In comparison, temporally modulated cells in the prefrontal cortex showed more monotonically changing firing rates, ramping up or decaying with the passage of time, and exhibited greater temporal precision for Bayesian decoding of time at long time lags. These time cells show exquisite temporal resolution both in their firing fields and in the fine timing of spikes relative to the phase of theta oscillations. Here, we report evidence of theta phase precession in both the prefrontal cortex and hippocampus during the temporal delay, however, hippocampal cells exhibited steeper phase precession slopes and more punctate time fields. To disentangle whether time cell activity reflects elapsed time or distance traveled, we varied the treadmill running speed on each trial. While many neurons contained multiplexed representations of time and distance, both regions were more strongly influenced by time than distance. Overall, these results demonstrate the flexible integration of spatiotemporal dimensions and reveal complementary representations of time in the prefrontal cortex and hippocampus in supporting memory‐guided behavior.

Methods to study adult hippocampal neurogenesis in humans and across the phylogeny

Abstract: The hippocampus hosts the continuous addition of new neurons throughout life—a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian species, including humans, and discuss the further validation of these data by single‐cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long‐standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high‐quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research field.

Integration of the CA2 region in the hippocampal network during epileptogenesis

Abstract: The CA2 pyramidal cells are mostly resistant to cell death in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis, but they are aberrantly integrated into the epileptic hippocampal network via mossy fiber sprouting. Furthermore, they show increased excitability in vitro in hippocampal slices obtained from human MTLE specimens or animal epilepsy models. Although these changes promote CA2 to contribute to epileptic activity (EA) in vivo, the role of CA2 in the epileptic network within and beyond the sclerotic hippocampus is still unclear. We used the intrahippocampal kainate mouse model for MTLE, which recapitulates most features of the human disease including pharmacoresistant epileptic seizures and hippocampal sclerosis, with preservation of dentate gyrus (DG) granule cells and CA2 pyramidal cells. In vivo recordings with electrodes in CA2 and the DG showed that EA occurs at high coincidence between the ipsilateral DG and CA2 and current source density analysis of silicon probe recordings in dorsal ipsilateral CA2 revealed CA2 as a local source of EA. Cell‐specific viral tracing in Amigo2‐icreERT2 mice confirmed the preservation of the axonal projection from ipsilateral CA2 pyramidal cells to contralateral CA2 under epileptic conditions and indeed, EA propagated from ipsi‐ to contralateral CA2 with increasing likelihood with time after KA injection, but always at lower intensity than within the ipsilateral hippocampus. Furthermore, we show that CA2 presents with local theta oscillations and like the DG, shows a pathological reduction of theta frequency already from 2 days after KA onward. The early changes in activity might be facilitated by the loss of glutamic acid decarboxylase 67 (Gad67) mRNA‐expressing interneurons directly after the initial status epilepticus in ipsi‐ but not contralateral CA2. Together, our data highlight CA2 as an active player in the epileptic network and with its contralateral connections as one possible router of aberrant activity.

Temporal pole volume is associated with episodic autobiographical memory in healthy older adults

Abstract: Recollection of personal past events differs across the lifespan. Older individuals recall fewer episodic details and convey more semantic information than young. Here we examine how gray matter volumes in temporal lobe regions integral to episodic and semantic memory (hippocampus and temporal poles, respectively) are related to age differences in autobiographical recollection. Gray matter volumes were obtained in healthy young (n = 158) and old (n = 105) adults. The temporal pole was demarcated and hippocampus segmented into anterior and posterior regions to test for volume differences between age groups. The Autobiographical Interview was administered to measure episodic and semantic autobiographical memory. Volume associations with episodic and semantic autobiographical memory were then assessed. Brain volumes were smaller for older adults in the posterior hippocampus. Autobiographical memory was less episodic and more semanticized for older versus younger adults. Older adults also showed positive associations between temporal pole volumes and episodic autobiographical recall; in the young, temporal pole volume was positively associated with performance on standard laboratory measures of semantic memory. Exploratory analyses revealed that age‐related episodic autobiographical memory associations with anterior hippocampal volumes depended on sex. These findings suggest that age differences in brain structures implicated in episodic and semantic memory may portend reorganization of neural circuits to support autobiographical memory in later life.

From mechanisms to functions: The role of theta and gamma coherence in the intrahippocampal circuits

Abstract: Brain rhythms are essential for information processing in neuronal networks. Oscillations recorded in different brain regions can be synchronized and have a constant phase difference, that is, they can be coherent. Coherence between local field potential (LFP) signals from different brain regions may be correlated with the performance of cognitive tasks, indicating that these regions of the brain are jointly involved in the information processing. Why does coherence occur and how is it related to the information transfer between different regions of the hippocampal formation? In this article, we discuss possible mechanisms of theta and gamma coherence and its role in the hippocampus‐dependent attention and memory processes, since theta and gamma rhythms are most pronounced in these processes. We review in vivo studies of interactions between different regions of the hippocampal formation in theta and gamma frequency bands. The key propositions of the review are as follows: (1) coherence emerges from synchronous postsynaptic currents in principal neurons as a result of synchronization of neuronal spike activity; (2) the synchronization of neuronal spike patterns in two regions of the hippocampal formation can be realized through induction or resonance; (3) coherence at a specific time point reflects the transfer of information between the regions of the hippocampal formation; (4) the physiological roles of theta and gamma coherence are different due to their different functions and mechanisms of generation. All hippocampal neurons are involved in theta activity, and theta coherence arranges the firing order of principal neurons throughout the hippocampal formation. In contrast, gamma coherence reflects the coupling of active neuronal ensembles. Overall, the coherence of LFPs between different areas of the brain is an important physiological process based on the synchronized neuronal firing, and it is essential for cooperative information processing.

Intact high‐resolution working memory binding in a patient with developmental amnesia and selective hippocampal damage

Abstract: Debate continues regarding the possible role of the hippocampus across short-term and working memory tasks. The current study examined the possibility of a hippocampal contribution to precise, high-resolution cognition and conjunctive memory. We administered visual working memory tasks featuring a continuous response component to a well-established developmental amnesic patient with relatively selective bilateral hippocampal damage (Jon) and healthy controls. The patient was able to produce highly accurate response judgments regarding conjunctions of color and orientation or color and location, using simultaneous or sequential presentation of stimuli, with no evidence of any impairment in working memory binding, categorical accuracy, or continuous precision. These findings indicate that hippocampal damage does not necessarily lead to deficits in high-resolution cognitive performance, even when the damage is severe and bilateral.

Environmental enrichment and social isolation modulate inhibitory transmission and plasticity in hippocampal area CA2

Abstract: Environmental factors are well‐accepted to play a complex and interdependent role with genetic factors in learning and memory. The goal of this study was to examine how environmental conditions altered synaptic plasticity in hippocampal area CA2. To do this, we housed adult mice for 3 weeks in an enriched environment (EE) consisting of a larger cage with running wheel, and regularly changed toys, tunnels and treats. We then performed whole‐cell or extracellular field recordings in hippocampal area CA2 and compared the synaptic plasticity from EE‐housed mice with slices from littermate controls housed in standard environment (SE). We found that the inhibitory transmission recruited by CA3 input stimulation in CA2 was significantly less plastic in EE conditions as compared to SE following an electrical tetanus. We demonstrate that delta‐opioid receptor (DOR) mediated plasticity is reduced in EE conditions by direct application of DOR agonist. We show that in EE conditions the overall levels of GABA transmission is reduced in CA2 cells by analyzing inhibition of ErbB4 receptor, spontaneous inhibitory currents and paired‐pulse ratio. Furthermore, we report that the effect of EE of synaptic plasticity can be rapidly reversed by social isolation. These results demonstrate how the neurons in hippocampal area CA2 are sensitive to environment and may lead to promising therapeutic targets.

Plasticity impairment exposes CA3 vulnerability in a hippocampal network model of mild traumatic brain injury

Abstract: Proper function of the hippocampus is critical for executing cognitive tasks such as learning and memory. Traumatic brain injury (TBI) and other neurological disorders are commonly associated with cognitive deficits and hippocampal dysfunction. Although there are many existing models of individual subregions of the hippocampus, few models attempt to integrate the primary areas into one system. In this work, we developed a computational model of the hippocampus, including the dentate gyrus, CA3, and CA1. The subregions are represented as an interconnected neuronal network, incorporating well‐characterized ex vivo slice electrophysiology into the functional neuron models and well‐documented anatomical connections into the network structure. In addition, since plasticity is foundational to the role of the hippocampus in learning and memory as well as necessary for studying adaptation to injury, we implemented spike‐timing‐dependent plasticity among the synaptic connections. Our model mimics key features of hippocampal activity, including signal frequencies in the theta and gamma bands and phase‐amplitude coupling in area CA1. We also studied the effects of spike‐timing‐dependent plasticity impairment, a potential consequence of TBI, in our model and found that impairment decreases broadband power in CA3 and CA1 and reduces phase coherence between these two subregions, yet phase‐amplitude coupling in CA1 remains intact. Altogether, our work demonstrates characteristic hippocampal activity with a scaled network model of spiking neurons and reveals the sensitive balance of plasticity mechanisms in the circuit through one manifestation of mild traumatic injury.

Cell population dynamics in the course of adult hippocampal neurogenesis: Remaining unknowns

Abstract: Neural stem cells (NSCs) generate new neurons throughout life in the mammalian hippocampus. The distinct developmental steps in the course of adult neurogenesis, including NSC activation, expansion, and neuronal integration, are increasingly well characterized down to the molecular level. However, substantial gaps remain in our knowledge about regulators and mechanisms involved in this biological process. This review highlights three long‐standing unknowns. First, we discuss potency and identity of NSCs and the quest for a unifying model of short‐ and long‐term self‐renewal dynamics. Next, we examine cell death, specifically focusing on the early demise of newborn cells. Then, we outline the current knowledge on cell integration dynamics, discussing which (if any) neurons are replaced by newly added neurons in the hippocampal circuits. For each of these unknowns, we summarize the trajectory of studies leading to the current state of knowledge. Finally, we offer suggestions on how to fill the remaining gaps by taking advantage of novel technology to reveal currently hidden secrets in the course of adult hippocampal neurogenesis.

Postnatal development of hippocampal CA2 structure and function during the emergence of social recognition of peers

Abstract: It is now well‐established that the hippocampal CA2 region plays an important role in social recognition memory in adult mice. The CA2 is also important for the earliest social memories, including those that mice have for their mothers and littermates, which manifest themselves as a social preference for familiarity over novelty. The role of the CA2 in the development of social memory for recently encountered same‐age conspecifics, that is, peers, has not been previously reported. Here, we used a direct social interaction test to characterize the emergence of novelty preference for peers during development and found that at the end of the second postnatal week, pups begin to significantly prefer novel over familiar peers. Using chemogenetic inhibition at this time, we showed that CA2 activity is necessary for the emergence of novelty preference and for the ability to distinguish never encountered from recently encountered peers. In adulthood, the CA2 region is known to integrate a large number of inputs from various sources, many of which participate in social recognition memory, but previous studies have not determined whether these afferents are present at adult levels by the end of the second postnatal week. To explore the development of CA2 inputs, we used immunolabeling and retrograde adenovirus circuit tracing and found that, by the end of the second postnatal week, the CA2 is innervated by many regions, including the dentate gyrus, supramammillary nucleus of the hypothalamus, the lateral entorhinal cortex, and the median raphe nucleus. Using retroviral labeling of postnatally generated granule cells in the dentate gyrus, we found that mossy fiber projections to the CA2 mature faster during development than those generated in adulthood. Together, our findings indicate that the CA2 is partially mature in afferent connectivity by the end of the second postnatal week, connections that likely facilitate the emergence of social recognition memory and preference for novel peers.

RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

Abstract: RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H‐Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long‐term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

Introduction to the special issue on the ontogeny of hippocampal functions

Abstract: The views on hippocampal function and role in cognition evolved considerably during the last century. While at first the hippocampus was considered a conduit (Papez, 1995) and later a hub for emotional processing (MacLeans, 1949), the description of Henry Molaison's case (Scoville & Milner, 1957), and the recording of place cells by O'Keefe and Dostrovsky (1971), uncovered a role for the hippocampus in memory and spatial cognition, which soon came to be viewed as its primary functions and prompted the theory of the hippocampus as a cognitive map (O'Keefe & Nadel, 1978). To date, memory and spatial cognition are widely accepted as the predominant functions of the hippocampus, but paramount evidence exists also for the involvement of the hippocampus in emotion regulation, social behavior and sensorimotor integration (Bast & Feldon, 2003; Davidson et al., 2000; H. Leblanc & Ramirez, 2020; Maren et al., 2013). Current theories suggest that these seemingly disparate functions might be achieved through shared neural processes taking place within the hippocampus, and broadcasted globally to the rest of the brain by distributed networks connecting the hippocampus to multiple cortical and subcortical regions (Buzsaki & Moser, 2013; Eichenbaum, 2017). Across this wide diversity of cognitive domains, the key process engaging the hippocampus and relying on it is learning and memory. The ability to learn from experience is arguably one of the most important functions of the brain and is critical for one's own survival, as it allows animals to compare current contingencies to previously encountered episodes, build expectations, and select appropriate behaviors based on predicted outcomes (Buzsaki & Moser, 2013; Tulving, 2002). This ability critically relies on the engagement of the hippocampus-dependent memory system, which promotes the acquisition and consolidation of episodic memories (i.e., memories of autobiographical events that occurred in a specific spatial and temporal context; Eichenbaum et al., 2007; Scoville & Milner, 1957; Squire et al., 2004; Treves & Rolls, 1994; Tulving, 2002; Wood et al., 1999). Infancy and childhood are characterized by a high need for learning at a rapid pace. In fact, during this period, humans and animals acquire motor, social and communication skills, and build intrinsic representations of the world to which future experience might be compared (Buzsaki & Moser, 2013). Yet, the structural and functional maturation of the hippocampus, so important for these functions, extends pasts these windows. In altricial mammals, from rodents to humans, the number of neurons and synapses in the entorhinal-hippocampal network increases dramatically after birth, due to a protracted period of neurogenesis and synaptogenesis that does not reach adult-like levels until late childhood (Deguchi et al., 2011; Donato et al., 2017; Travaglia, Bisaz, Cruz, et al., 2016). Different areas of the circuit mature sequentially with distinct time courses. In the mouse, the medial entorhinal cortex, which processes information about the context of experience (Kitamura et al., 2015; Knierim et al., 2014), is already mature by the beginning of the third postnatal week (Donato et al., 2017; Ray & Brecht, 2016), while the lateral entorhinal cortex, which provides information about the content of experience and about episodic time (Deshmukh & Knierim, 2011; Tsao et al., 2013; Tsao et al., 2018), is largely immature until the end of the fourth (Donato et al., 2017). Prefrontal circuits take even longer to reach adult-like levels of maturity, as the establishment of new connections and synaptic remodeling processes associated with developmental plasticity extends into the sixth weeks of life in rodents (roughly DOI: 10.1002/hipo.23406

Dominant role of adult neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

Abstract: Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, which have been implicated in context-specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic physiologically constrained parametric search to identify the cellular mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We used heterogeneous model populations to ensure that our conclusions were not biased by parametric choices in a single hand-tuned model. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneities in synaptic plasticity profiles obtained with two different induction protocols. However, among the disparate forms of neural-circuit heterogeneities, our analyses demonstrated the dominance of neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in granule cells. We found that strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult neurogenesis-induced heterogeneities in neural structure were accounted for. Importantly, our analyses showed that it was not imperative that the manifestation of neural-circuit heterogeneities must translate to heterogeneities in plasticity profiles. Specifically, despite the expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable across all models through synergistic interactions among these heterogeneities. We assessed the parametric combinations required for the manifestation of such degeneracy in the expression of plasticity profiles. We found that immature cells showed physiological plasticity profiles despite receiving afferent inputs with weak synaptic strengths. Thus, the high intrinsic excitability of immature granule cells was sufficient to counterbalance their low excitatory drive in the expression of plasticity profile degeneracy. Together, our analyses demonstrate that disparate forms of neural-circuit heterogeneities could mechanistically drive plasticity heterogeneity, but also caution against treating neural-circuit heterogeneities as proxies for plasticity heterogeneity. Our study emphasizes the need for quantitatively characterizing the relationship between neural-circuit and plasticity heterogeneities across brain regions.

Episodic boundary cells in human medial temporal lobe during the free recall task

Abstract: A necessary condition for forming episodic memories is the construction of specific episodes demarcated from other episodes in space and time. Evidence from studies of episodic memory formation using rodent models suggest that the medial temporal lobe (MTL) supports the representation of boundary information. Building on recent work using human microelectrode recordings as well, we hypothesized of human MTL neurons with firing rates sensitive to episodic boundary information. We identified 27 episodic boundary neurons out of 736 single neurons recorded across 27 subjects. Firing of these neurons increased at the beginning and end of mnemonically relevant episodes in the free recall task. We distinguish episodic boundary neurons from a population of ramping neurons (n = 58), which are time‐sensitive neurons whose activity provides complementary information during episodic representation. Episodic boundary neurons exhibited a U‐shaped activity pattern demonstrating increased activity after both beginning and end boundaries of encoding and retrieval epochs. We also describe evidence that the firing of boundary neurons within episodic boundaries is organized by hippocampal theta oscillations, using spike‐field coherence metrics.

Significance of visual scene‐based learning in the hippocampal systems across mammalian species

Abstract: The hippocampus and its associated cortical regions in the medial temporal lobe play essential roles when animals form a cognitive map and use it to achieve their goals. As the nature of map‐making involves sampling different local views of the environment and putting them together in a spatially cohesive way, visual scenes are essential ingredients in the formative process of cognitive maps. Visual scenes also serve as important cues during information retrieval from the cognitive map. Research in humans has shown that there are regions in the brain that selectively process scenes and that the hippocampus is involved in scene‐based memory tasks. The neurophysiological correlates of scene‐based information processing in the hippocampus have been reported as “spatial view cells” in nonhuman primates. Like primates, it is widely accepted that rodents also use visual scenes in their background for spatial navigation and other kinds of problems. However, in rodents, it is not until recently that researchers examined the neural correlates of the hippocampus from the perspective of visual scene‐based information processing. With the advent of virtual reality (VR) systems, it has been demonstrated that place cells in the hippocampus exhibit remarkably similar firing correlates in the VR environment compared with that of the real‐world environment. Despite some limitations, the new trend of studying hippocampal functions in a visually controlled environment has the potential to allow investigation of the input–output relationships of network functions and experimental testing of traditional computational predictions more rigorously by providing well‐defined visual stimuli. As scenes are essential for navigation and episodic memory in humans, further investigation of the rodents' hippocampal systems in scene‐based tasks will provide a critical functional link across different mammalian species.

Computational constraints on the associative recall of spatial scenes

Abstract: We consider a model of associative storage and retrieval of compositional memories in an extended cortical network. Our model network is comprised of Potts units, which represent patches of cortex, interacting through long-range connections. The critical assumption is that a memory is composed of a limited number of items, each of which has a pre-established representation: storing a new memory only involves acquiring the connections, if novel, among the participating items. The model is shown to have a much lower storage capacity than when it stores simple unitary representations. It is also shown that an input from the hippocampus facilitates associative retrieval. When it is absent, it is advantageous to cue rare rather than frequent items. The implications of these results for emerging trends in empirical research are discussed.

A meta‐analysis of the relation between hippocampal volume and memory ability in typically developing children and adolescents

Abstract: Memory is supported by a network of brain regions, with the hippocampus serving a critical role in this cognitive process. Previous meta‐analyses on the association between hippocampal structure and memory have largely focused on adults. Multiple studies have since suggested that hippocampal volume is related to memory performance in children and adolescents; however, the strength and direction of this relation varies across reports, and thus, remains unclear. To further understand this brain–behavior relation, we conducted a meta‐analysis to investigate the association between hippocampal volume (assessed as total volume) and memory during typical development. Across 25 studies and 61 memory outcomes with 1357 participants, results showed a small, but significant, positive association between total hippocampal volume and memory performance. Estimates of the variability across studies in the relation between total volume and memory were not explained by differences in memory task type (delayed vs. immediate; relational vs. nonrelational), participant age range, or the method of normalization of hippocampal volumes. Overall, findings suggest that larger total hippocampal volume relates to better memory performance in children and adolescents and that this relation is similar across the memory types and age ranges assessed. To facilitate enhanced generalization across studies in the future, we discuss considerations for the field moving forward.

Assessing mild cognitive impairment using object‐location memory in immersive virtual environments

Abstract: Pathological changes in the medial temporal lobe (MTL) are found in the early stages of Alzheimer's disease (AD) and aging. The earliest pathological accumulation of tau colocalizes with the areas of the MTL involved in object processing as part of a wider anterolateral network. Here, we sought to assess the diagnostic potential of memory for object locations in iVR environments in individuals at high risk of AD dementia (amnestic mild cognitive impairment [aMCI] n = 23) as compared to age‐related cognitive decline. Consistent with our primary hypothesis that early AD would be associated with impaired object location, aMCI patients exhibited impaired spatial feature binding. Compared to both older (n = 24) and younger (n = 53) controls, aMCI patients, recalled object locations with significantly less accuracy (p < .001), with a trend toward an impaired identification of the object's correct context (p = .05). Importantly, these findings were not explained by deficits in object recognition (p = .6). These deficits differentiated aMCI from controls with greater accuracy (AUC = 0.89) than the standard neuropsychological tests. Within the aMCI group, 16 had CSF biomarkers indicative of their likely AD status (MCI+ n = 9 vs. MCI− n = 7). MCI+ showed lower accuracy in the object‐context association than MCI− (p = .03) suggesting a selective deficit in object‐context binding postulated to be associated with anterior‐temporal areas. MRI volumetric analysis across healthy older participants and aMCI revealed that test performance positively correlates with lateral entorhinal cortex volumes (p < .05) and hippocampus volumes (p < .01), consistent with their hypothesized role in binding contextual and spatial information with object identity. Our results indicate that tests relying on the anterolateral object processing stream, and in particular requiring successful binding of an object with spatial information, may aid detection of pre‐dementia AD due to the underlying early spread of tau pathology.

Interneuron diversity in the rat dentate gyrus: An unbiased in vitro classification

Abstract: Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, and physiological characteristics. In the major input region of the hippocampus, the dentate gyrus (DG), a number of IN types have been described which provide synaptic inhibition to distinct compartments of excitatory principal cells (PrCs) and other INs. In this study, we perform an unbiased classification of GABAergic INs in the DG by combining in vitro whole‐cell patch‐clamp recordings, intracellular labeling, morphological analysis, and unsupervised cluster analysis to better define IN type diversity in this region. This analysis reveals that DG INs divide into at least 13 distinct morpho‐physiological types which reflect the complexity of the local IN network and serve as a basis for further network analyses.

Natural acoustic stimuli evoke selective responses in the hippocampus of passive listening bats

Abstract: A growing body of research details spatial representation in bat hippocampus, and experiments have yet to explore hippocampal neuron responses to sonar signals in animals that rely on echolocation for spatial navigation. To bridge this gap, we investigated bat hippocampal responses to natural echolocation sounds in a non‐spatial context. In this experiment, we recorded from CA1 of the hippocampus of three awake bats that listened passively to single echolocation calls, call‐echo pairs, or natural echolocation sequences. Our data analysis identified a subset of neurons showing response selectivity to the duration of single echolocation calls. However, the sampled population of CA1 neurons did not respond selectively to call‐echo delay, a stimulus dimension posited to simulate target distance in recordings from auditory brain regions of bats. A population analysis revealed ensemble coding of call duration and sequence identity. These findings open the door to many new investigations of auditory coding in the mammalian hippocampus.

Consistent population activity on the scale of minutes in the mouse hippocampus

Abstract: Neurons in the hippocampus fire in consistent sequence over the timescale of seconds during the delay period of some memory experiments. For longer timescales, the firing of hippocampal neurons also changes slowly over minutes within experimental sessions. It was thought that these slow dynamics are caused by stochastic drift or a continuous change in the representation of the episode, rather than consistent sequences unfolding over minutes. This paper studies the consistency of contextual drift in three chronic calcium imaging recordings from the hippocampus CA1 region in mice. Computational measures of consistency show reliable sequences within experimental trials at the scale of seconds as one would expect from time cells or place cells during the trial, as well as across experimental trials on the scale of minutes within a recording session. Consistent sequences in the hippocampus are observed over a wide range of time scales, from seconds to minutes. The hippocampal activity could reflect a scale-invariant spatiotemporal context as suggested by theories of memory from cognitive psychology.

New hues for CA2

Abstract: Described by Lorente de N o as a small area between CA1 and CA3, area CA2 then disappeared from most representations of the hippocampal diagram. While it is progressively included back into the hippocampal circuit, much remains to be done to uncover the properties and functions of area CA2. Here, we summarize recent evidence supporting the idea that CA2 should be divided into subareas and propose that because of its high sensitivity to environmental conditions, the contribution of CA2 to hippocampal functions apart from social memory formation has likely been underestimated.

Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches

Abstract: Most commonly used behavioral measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal's residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal's performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (NS; Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of NS, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the MWM into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.

Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

Abstract: Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. What is not well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through selective expression of its receptor, GLP-1R. RNA-seq demonstrated that most Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study identifies a potential neurohormonal mechanism linking a critically important satiety signal with activity of MCs in the ventral DG that might have functional effects on learning and memory during distinct states.

Risk factors for hippocampal cavities in a marginally housed population

Abstract: Cavities in the hippocampus are morphological variants of uncertain significance. Aberrant neurodevelopment along with vascular and inflammatory etiologies have been proposed. We sought to characterize these cavities and their potential risk factors in a marginally housed population, with high rates of viral infection, addiction, and mental illness. (1) The volume of hippocampal cavities (HCavs) is greater in this highly multimorbid population compared to the general population. (2) Conventional vascular risk factors such as greater age and systolic blood pressure are associated with higher HCav volume. (3) Nonprescribed substance‐related risk factors such as stimulant use or dependence, and smoking are associated with increased HCav volume independent of vascular risk factors. This is a retrospective analysis of an ongoing prospective study. We analyzed baseline data, including medical history, physical exam, psychiatric diagnosis, and MRI from a total of 375 participants. Hippocampal cavities were defined as spaces isointense to CSF on T1 MRI sequences, bounded on all sides by hippocampal tissue, with a volume of at least 1 mm3. Risk factors were evaluated using negative binomial multiple regression. Stimulant use was reported by 87.3% of participants, with stimulant dependence diagnosed in 83.3% of participants. Prevalence of cavities was 71.6%, with a mean total bilateral HCav volume of 13.89 mm3. On average, a 1 mmHg greater systolic blood pressure was associated with a 2.17% greater total HCav volume (95% CI = [0.57%, 3.79%], p = .0076), while each cigarette smoked per day trended toward a 2.69% greater total HCav volume (95% CI = [−0.87%, 5.54%], p = .058). A diagnosis of stimulant dependence was associated with a 95.6% greater total HCav volume (95% CI = [5.39%, 263.19%], p = .0335). Hypertension and diagnosis of stimulant dependence were associated with a greater total volume of HCav.

Place cells are non-randomly clustered by field location in CA1 hippocampus

Abstract: A challenge in both modern and historic neuroscience has been achieving an understanding of neuron circuits, and determining the computational and organizational principles that underlie these circuits. Deeper understanding of the organization of brain circuits and cell types, including in the hippocampus, is required for advances in behavioral and cognitive neuroscience, as well as for understanding principles governing brain development and evolution. In this manuscript, we pioneer a new method to analyze the spatial clustering of active neurons in the hippocampus. We use calcium imaging and a rewarded navigation task to record from 100s of place cells in the CA1 of freely moving rats. We then use statistical techniques developed for and in widespread use in geographic mapping studies, global Moran’s I and local Moran’s I to demonstrate that cells that code for similar spatial locations tend to form small spatial clusters. We present evidence that this clustering is not the result of artifacts from calcium imaging, and show that these clusters are primarily formed by cells that have place field around previously rewarded locations. We go on to show that, although cells with similar place fields tend to form clusters, there is no obvious topographic mapping of environmental location onto the hippocampus, such as seen in the visual cortex. Insights into hippocampal organization, as in this study, can elucidate mechanisms underlying motivational behaviors, spatial navigation, and memory formation.

Transcriptomic analysis of dorsal and ventral subiculum after induction of acute seizures by electric stimulation of the perforant pathway in rats

Abstract: Preconditioning is a mechanism in which injuries induced by non-lethal hypoxia or seizures trigger cellular resistance to subsequent events. Norwood et al., in a 2010 study, showed that an 8-h-long period of electrical stimulation of the perforant pathway in rats is required for the induction of hippocampal sclerosis. However, in order to avoid generalized seizures, status epilepticus (SE), and death, a state of resistance to seizures must be induced in the hippocampus by a preconditioning paradigm consisting of two daily 30-min stimulation periods. Due to the importance of the subiculum in the hippocampal formation, this study aims to investigate differential gene expression patterns in the dorsal and ventral subiculum using RNA-sequencing, after induction of a preconditioning protocol by electrical stimulation of the perforant pathway. The dorsal (dSub) and ventral (vSub) subiculum regions were collected by laser-microdissection 24 h after preconditioning protocol induction in rats. RNA sequencing was performed in a Hiseq 4000 platform, reads were aligned using the STAR and DESEq2 statistics package was used to estimate gene expression. We identified 1176 differentially expressed genes comparing control to preconditioned subiculum regions, 204 genes were differentially expressed in dSub and 972 in vSub. The gene ontology enrichment analysis showed that the most significant common enrichment pathway considering up-regulated genes in dSub and vSub was steroid metabolism. In contrast, the most significant enrichment pathway considering down-regulated genes in vSub was axon guidance. Our results indicate that preconditioning induces changes in the expression of genes related to synaptic reorganization, increased cholesterol metabolism, and astrogliosis in both dSub and vSub. Both regions also presented a decrease in the expression of genes related to glutamatergic transmission and an increase in expression of genes related to complement system activation and GABAergic transmission. The down-regulation of proapoptotic and axon guidance genes in the ventral subiculum suggests that preconditioning may induce a neuroprotective environment in this region.

Hippocampal responses to electrical stimulation of the major input pathways are modulated by dentate spikes

Abstract: Dentate gyrus (DG) is important for pattern separation and spatial memory, and it is thought to gate information flow to the downstream hippocampal subregions. Dentate spikes (DSs) are high‐amplitude, fast, positive local‐field potential events taking place in the DG during immobility and sleep, and they have been connected to memory consolidation in rodents. DSs are a result of signaling from the entorhinal cortex (EC) to the DG, and they suppress firing of pyramidal cells in the CA3 and CA1. To study the effects of DSs to signaling in the hippocampal tri‐synaptic loop, we electrically stimulated the afferent fibers of the DG, CA3, and CA1 in adult male Sprague–Dawley rats at different delays from DSs. Responses to stimulation were increased in the EC‐DG synapse during DSs, and the effect was amplified after theta‐burst stimulation. We concluded that DSs strengthen the excitatory signal from the EC to the DG, which is reinforced by synapse potentiation and increased excitability of granule cells after theta‐burst stimulation. This signal boosting may function in enhancing plastic changes in the DG‐CA3 synapse. As responses in the CA3 and CA1 remained unaffected by the DS, the DS‐contingent silencing of pyramidal cells seems to be a result of a decrease in excitatory input rather than a decrease in the excitability of the pyramidal cells themselves. In addition, we found that the DSs occur asynchronously in the left and right hippocampi, giving novel evidence of lateralization of the rodent hippocampus.

Properties and hemispheric differences of theta oscillations in the human hippocampus

Abstract: The left and right primate hippocampi (LH and RH) are thought to support distinct functions, but little is known about differences between the hemispheres at the neuronal level. We recorded single‐neuron and local field potentials from the human hippocampus in epilepsy patients implanted with depth electrodes. We detected theta‐frequency bouts of oscillatory activity while patients performed a visual recognition memory task. Theta appeared in bouts of 3.16 cycles, with sawtooth‐shaped oscillations that had a prolonged downswing period. Outside the seizure onset zone, the average frequency of theta bouts was higher in the RH compared to the LH (6.0 vs. 5.3 Hz). LH theta bouts had lower amplitudes and a higher prevalence compared to the RH (26% vs. 21% of total time). Additionally, the RH contained a population of thin spiking visually tuned neurons that were not present in the LH. These data show that human theta appears in short oscillatory bouts whose properties vary between hemispheres, thereby revealing neurophysiological properties of the hippocampus that differ between the hemispheres.