Mammalian Hippocampus Research Articles

Theta oscillations optimize a speed-precision trade-off in phase coding neurons

Theta-band oscillations (3–8 Hz) in the mammalian hippocampus organize the temporal structure of cortical inputs, resulting in a phase code that enables rhythmic input sampling for episodic memory formation and spatial navigation. However, it remains unclear what evolutionary pressures might have driven the selection of theta over higher-frequency bands that could potentially provide increased input sampling resolution. Here, we address this question by introducing a theoretical framework that combines the efficient coding and neural oscillatory sampling hypotheses, focusing on the information rate (bits/s) of phase coding neurons. We demonstrate that physiologically realistic noise levels create a trade-off between the speed of input sampling, determined by oscillation frequency, and encoding precision in rodent hippocampal neurons. This speed-precision trade-off results in a maximum information rate of ∼1–2 bits/s within the theta frequency band, thus confining the optimal oscillation frequency to the low end of the spectrum. We also show that this framework accounts for key hippocampal features, such as the preservation of the theta band along the dorsoventral axis despite physiological gradients, and the modulation of theta frequency and amplitude by running speed. Extending the analysis beyond the hippocampus, we propose that theta oscillations could also support efficient stimulus encoding in the visual cortex and olfactory bulb. More broadly, our framework lays the foundation for studying how system features, such as noise, constrain the optimal sampling frequencies in both biological and artificial brains.

Mapping spatial memory in teleosts: a new Frontier in neural logging techniques.

Recent advancements in microelectromechanical system technology have significantly enhanced our ability to monitor neuronal activity in free-swimming fish without disrupting their natural movement, thereby greatly improving the capabilities of neural logging using "neurologger" technology. In this review, we compiled the findings from studies applying neurologgers to teleost fish, emphasizing the discovery of various spatial-cognition cells in regions of the telencephalon analogous to the mammalian hippocampus that are deeply involved in spatial navigation. We detailed how different fish species, such as goldfish and salmonids, correlate their neural activity with environmental boundaries, head direction, speed, and other navigational cues for spatial memory and navigation strategies. We critically analyzed the similarities and differences in these mechanisms to provide insights into the evolutionary aspects of spatial cognition. We also identified gaps in current methodologies and suggest directions for future research, emphasizing the need for further exploration of spatial encoding in aquatic environments. The insights gained herein suggest the existence of a complex and evolutionarily conserved substrate for navigation and memory in vertebrates, highlighting the potential of neurologgers to expand our understanding of spatial cognition.

Functional Differentiation along the Rostro-Caudal Axis of the Avian Hippocampal Formation.

Introduction Different functional domains can be identified along the longitudinal axis of the mammalian hippocampus. We have recently hypothesized that a similar functional gradient may exist along the longitudinal axis of the avian hippocampal formation (HF) as well. If the two gradients are homologous, we would expect the caudal HF to be more responsive to acute stress than the rostral HF. Methods We restrained 8 adult Dekalb White hens in a bag for 30 minutes under red-light conditions and compared FOS immunoreactive (FOS-ir) cell densities in different hippocampal subdivisions to control hens. Results Although we could find no evidence of an activated stress response in the Hypothalamic-Pituitary-Adrenal (HPA) axis of the restrained birds, we did find a significant increase in FOS-ir cell densities in the rostral HF of the restrained birds compared to controls. Conclusion We speculate that the HF response is not due to an acute stress response, but instead it is related to the change in spatial context that was part of taking the birds and restraining them in a different room. We see no activation in the caudal HF. This would be consistent with our hypothesis that the longitudinal axis of the avian HF is homologous to the long axis of the mammalian hippocampus.

Socialization causes long-lasting behavioral changes

In modern human societies, social isolation acts as a negative factor for health and life quality. On the other hand, social interaction also has profound effects on animal and human, impacting aggressiveness, feeding and sleep, among many other behaviors. Here, we observe that in the fly Drosophila melanogaster these behavioral changes long-last even after social interaction has ceased, suggesting that the socialization experience triggers behavioral plasticity. These modified behaviors maintain similar levels for 24 h and persist up to 72 h, although showing a progressive decay. We also find that impairing long-term memory mechanisms either genetically or by anesthesia abolishes the expected behavioral changes in response to social interaction. Furthermore, we show that socialization increases CREB-dependent neuronal activity and synaptic plasticity in the mushroom body, the main insect memory center analogous to mammalian hippocampus. We propose that social interaction triggers socialization awareness, understood as long-lasting changes in behavior caused by experience with mechanistic similarities to long-term memory formation.

NECAB1-3, parvalbumin, calbindin, and calretinin in the hippocampus of the European mole.

Many calcium-binding proteins are expressed in a region-and cell-type specific manner in the mammalian hippocampus. Neuronal calcium-binding proteins (NECABs) are also expressed in hippocampal neurons, but few species have been investigated, with partly controversial findings. We here describe NECAB1, NECAB2 and NECAB3 as well as parvalbumin, calbindin, and calretinin in the European mole, and compare staining patterns of these proteins with those in mouse and other species. While subtle differences are present, NECAB staining in the European mole was generally similar to those in mouse. Common to European moles, mice, and other species we investigated, large hilar polymorphic cells, likely to represent mossy cells, were positive for all three NECABs. NECAB1 and 2 are suitable as markers for these cells along the entire septotemporal axis of the hippocampus. In the European mole, parvalbumin, calbindin and calretinin showed traits that have been described in other species before, albeit in a unique combination. In summary, we provide the first description of distribution of these proteins in the hippocampus of the European mole. This subterranean, insectivorous, and solitary living species belongs to the Order of Eulipotyphla. Despite many similarities with other subterranean species from the rodent order in terms of lifestyle, its hippocampus is cytoarchitecturally much more elaborated than in, e.g., mole-rats. It remains an open question if the hippocampal structure of the European mole reflects evolutionary constraints or ecology. Our descriptive study highlights the diversity in hippocampal cytoarchitecture even in small mammalian species.

The estrous cycle modulates hippocampal spine dynamics, dendritic processing, and spatial coding.

Histological evidence suggests that the estrous cycle exerts a powerful effect on CA1 neurons in mammalian hippocampus. Decades have passed since this landmark observation, yet how the estrous cycle shapes dendritic spine dynamics and hippocampal spatial coding in vivo remains a mystery. Here, we used a custom hippocampal microperiscope and two-photon calcium imaging to track CA1 pyramidal neurons in female mice over multiple cycles. Estrous cycle stage had a potent effect on spine dynamics, with heightened density during periods of greater estradiol (proestrus). These morphological changes were accompanied by greater somatodendritic coupling and increased infiltration of back-propagating action potentials into the apical dendrite. Finally, tracking CA1 response properties during navigation revealed enhanced place field stability during proestrus, evident at the single-cell and population level. These results establish the estrous cycle as a driver of large-scale structural and functional plasticity in hippocampal circuits essential for learning and memory.

Microwave Radiation Caused Dynamic Metabolic Fluctuations in the Mammalian Hippocampus.

To investigate the dynamic changes in hippocampal metabolism after microwave radiation using liquid chromatography in tandem with mass spectrometry/mass spectrometry (LC-MS/MS) and to identify potential biomarkers. Wistar rats were randomly assigned to a sham group and a microwave radiation group. The rats in the microwave radiation group were exposed to 2.856 GHz for 15 min for three times, with 5 min intervals. The rats in the sham group were not exposed. Transmission electron microscope revealed blurring of the synaptic cleft and postsynaptic dense thickening in hippocampal neurons after microwave radiation. Metabolomic analysis revealed 38, 24, and 39 differentially abundant metabolites at 3, 7, and 14 days after radiation, respectively, and the abundance of 9 metabolites, such as argininosuccinic acid, was continuously decreased. After microwave radiation, the abundance of metabolites such as argininosuccinic acid was successively decreased, indicating that these metabolites could be potential biomarkers for hippocampal tissue injury.

Context and space coding in mossy cell population activity

The dentate gyrus plays a key role in the discrimination of memories by segregating and storing similar episodes. Whether hilar mossy cells, which constitute a major excitatory principal cell type in the mammalian hippocampus, contribute to this decorrelation function has remained largely unclear. Using two-photon calcium imaging of head-fixed mice performing a spatial virtual reality task, we show that mossy cell populations robustly discriminate between familiar and novel environments. The degree of discrimination depends on the extent of visual cue differences between contexts. A context decoder revealed that successful environmental classification is explained mainly by activity difference scores of mossy cells. By decoding mouse position, we reveal that in addition to place cells, the coordinated activity among active mossy cells markedly contributes to the encoding of space. Thus, by decorrelating context information according to the degree of environmental differences, mossy cell populations support pattern separation processes within the dentate gyrus.

Overwintering Induces Ischemia-Tolerance of Synaptic Function in the Forebrain of Bullfrogs

Healthy brain function requires the continuous delivery of oxygen and glucose to nerve cells. Interruptions result in rapid cessation of normal circuit function in most vertebrates. The American bullfrog ( Lithobates catesbeianus) is an interesting model, as we have shown that brainstem synapses increase their capacity to function during hypoxia and ischemia by roughly 20-30 fold following aquatic overwintering (cold-acclimated, CA) compared to control conditions (warm-acclimated, WA). Here, we tested the hypothesis that other synapses, specially those in the forebrain, also improve their function to determine if extreme metabolic plasticity is specific to the brainstem, or a generalized response throughout the central nervous system. We used the synapse that carries thalamic input to dorsal pallium, which is involved in sensory processing and associative memory. To measure synaptic function, we stimulated thalamic axons and recorded evoked excitatory postsynaptic currents (eEPSCs) in the medial dorsal pallium, the proposed homolog to the mammalian hippocampus, in normoxic conditions and in oxygen and glucose deprivation (OGD). eEPSC amplitude at a baseline frequency of 0.5 Hz was depressed at OGD onset in WA frogs (paired t-test, p=0.0002, n=12) but not in CA animals (paired t-test, p=0.1602, n=6). This suggests that unlike WA frogs, overwintering allows maintained synaptic function in OGD within the forebrain, as well as the brainstem. Mechanistically, the maintenance of synaptic function in OGD appeared to be associated with dynamic increase in the probability of neurotransmitter release. Paired-pulse experiments to assess dynamics in neurotransmitter release in response to high-frequency stimulus pairs showed that synapses depressed in normoxic conditions in both WA (9 of 11 cells) and CA (4 out of 6 cells) groups. In OGD, synaptic depression was maintained in WA frogs (paired t-test, p=0.9192); however, synaptic depression reversed, whereby paired-pulse stimulation instead led to synaptic facilitation in 5 out of 6 neurons (paired t-test, p=0.0113). This suggests that synapses may alter the probability of glutamate release to act as a countermeasure to maintain forebrain function during energetic stress associated with emergence. Overall, these results show that metabolic plasticity to restart critical behaviors in hypoxia following hibernation is preserved across the brain and that altered synaptic dynamics may play a role in this response. This research was funded by the National Institutes of Health (R01NS114514, R15NS112920-01A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Autocrine VEGF drives neural stem cell proximity to the adult hippocampus vascular niche.

The vasculature is a key component of adult brain neural stem cell (NSC) niches. In the adult mammalian hippocampus, NSCs reside in close contact with a dense capillary network. How this niche is maintained is unclear. We recently found that adult hippocampal NSCs express VEGF, a soluble factor with chemoattractive properties for vascular endothelia. Here, we show that global and NSC-specific VEGF loss led to dissociation of NSCs and their intermediate progenitor daughter cells from local vasculature. Surprisingly, though, we found no changes in local vascular density. Instead, we found that NSC-derived VEGF supports maintenance of gene expression programs in NSCs and their progeny related to cell migration and adhesion. In vitro assays revealed that blockade of VEGF receptor 2 impaired NSC motility and adhesion. Our findings suggest that NSCs maintain their own proximity to vasculature via self-stimulated VEGF signaling that supports their motility towards and/or adhesion to local blood vessels.

Coupling of Sharp Wave Events between Zebrafish Hippocampal and Amygdala Homologs.

The mammalian hippocampus exhibits spontaneous sharp wave events (1-30 Hz) with an often-present superimposed fast ripple oscillation (120-220 Hz) to form a sharp wave ripple (SWR) complex. During slow-wave sleep or quiet restfulness, SWRs result from the sequential spiking of hippocampal cell assemblies initially activated during learned or imagined experiences. Additional cortical/subcortical areas exhibit SWR events that are coupled to hippocampal SWRs, and studies in mammals suggest that coupling may be critical for the consolidation and recall of specific memories. In the present study, we have examined juvenile male and female zebrafish and show that SWR events are intrinsically generated and maintained within the telencephalon and that their hippocampal homolog, the anterodorsolateral lobe (ADL), exhibits SW events with ∼9% containing an embedded ripple (SWR). Single-cell calcium imaging coupled to local field potential recordings revealed that ∼10% of active cells in the dorsal telencephalon participate in any given SW event. Furthermore, fluctuations in cholinergic tone modulate SW events consistent with mammalian studies. Moreover, the basolateral amygdala (BLA) homolog exhibits SW events with ∼5% containing an embedded ripple. Computing the SW peak coincidence difference between the ADL and BLA showed bidirectional communication. Simultaneous coupling occurred more frequently within the same hemisphere, and in coupled events across hemispheres, the ADL more commonly preceded BLA. Together, these data suggest conserved mechanisms across species by which SW and SWR events are modulated, and memories may be transferred and consolidated through regional coupling.

Cellular and Molecular Mechanisms Underlying Synaptic Subcellular Specificity.

Chemical synapses are essential for neuronal information storage and relay. The synaptic signal received or sent from spatially distinct subcellular compartments often generates different outcomes due to the distance or physical property difference. Therefore, the final output of postsynaptic neurons is determined not only by the type and intensity of synaptic inputs but also by the synaptic subcellular location. How synaptic subcellular specificity is determined has long been the focus of study in the neurodevelopment field. Genetic studies from invertebrates such as Caenorhabditis elegans (C. elegans) have uncovered important molecular and cellular mechanisms required for subcellular specificity. Interestingly, similar molecular mechanisms were found in the mammalian cerebellum, hippocampus, and cerebral cortex. This review summarizes the comprehensive advances in the cellular and molecular mechanisms underlying synaptic subcellular specificity, focusing on studies from C. elegans and rodents.

Azithromycin preserves adult hippocampal neurogenesis and behavior in a mouse model of sepsis

The mammalian hippocampus can generate new neurons throughout life. Known as adult hippocampal neurogenesis (AHN), this process participates in learning, memory, mood regulation, and forgetting. The continuous incorporation of new neurons enhances the plasticity of the hippocampus and contributes to the cognitive reserve in aged individuals. However, the integrity of AHN is targeted by numerous pathological conditions, including neurodegenerative diseases and sustained inflammation. In this regard, the latter causes cognitive decline, mood alterations, and multiple AHN impairments. In fact, the systemic administration of Lipopolysaccharide (LPS) from E. coli to mice (a model of sepsis) triggers depression-like behavior, impairs pattern separation, and decreases the survival, maturation, and synaptic integration of adult-born hippocampal dentate granule cells. Here we tested the capacity of the macrolide antibiotic azithromycin to neutralize the deleterious consequences of LPS administration in female C57BL6J mice. This antibiotic exerted potent neuroprotective effects. It reversed the increased immobility time during the Porsolt test, hippocampal secretion of pro-inflammatory cytokines, and AHN impairments. Moreover, azithromycin promoted the synaptic integration of adult-born neurons and functionally remodeled the gut microbiome. Therefore, our data point to azithromycin as a clinically relevant drug with the putative capacity to ameliorate the negative consequences of chronic inflammation by modulating AHN and hippocampal-related behaviors.

Emergence of the Hippocampus as a Vector for Goal-Directed Spatial Navigation.

The hippocampus, which is deeply involved in episodic memory, plays a pivotal role in spatial navigation, an essential animal behavior. Spatial navigation requires the calculation of the distance and direction from a current to the final position, i.e., a vector to a goal. Place cells in the mammalian hippocampus maximally increase their firing rates when the animal passes a particular location and then encode the animal's current location. The entorhinal cortex, one synapse upstream of the hippocampus, contains both grid and head direction cells that encode distance and direction information, respectively. However, the question of whether the hippocampus generates a vector for goal-directed navigation during the integration of distance and direction to the destination remains unclear. Mounting evidence of the cell types involved in spatial navigation has been obtained mainly in mammalian model animals such as rats and mice. Recent advances in wireless and miniaturized neural activity monitoring devices have begun to yield results not only in model organisms but also in wild mammals, birds, fish, and insects. A scrutiny of the literature examining neural correlates of spatial navigation across multiple animal species reveals that few place cells or grid cells have been found, but that head direction cells are commonly present in multiple animal species. Exceptionally, rodent-like place cells were only found in the medial pallium of tufted titmice, a food-caching bird. The medial pallium is an avian brain region homologous to the mammalian hippocampus. By contrast, rodent-like head direction cells are found in the medial pallium of quails. Head direction cells are also found in the medial pallium of streaked shearwaters, a migratory bird. The avian hippocampus contains information about the animal's current location or direction, but the neural encoding may differ depending on the ecological characteristics of the bird species. The place cells of bats, which are mammals, fly in three-dimensional space and encode vectorial information toward the goal. Training rats with an ingenious task that required them to choose a direction for each run in a maze suggested that place cells encode a vector for goal-directed spatial navigation. Thus, the scrutiny of the literature on spatial navigation-related neuronal activity across multiple animal species suggests that depending on a combination of external conditions such as the context in which the animal is situated (e.g., the context or the framework composed of landmarks in the environment) and internal conditions such as the ecological and behavioral characteristics of the animal, hippocampal neurons can be identified as place cells or head direction cells. We thus propose a conjecture that primitively, the hippocampus, or its homolog, contains information about the travel direction and that the emergence of the hippocampus during evolution has enabled the generation of vector information to the goal for advanced spatial navigation such as the search for the shortcut path and episodic memory capacity.

Sharpening the blades of the dentate gyrus: how adult-born neurons differentially modulate diverse aspects of hippocampal learning and memory.

For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above-mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into "supra-pyramidal" and "infra-pyramidal". Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.

Cell-autonomous and non-cell-autonomous roles of NKCC1 in regulating neural stem cell quiescence in the hippocampal dentate gyrus.

Quiescence is a hallmark of adult neural stem cells (NSCs) in the mammalian brain, and establishment and maintenance of quiescence is essential for life-long continuous neurogenesis. How NSCs in the dentate gyrus (DG) of the hippocampus acquire their quiescence during early postnatal stages and continuously maintain quiescence in adulthood is poorly understood. Here, we show that Hopx-CreERT2-mediated conditional deletion of Nkcc1, which encodes a chloride importer, in mouse DG NSCs impairs both their quiescence acquisition at early postnatal stages and quiescence maintenance in adulthood. Furthermore, PV-CreERT2-mediated deletion of Nkcc1 in PV interneurons in the adult mouse brain leads to activation of quiescent DG NSCs, resulting in an expanded NSC pool. Consistently, pharmacological inhibition of NKCC1 promotes NSC proliferation in both early postnatal and adult mouse DG. Together, our study reveals both cell-autonomous and non-cell-autonomous roles of NKCC1 in regulating the acquisition and maintenance of NSC quiescence in the mammalian hippocampus.

Assessments of dentate gyrus function: discoveries and debates.

There has been considerable speculation regarding the function of the dentate gyrus (DG) - a subregion of the mammalian hippocampus - in learning and memory. In this Perspective article, we compare leading theories of DG function. We note that these theories all critically rely on the generation of distinct patterns of activity in the region to signal differences between experiences and toreduce interference between memories. However, these theories are divided by the roles they attribute to the DG during learning and recall and by the contributions they ascribe to specific inputs or cell types within the DG. These differences influence the information that the DG is thought to impart to downstream structures. We work towards a holistic view of the role of DG in learning and memory by first developing three critical questions to foster a dialogue between the leading theories. We then evaluate the extent to which previous studies address our questions, highlight remaining areas of conflict, and suggest future experiments to bridge these theories.

Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling

The regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of specific circadian genes on cellular and molecular mechanisms controlling synaptic plasticity and cognitive function remains elusive. Here, we show that the expression of the circadian protein TIMELESS displays circadian rhythmicity in the mammalian hippocampus. We identify TIMELESS as a chromatin-bound protein that targets synaptic-plasticity-related genes such as phosphodiesterase 4B (Pde4b). By promoting Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and influence synaptic plasticity. Conditional deletion of Timeless in the adult forebrain impairs working and contextual fear memory in mice. These cognitive phenotypes were accompanied by attenuation of hippocampal Schaffer-collateral synapse long-term potentiation. Together, these data establish a neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.

Adult-born neurons add flexibility to hippocampal memories.

Although most neurons are generated embryonically, neurogenesis is maintained at low rates in specific brain areas throughout adulthood, including the dentate gyrus of the mammalian hippocampus. Episodic-like memories encoded in the hippocampus require the dentate gyrus to decorrelate similar experiences by generating distinct neuronal representations from overlapping inputs (pattern separation). Adult-born neurons integrating into the dentate gyrus circuit compete with resident mature cells for neuronal inputs and outputs, and recruit inhibitory circuits to limit hippocampal activity. They display transient hyperexcitability and hyperplasticity during maturation, making them more likely to be recruited by any given experience. Behavioral evidence suggests that adult-born neurons support pattern separation in the rodent dentate gyrus during encoding, and they have been proposed to provide a temporal stamp to memories encoded in close succession. The constant addition of neurons gradually degrades old connections, promoting generalization and ultimately forgetting of remote memories in the hippocampus. This makes space for new memories, preventing saturation and interference. Overall, a small population of adult-born neurons appears to make a unique contribution to hippocampal information encoding and removal. Although several inconsistencies regarding the functional relevance of neurogenesis remain, in this review we argue that immature neurons confer a unique form of transience on the dentate gyrus that complements synaptic plasticity to help animals flexibly adapt to changing environments.

Spatial coding in the hippocampus and hyperpallium of flying owls

The elucidation of spatial coding in the hippocampus requires exploring diverse animal species. While robust place-cells are found in the mammalian hippocampus, much less is known about spatial coding in the hippocampus of birds. Here we used a wireless-electrophysiology system to record single neurons in the hippocampus and other two dorsal pallial structures from freely flying barn owls (Tyto alba), a central-place nocturnal predator species with excellent navigational abilities. The owl's 3D position was monitored while it flew between perches. We found place cells-neurons that fired when the owl flew through a spatially restricted region in at least one direction-as well as neurons that encoded the direction of flight, and neurons that represented the owl's perching position between flights. Many neurons encoded combinations of position, direction, and perching. Spatial coding was maintained stable and invariant to lighting conditions. Place cells were observed in owls performing two different types of flying tasks, highlighting the generality of the result. Place coding was found in the anterior hippocampus and in the posterior part of the hyperpallium apicale, and to a lesser extent in the visual Wulst. The finding of place-cells in flying owls suggests commonalities in spatial coding across mammals and birds.