Early protein malnutrition has been shown to affect the brain reward circuitry, leading to enduring molecular, neurochemical, and behavioral alterations. This study explored how maternal protein restriction contributes to anhedonia, a key depression symptom, focusing on the hippocampal BDNF-TrkB signaling and structural plasticity changes in the CA1 subregion of the dorsal hippocampus (DH). To achieve our goal, adult rats submitted to a protein restriction schedule from the 14th day of gestation up to 30 days of age (PR-rats) were subjected to the sucrose preference test (SPT) and compared with animals fed a normoprotein diet. Immediately after SPT, we assessed the levels of BDNF and its receptor TrkB and structural plasticity changes. Interestingly, PR-rats showed a significant decrease in sucrose preference. Furthermore, perinatal protein-restriction-induced anhedonia correlated with decreased BDNF and p-TrkB levels in the DH, alongside reduced dendritic spine density in CA1 pyramidal neurons, particularly mature spines (i.e., stubby and mushroom spines). These findings suggest that decreased hippocampal BDNF-TrkB signaling accompanied by structural remodeling in the CA1 pyramidal neurons may contribute to the reduced ability of undernourished animals to respond to rewarding stimuli, increasing their vulnerability to anhedonia later in life.

The ability to navigate spatially in the physical world is a fundamental cognitive skill. This study examines the anatomical correlates of map-assisted wayfinding in an unfamiliar virtual environment using structural magnetic resonance magining (MRI). Thirty-three participants were required to reach up to seven different locations represented on a navigational map in a simulated environment, while their gazing behavior was recorded, and, in close temporal proximity, the anatomical MRI of their brain was acquired. Significant predictors of wayfinding performance were the volumes of the right hippocampus, left retrosplenial cortex, and posterior cingulate cortex-left inferior frontal gyrus, right superior frontal gyrus, and right cerebellar lobule VIIB. Detailed analyses revealed a dissociation between two clusters of gray matter density in the right hippocampus. Compared with the poorest wayfinders, the best wayfinders exhibited more gray matter density in a cluster located in the right posterior hippocampus but less gray matter density in a cluster located in the anterior section of the hippocampus. In addition, top performers spent more time gazing at the map, highlighting the benefit of using external aids during navigation tasks. Altogether, these results underscore how structural adaptations are associated with spatial navigation performance.

Adolescent intermittent ethanol (AIE) exposure leads to persisting increases in glial markers and significantly decreases the neurogenic niche in the dentate gyrus of the hippocampus. Our previous study indicated that donepezil (DZ), a cholinesterase inhibitor, can reverse the AIE effect of decreased doublecortin (DCX), a neurogenic marker, and increased cleaved caspase 3, a marker of apoptosis, in the dentate gyrus of male rats. However, to date, no studies have assessed the effects of DZ on AIE effects in females. The purpose of this study was to determine whether DZ can reverse neuroimmune, neurogenic, and neuronal death effects in adulthood after AIE in female rats. Adolescent female rats were given 14 doses of ethanol (5 g/kg) over 24 days by intragastric gavage. Seventeen days later, DZ (2.5 mg/kg, 1.88 mL/kg, i.g., in water) was then administered daily for 4 days prior to sacrifice. Immunohistochemical techniques were utilized to determine the effects of DZ on AIE-induced changes in neurogenesis, cell death, glial, and neuroimmune markers. As expected, AIE decreased the neurogenic markers DCX, SOX2, and Ki-67 in the dentate gyrus and also caused an increase in the glial markers GFAP and Iba-1 in the hippocampus. The effects of AIE on neurogenic and glial markers were reversed by DZ treatment, but the reversal of AIE effects on glial markers was regionally specific within the hippocampus. Overall, these findings indicate that systemic DZ in adult female rats ameliorates the effects of AIE on neurogenesis, neuronal cell death, neuroimmune markers, and glial activation markers. Future studies will determine if DZ alters hippocampally driven behaviors, as well as the mechanisms underlying donepezil's effects.

The hippocampus plays a crucial role in acquiring, storing, and retrieving associative experience. Whereas neuromodulatory control of the hippocampus by the locus coeruleus (LC) enhances memory acquisition and consolidation, less is known about its influence on memory retrieval. The LC fires at tonic (0.5-8 Hz) and phasic frequencies (10-25 Hz), relative to arousal and affective states. Here, we explored to what extent LC stimulation at different frequencies (2-100 Hz) and respective stimulation patterns, before retrieval of recently acquired or remote spatial memory, alter working memory (WM) or reference memory (RM) in male rats. Here, animals learned a spatial memory task in an eight-arm radial maze over a period of 15 days. LC stimulation before recent memory testing did not affect WM. However, LC stimulation at 20 or 100 Hz, but not 5-10 Hz, impaired retrieval of recently consolidated RM. These frequency-dependent impairments were abolished by intracerebral β-adrenergic receptor (β-AR), but not D1/D5 receptor, antagonism. When memory retrieval was assessed 4 weeks after initial consolidation (Day 34), RM was significantly impaired compared to the final day of recent memory testing (on Day 6). RM was not altered by LC stimulation before remote memory retrieval. However, LC stimulation at 2-100 Hz improved WM. Taken together, these data suggest that frequency-dependent NA release from the LC disrupts retrieval of recently acquired RM via activation of β-AR. Strikingly, increasing LC activity in general improves WM of a remotely acquired spatial learning task, assessed 4 weeks after the recent memory testing, suggesting that the increased effort of sustaining WM of a task learned in the past requires higher LC engagement.

The entorhinal cortex sends afferent information to the hippocampus by means of the perforant path (PP). The PP input to the dentate gyrus (DG) terminates in the suprapyramidal (sDG) and infrapyramidal (iDG) blades. Different electrophysiological stimulation patterns of the PP can generate hippocampal synaptic plasticity. Whether frequency-dependent synaptic plasticity differs in the sDG and iDG is unclear. Here, we compared medial PP-DG responses in freely behaving adult rats and found that synaptic plasticity in the sDG is broadly frequency dependent, whereby long-term depression (LTD, > 24 h) is induced with stimulation at 1 Hz, short-term depression (< 2 h) is triggered by 5 or 10 Hz, and long-term potentiation (LTP) of increasing magnitudes is induced by 200 and 400 Hz stimulation, respectively. By contrast, although the iDG expresses STD following 5 or 10 Hz stimulation, LTD induced by 1 Hz is weaker, LTP is not induced by 200 Hz and LTP induced by 400 Hz stimulation is significantly smaller in magnitude than LTP induced in sDG. Furthermore, the stimulus-response relationship of iDG is suppressed compared to sDG. These differences may arise from differences in granule cell properties, or the complement of NMDA receptors. Patch clamp recordings, in vitro, revealed reduced firing frequencies in response to high currents, and different action potential thresholds in iDG compared to sDG. Assessment of the expression of GluN subunits revealed significantly lower expression levels of GluN1, GluN2A, and GluN2B in the middle molecular layer of iDG compared to sDG. Taken together, these data indicate that synaptic plasticity in the iDG is weaker, less persistent and less responsive to afferent frequencies than synaptic plasticity in sDG. Effects may be mediated by weaker NMDA receptor expression and differences in neuronal responses in iDG versus sDG. These characteristics may explain reported differences in experience-dependent information processing in the suprapyramidal and infrapyramidal blades of the DG.

This paper provides a personal history of work starting with the discovery that anxiolytic drugs reduce hippocampal theta frequency. It includes parallel work on septal elicitation of theta carried out in Jeffrey Gray's laboratory in Oxford; a statement of my original scientific perspective on the work; and a description of later work in my laboratory in New Zealand confirming the function of theta rhythmicity per se and its mediation of the effects of anxiolytic drugs on behavior. I finish with comments on risk management with such experiments and their use in larger scale theory development.

Accumulating evidence indicates that inherited astrocyte dysfunction can be a primary trigger for epilepsy development; however, the available data are rather limited. In addition, astrocytes are considered as a perspective target for the design of novel and improvement of the existing antiepileptic therapy. Piracetam and related nootropic drugs are widely used in the therapy of various epileptic disorders, but detailed mechanisms of racetams action and, in particular, their effects on glial functions are poorly understood. In this study, we explored the functional state of astrocytes in the dentate gyrus (DG) of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures and compared the action of piracetam on the DG astrocytes in KM and normal Wistar rats. Wistar and naïve KM rats which received injections of saline (control) or piracetam (100 mg/kg) for 21 days were recruited in our studies. Comparative analysis of control Wistar and KM rats revealed genetically determined abnormalities in DG astrocytes of KM rats including an increased expression of NFIA but a decreased GFAP, ALDH1L1, EAATs, and glutamine synthetase (GS). Piracetam treatment normalized the expression of all studied markers, except NFIA, in KM rats, while in Wistar rats, it potentiated only GS and NFIA. The results suggested that the nootropic and antiepileptic effects of piracetam may be, at least partially, mediated by the modulation of astroglia functions. In addition, analysis of NFIA and GS colocalization revealed the novel pattern of astrocyte heterogeneity in the DG which was significantly altered in epileptic rats but corrected by piracetam.

Although the medial temporal lobe (MTL) is traditionally considered a region dedicated to long-term memory, recent neuroimaging and intracranial recording evidence suggests that the MTL also contributes to certain aspects of visual short-term memory (VSTM), such as the quality or precision of retained VSTM content. This study aims to further investigate the MTL's role in VSTM precision through the application of transcranial direct current stimulation (tDCS) and functional magnetic resonance imaging (fMRI). Participants underwent 1.5 mA offline tDCS over bilateral temporal lobes using left cathodal and right anodal electrodes, administered for either 20 min (active) or 0.5 min within a 20-min window (sham), in a counterbalanced design. As the electrical current passes through midbrain structures with this bilateral stimulation montage, prior behavioral and modeling evidence suggests that this tDCS protocol can modulate MTL functions. To confirm this and examine its impacts on VSTM, participants completed a VSTM color recall task immediately following tDCS, while undergoing a 20-min fMRI scan and a subsequent 7.5-min resting-state scan, during which they focused on a fixation cross. Behavioral results indicated that this tDCS protocol decreased VSTM precision without significantly affecting overall recall success. Furthermore, psychophysiological interaction analysis revealed that tDCS over the temporal lobe modulated hippocampal-occipital functional connectivity during the VSTM task, despite no main effect on fMRI BOLD activity. Notably, this modulation was also observed during resting-state fMRI 15-20 min post-tDCS, with the magnitude of the effect correlating with participants' behavioral changes in VSTM precision across active and control conditions. Combined, these findings suggest that tDCS over the temporal lobe can modulate the intrinsic functional connectivity between the MTL and visual sensory areas, thereby affecting VSTM precision.

As requested by the editors of this special issue of Hippocampus on Scientific Histories of Hippocampal Research, this review provides a detailed personal perspective and historical background on the research involved in a number of findings. The review includes description of the development of the water maze and its use in providing evidence to support the role of the hippocampus in spatial memory function. The review also describes how the water maze was then used in further work to support the proposal that NMDA-dependent synaptic modification in the hippocampus mediates the encoding of new spatial memories. This personal history gives a perspective on the convergence of different streams of physiological, biochemical, theoretical and behavioral research that resulted in these findings on hippocampal function.

Two key series of discoveries about the hippocampus are described. One is the discovery of hippocampal spatial view cells in primates. This discovery opens the way to a much better understanding of human episodic memory, for episodic memory prototypically involves a memory of where people or objects or rewards have been seen in locations "out there" which could never be implemented by the place cells that encode the location of a rat or mouse. Further, spatial view cells are valuable for navigation using vision and viewed landmarks, and provide for much richer, vision-based, navigation than the place to place self-motion update performed by rats and mice who live in dark underground tunnels. Spatial view cells thus offer a revolution in our understanding of the functions of the hippocampus in memory and navigation in humans and other primates with well-developed foveate vision. The second discovery describes a computational theory of the hippocampal-neocortical memory system that includes the only quantitative theory of how information is recalled from the hippocampus to the neocortex. It is shown how foundations for this research were the discovery of reward neurons for food reward, and non-reward, in the primate orbitofrontal cortex, and representations of value including of monetary value in the human orbitofrontal cortex; and the discovery of face identity and face expression cells in the primate inferior temporal visual cortex and how they represent transform-invariant information. This research illustrates how in order to understand a brain computation, a whole series of integrated interdisciplinary discoveries is needed to build a theory of the operation of each neural system.

I have been incredibly fortunate to have worked in the field of hippocampal spatial coding during three of its most exciting decades, the 1990s, 2000s, and 2010s. During this time I had a ringside view of some of the foundational discoveries that were made which have transformed our understanding of the hippocampal system and its role in cognition (especially spatial cognition) and memory. These discoveries inspired me in my own lab over the years to pursue three broad lines of enquiry-3D spatial encoding, context and the sense of direction-which are outlined here. If some of my personal recollections are a little inaccurate (such is the nature of episodic memory!) I apologize in advance.

In 1979, I joined Jim Ranck's group in Brooklyn and began recording hippocampal neurons. The first project was to record single neurons across three behaviors in different chambers: pellet retrieval on a radial-arm maze, bar-pressing for food reward in an operant chamber, and maternal pup-retrieval in a large home box. We found spatial firing in all three chambers, with a single-neuron's firing pattern unpredictable from one chamber to the next. We interpreted the spatial firing patterns as representing "context." Later, in the 1980s, I began collaborating with Bob Muller (and Jim Ranck). In the first of a pair of 1987 papers, we used computerized data acquisition, recorded in simple, reduced environments to demonstrate robust, stable place cell firing and the characteristic features of firing fields. In the second paper we showed that when a rat is transferred from one environment to another, the set of place cells "remaps." "Remapping" was defined later, in a pair of 1990 papers. "Context" was introduced in the early three-behavior experiment but was not discussed in the 1987 papers. What is the true relationship between the biological observation of "remapping" and the psychological concept of "context"? This difficult question is addressed here and in more detail in our recent paper.

During the 1990s and early 2000s, research in humans and in the nonhuman primate model of human amnesia revealed that tasks involving free viewing of images provided an exceptionally sensitive measure of recognition memory. Performance on these tasks was sensitive to damage restricted to the hippocampus as well as to damage that included medial temporal lobe cortices. Early work in my laboratory used free-viewing tasks to assess the neurophysiological correlates of recognition memory, and the use of naturalistic visual exploration opened rich avenues to assess other aspects of the impact of eye movements on neural activity in the hippocampus and entorhinal cortex. Here, I summarize two main lines of this work and some of the stories of the trainees who made essential contributions to these discoveries.

Numerous scientific advances and discoveries have arisen from research on the hippocampal formation. This special issue provides first-person historical descriptions of these advances and discoveries in hippocampal research, written by those directly involved in the research. This is the first section of a special issue that will also include future articles on this topic. Here, we discuss some of the factors that motivated this special issue, and the major themes of hippocampal research that are addressed.

This article is my recollection of events surrounding the discovery of head direction (HD) cells by Jim Ranck in 1984 and the first journal publications 6 years later. Ranck first described the fundamental properties of HD cells qualitatively in a Society for Neuroscience abstract (1984) and in the proceedings to a conference. Ranck, however, was convinced by Bob Muller, a faculty colleague in the lab, to delay writing up Jim's discovery until they developed a two-spot video tracking system, which would enable proper quantitative analyses. The development of this system was complex and was still undergoing development when I arrived in the Brooklyn lab in 1986. By this time, Jim had begun to refocus his efforts on thinking about the relationship between space and manifolds and was no longer engaged in active research. It thus befell me (unintentionally) to complete the recordings of these fascinating cells. This endeavor involved recording additional HD cells with the new video tracking system, monitoring the cells' responses following a series of environmental manipulations, and performing quantitative analyses on the data. Throughout 1987, I recorded most of the cells that would form the basis for our 1990 papers published in the Journal of Neuroscience. Along the way, there were many events and emotions: luck, excitement, humor, frustration, tutorials, unintended outcomes, and long-lasting friendships. I was guided and supported during this time by both Bob Muller and John Kubie, but remain forever grateful to Jim for this wonderful opportunity.

The ground-breaking research of patient H.M. brought to light the importance of the hippocampus for our memories of everyday and special events. Three quarters of a century of intense neurobiological and neuropsychological research would follow as scientists sought to understand why the hippocampus is such an important memory structure in the brain. Navigating a career during this time required adaptive research strategies as new evidence emerged. Although exciting progress has been made, complex challenges remain.

In keeping with the historical focus of this special issue of Hippocampus, this paper reviews the history of my development of the SPEAR model. The SPEAR model proposes that separate phases of encoding and retrieval (SPEAR) allow effective storage of multiple overlapping associative memories in the hippocampal formation and other cortical structures. The separate phases for encoding and retrieval are proposed to occur within different phases of theta rhythm with a cycle time on the order of 125 ms. The same framework applies to the slower transition between encoding and consolidation dynamics regulated by acetylcholine. The review includes description of the experimental data on acetylcholine and theta rhythm that motivated this model, the realization that existing associative memory models require these different dynamics, and the subsequent experimental data supporting these dynamics. The review also includes discussion of my work on the encoding of episodic memories as spatiotemporal trajectories, and some personal description of the episodic memories from my own spatiotemporal trajectory as I worked on this model.

I am lucky to be part of the hippocampus story, if not from the beginning but at least in its formative decades. Being part of this community is a true privilege. As I try to illustrate below, science is made by scientists. My fierce competitors over the years have become my close friends. I hope the field of hippocampus research will stay that way forever.

For most of my career, I focused on understanding how and where spatial context, the place where things happen, is represented in the brain. My interest in this began in the early 1990's, during my postdoctoral training with David Amaral, when we defined the rodent homolog of the primate parahippocampal cortex, a region implicated in processing spatial and contextual information. We parceled out the caudal portion of the rat perirhinal cortex (PER) and called it the postrhinal cortex (POR). In my own lab at Brown University, I continued to study the anatomy of the PER, POR, and entorhinal cortices. I also began to characterize and differentiate the functions of these regions, particularly the newly defined POR and the redefined PER. Our electrophysiological and behavioral evidence supports a view of POR function that aligns with our anatomical evidence. Briefly, the POR integrates object and feature information from the PER with spatial information from the retrosplenial, posterior parietal, and secondary visual cortices and the pulvinar and uses this information to represent specific environmental contexts, including the spatial arrangement of objects and features within each context. In addition to maintaining a representation of the current context, the POR plays an attentional role by continually monitoring the context for changes and updating the context representation when changes occur. This context representation is accessible to other regions for cognitive processes, including binding life events with context to form episodic memories, guiding context-relevant behavior, and recognizing objects within scenes and contexts.

This contribution is part of the special issue on the Hippocampus focused on personal histories of advances in knowledge on the hippocampus and related structures. An account is offered of the author's role in the development of neural ensemble recording: stereo recording (stereotrodes, tetrodes) and the use of this approach to search for evidence of Hebb's "cell assemblies" and "phase sequences", the holy grail of the neuroscience of learning and memory.

For many years, the hilus of the dentate gyrus (DG) was a mystery because anatomical data suggested a bewildering array of cells without clear organization. Moreover, some of the anatomical information led to more questions than answers. For example, it had been identified that one of the major cell types in the hilus, the mossy cell, innervates granule cells (GCs). However, mossy cells also targeted local GABAergic neurons. Furthermore, it was not yet clear if mossy cells were glutamatergic or GABAergic. This led to many debates about the role of mossy cells. However, it was clear that hilar neurons, including mossy cells, were likely to have very important functions because they provided strong input to GCs. Hilar neurons also attracted attention in epilepsy because pathological studies showed that hilar neurons were often lost, but GCs remained. Vulnerability of hilar neurons also occurred after traumatic brain injury and ischemia. These observations fueled an interest to understand hilar neurons and protect them, an interest that continues to this day. This article provides a historical and personal perspective into the ways that I sought to contribute to resolving some of the debates and moving the field forward. Despite several technical challenges the outcomes of the studies have been worth the effort with some surprising findings along the way. Given the growing interest in the hilus, and the advent of multiple techniques to selectively manipulate hilar neurons, there is a great opportunity for future research.