ABSTRACT

Grid and place cells typically fire at progressively earlier phases within each cycle of the theta rhythm as rodents run across their firing fields, a phenomenon known as theta phase precession. Here, we report theta phase precession relative to turning angle in theta-modulated head direction cells within the anteroventral thalamic nucleus (AVN). As rodents turn their heads, these cells fire at progressively earlier phases as head direction sweeps over their preferred tuning direction. The degree of phase precession increases with angular head velocity. Moreover, phase precession is more pronounced in those theta-modulated head direction cells that exhibit theta skipping, with a stronger theta-skipping effect correlating with a higher degree of phase precession. These findings are consistent with a ring attractor model that integrates external theta input with internal firing rate adaptation—a phenomenon we identified in head direction cells within AVN. Our results broaden the range of information known to be subject to neural phase coding and enrich our understanding of the neural dynamics supporting spatial orientation and navigation.

ABSTRACT

Long-term potentiation (LTP) is proposed to be the molecular mechanism underlying learning and memory in the brain. A key event for LTP is the influx of calcium into post-synaptic neurons via multiple ion channel control systems. One such system involves N-methyl-D-aspartate receptors (NMDARs), which were originally believed to be essential for LTP and new learning. Recent studies have demonstrated that hippocampal NMDARs are critical for learning new spatial information in a novel environment; however, when pre-training occurs prior to new spatial learning, these receptors are not needed. Additionally, researchers have shown that activation of voltage-gated calcium channels (VGCCs) and their associated calcium influx can induce LTP independent of NMDARs. These findings led to the idea that the amount of calcium required for learning in hippocampus depends on whether the new learning takes place in a novel or familiar environment, with a novel environment demanding greater calcium influx. It was hypothesized that to impair new learning in a familiar environment both NMDARs and VGCCs would need to be blocked. Long-Evans rats were trained in a three-phase version of the Morris water task, which included pre-training, new learning mass-training, and a probe test. Prior to mass-training, intrahippocampal VGCCs were blocked individually or in combination with NMDARs blockade to evaluate their effects on the rats learning and memory. The results showed that blocking both NMDARs and VGCCs simultaneously impaired new spatial learning with familiar information, whereas VGCC blockade alone did not.

The cover image is based on the article The Suprapyramidal and Infrapyramidal Blades of the Dentate Gyrus Exhibit Different GluN Subunit Content and Dissimilar Frequency-Dependent Synaptic Plasticity In Vivo by Christina Strauch et al., https://doi.org/10.1002/hipo.70002.

ABSTRACT

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.

ABSTRACT

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.

ABSTRACT

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.

ABSTRACT

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.

ABSTRACT

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.

ABSTRACT

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.

ABSTRACT

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.