Hippocampus最新文献

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.

The hippocampus (HPC) and retrosplenial cortex (RSC) are key components of the brain's memory and navigation systems. Lesions of either region produce profound deficits in spatial cognition and HPC neurons exhibit well-known spatial firing patterns (place fields). Recent studies have also identified an array of navigation-related firing patterns in the RSC. However, there has been little work comparing the response properties and information coding mechanisms of these two brain regions. In the present study, we examined the firing patterns of HPC and RSC neurons in two tasks which are commonly used to study spatial cognition in rodents, open field foraging with an environmental context manipulation and continuous T-maze alternation. We found striking similarities in the kinds of spatial and contextual information encoded by these two brain regions. Neurons in both regions carried information about the rat's current spatial location, trajectories and goal locations, and both regions reliably differentiated the contexts. However, we also found several key differences. For example, information about head direction was a prominent component of RSC representations but was only weakly encoded in the HPC. The two regions also used different coding schemes, even when they encoded the same kind of information. As expected, the HPC employed a sparse coding scheme characterized by compact, high contrast place fields, and information about spatial location was the dominant component of HPC representations. RSC firing patterns were more consistent with a distributed coding scheme. Instead of compact place fields, RSC neurons exhibited broad, but reliable, spatial and directional tuning, and they typically carried information about multiple navigational variables. The observed similarities highlight the closely related functions of the HPC and RSC, whereas the differences in information types and coding schemes suggest that these two regions likely make somewhat different contributions to spatial cognition.

Classic research has shown a division in the neuroanatomical structures that support flexible (e.g., short-cutting) and habitual (e.g., familiar route following) navigational behavior, with hippocampal–caudate systems associated with the former and putamen systems with the latter. There is, however, disagreement about whether the neural structures involved in navigation process particular forms of spatial information, such as associations between constellations of cues forming a cognitive map, versus single landmark-action associations, or alternatively, perform particular reinforcement learning algorithms that allow the use of different spatial strategies, so-called model-based (flexible) or model-free (habitual) forms of learning. We sought to test these theories by asking participants (N = 24) to navigate within a virtual environment through a previously learned, 9-junction route with distinctive landmarks at each junction while undergoing functional magnetic resonance imaging (fMRI). In a series of probe trials, we distinguished knowledge of individual landmark-action associations along the route versus knowledge of the correct sequence of landmark-action associations, either by having absent landmarks, or “out-of-sequence” landmarks. Under a map-based perspective, sequence knowledge would not require hippocampal systems, because there are no constellations of cues available for cognitive map formation. Within a learning-based model, however, responding based on knowledge of sequence would require hippocampal systems because prior context has to be utilized. We found that hippocampal–caudate systems were more active in probes requiring sequence knowledge, supporting the learning-based model. However, we also found greater putamen activation in probes where navigation based purely on sequence memory could be planned, supporting models of putamen function that emphasize its role in action sequencing.

Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI (dMRI) and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N = 628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (ventral tegmental area) showed stronger connectivity with the anterior versus posterior hippocampus, the ventromedial prefrontal cortex showed stronger connectivity with the posterior hippocampus. The limbic (ventral) striatum demonstrated a more homogeneous connectivity profile along the hippocampal long axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.

Researchers who study the human hippocampus are naturally interested in how its subfields function. However, many researchers are precluded from examining subfields because their manual delineation from magnetic resonance imaging (MRI) scans (still the gold standard approach) is time consuming and requires significant expertise. To help ameliorate this issue, we present here two protocols, one for 3T MRI and the other for 7T MRI, that permit automated hippocampus segmentation into six subregions, namely dentate gyrus/cornu ammonis (CA)4, CA2/3, CA1, subiculum, pre/parasubiculum, and uncus along the entire length of the hippocampus. These protocols are particularly notable relative to existing resources in that they were trained and tested using large numbers of healthy young adults (n = 140 at 3T, n = 40 at 7T) whose hippocampi were manually segmented by experts from MRI scans. Using inter-rater reliability analyses, we showed that the quality of automated segmentations produced by these protocols was high and comparable to expert manual segmenters. We provide full open access to the automated protocols, and anticipate they will save hippocampus researchers a significant amount of time. They could also help to catalyze subfield research, which is essential for gaining a full understanding of how the hippocampus functions.

Our ability to navigate in a new environment depends on learning new locations. Mental representations of locations are quickly accessible during navigation and allow us to know where we are regardless of our current viewpoint. Recent functional magnetic resonance imaging (fMRI) research using pattern classification has shown that these location-based representations emerge in the retrosplenial cortex and parahippocampal gyrus, regions theorized to be critically involved in spatial navigation. However, little is currently known about the oscillatory dynamics that support the formation of location-based representations. We used magnetoencephalogram (MEG) recordings to investigate region-specific oscillatory activity in a task where participants could form location-based representations. Participants viewed videos showing that two perceptually distinct scenes (180° apart) belonged to the same location. This “overlap” video allowed participants to bind the two distinct scenes together into a more coherent location-based representation. Participants also viewed control “non-overlap” videos where two distinct scenes from two different locations were shown, where no location-based representation could be formed. In a post-video behavioral task, participants successfully matched the two viewpoints shown in the overlap videos, but not the non-overlap videos, indicating they successfully learned the locations in the overlap condition. Comparing oscillatory activity between the overlap and non-overlap videos, we found greater theta and alpha/beta power during the overlap relative to non-overlap videos, specifically at time-points when we expected scene integration to occur. These oscillations localized to regions in the medial parietal cortex (precuneus and retrosplenial cortex) and the medial temporal lobe, including the hippocampus. Therefore, we find that theta and alpha/beta oscillations in the hippocampus and medial parietal cortex are likely involved in the formation of location-based representations.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks—which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.