A Specific Role of the Human Hippocampus in Recall of Temporal Sequences

There is a growing interest in how temporal order of episodic memories is represented within the medial temporal lobe (MTL). Animal studies suggest that the hippocampal formation (HF) is critical for retrieving the temporal order of past experiences. However, human imaging studies that have tested recency discrimination between pairs of previously encoded items have generally failed to report HF activation. We hypothesized that recalling a naturalistic sequence of past events would be particularly sensitive to HF function, attributable to greater involvement of associative processes. To test this prediction, we let subjects watch a novel movie and later, during functional magnetic resonance imaging, asked them to rearrange and "replay" scenes from the movie in correct order. To identify areas specifically involved in retrieval of temporal order, we used a control condition where subjects logically inferred the order of scenes from the same movie. Extensive MTL activation was observed during sequence recall. Activation within the right HF was specifically related to retrieval of temporal order and correlated positively with accuracy of sequence recall. Also, the bilateral parahippocampal cortex responded to retrieval of temporal order, but the activation here was not related to performance. Our study is the first to unequivocally demonstrate that correct sequence recall depends on H

Challenges for identifying the neural mechanisms that support spatial navigation: the impact of spatial scale.

Spatial navigation is a fascinating behavior that is essential for our everyday lives. It involves nearly all sensory systems, it requires numerous parallel computations, and it engages multiple memory systems. One of the key problems in this field pertains to the question of reference frames: spatial information such as direction or distance can be coded egocentrically-relative to an observer-or allocentrically-in a reference frame independent of the observer. While many studies have associated striatal and parietal circuits with egocentric coding and entorhinal/hippocampal circuits with allocentric coding, this strict dissociation is not in line with a growing body of experimental data. In this review, we discuss some of the problems that can arise when studying the neural mechanisms that are presumed to support different spatial reference frames. We argue that the scale of space in which a navigation task takes place plays a crucial role in determining the processes that are being recruited. This has important implications, particularly for the inferences that can be made from animal studies in small scale space about the neural mechanisms supporting human spatial navigation in large (environmental) spaces. Furthermore, we argue that many of the commonly used tasks to study spatial navigation and the underlying neuronal mechanisms involve different types of reference frames, which can complicate the interpretation of neurophysiological data

From Rapid Place Learning to Behavioral Performance: A Key Role for the Intermediate Hippocampus

Rapid place encoding by hippocampal neurons, as reflected by place-related firing, has been intensely studied, whereas the substrates that translate hippocampal place codes into behavior have received little attention. A key point relevant to this translation is that hippocampal organization is characterized by functional-anatomical gradients along the septotemporal axis: Whereas the ability of hippocampal neurons to encode accurate place information declines from the septal to temporal end, hippocampal connectivity to prefrontal and subcortical sites that might relate such place information to behavioral-control processes shows an opposite gradient. We examined in rats the impact of selective lesions to relevant parts of the hippocampus on behavioral tests requiring place learning (watermaze procedures) and on in vivo electrophysiological models of hippocampal encoding (long-term potentiation [LTP], place cells). We found that the intermediate hippocampus is necessary and largely sufficient for behavioral performance based on rapid place learning. In contrast, a residual septal pole of the hippocampus, although displaying intact electrophysiological indices of rapid information encoding (LTP, precise place-related firing, and rapid remapping), failed to sustain watermaze performance based on rapid place learning. These data highlight the important distinction between hippocampal encoding and the behavioral performance based on such encoding, and suggest that the intermediate hippocampus, where substrates of rapid accurate place encoding converge with links to behavioral control, is critical to translate rapid (one-trial) place learning into navigational performance

Tuning of Synaptic Integration in the Medial Entorhinal Cortex to the Organization of Grid Cell Firing Fields

SummaryNeurons important for cognitive function are often classified by their morphology and integrative properties. However, it is unclear if within a single class of neuron these properties tune synaptic responses to the salient features of the information that each neuron represents. We demonstrate that for stellate neurons in layer II of the medial entorhinal cortex, the waveform of postsynaptic potentials, the time window for detection of coincident inputs, and responsiveness to gamma frequency inputs follow a dorsal-ventral gradient similar to the topographical organization of grid-like spatial firing fields of neurons in this area. We provide evidence that these differences are due to a membrane conductance gradient mediated by HCN and leak potassium channels. These findings suggest key roles for synaptic integration in computations carried out within the medial entorhinal cortex and imply that tuning of neural information processing by membrane ion channels is important for normal cognitive function

Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression

Neural circuits in the medial entorhinal cortex (MEC) encode an animal's position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations

Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex

The extensive connections of the entorhinal cortex with the hippocampus and the neocortex point to this region as a major interface in the hippocampal-neocortical interactions underlying memory. We asked whether hippocampal-dependent recall of spatial mem-ory depends on the entorhinal cortex, and, if so, which parts are critical. After training in a Morris water maze, rats received fiber-sparing lesions in the dorsolateral band of the entorhinal cortex, which mediates much of the visuospatial input to the dorsal hippocampus. These lesions entirely disrupted retention and re-tarded new learning. Spatial memory was spared by lesions in the ventromedial band, which connects primarily with ventral hippocampus, but these lesions reduced defensive behavior on an elevated plus maze, mirroring the effects of damage to ventral hippocampus. The results suggest that the functional differ-ences between dorsal and ventral hippocampus reflect their connectivity with modules of the entorhinal cortex that are differently linked to the rest of the cortex

Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory

This work was supported by BBSRC [Grant number BB/I019367/1]The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual details of episodic memory. Combined with spatial information from the medial entorhinal cortex it is hypothesised that this contextual information is used to form an integrated spatially selective, context-specific response in the hippocampus that underlies episodic memory. Recently, we reported that the LEC is required for recognition of objects that have been experienced in a specific context (Wilson et al. (2013) Hippocampus 23:352-366). Here, we sought to extend this work to assess the role of the LEC in recognition of all associative combinations of objects, places and contexts within an episode. Unlike controls, rats with excitotoxic lesions of the LEC showed no evidence of recognizing familiar combinations of object in place, place in context, or object in place and context. However, LEC lesioned rats showed normal recognition of objects and places independently from each other (nonassociative recognition). Together with our previous findings, these data suggest that the LEC is critical for associative recognition memory and may bind together information relating to objects, places, and contexts needed for episodic memory formation.Publisher PDFPeer reviewe