[show abstract][hide abstract] ABSTRACT: Principal cells in layer V of the medial entorhinal cortex (MEC) have a nodal position in the cortical-hippocampal network. They are the main recipients of hippocampal output and receive inputs from several cortical areas, including a prominent one from the retrosplenial cortex (RSC), likely targeting basal dendrites of layer V neurons. The latter project to extrahippocampal structures but also relay information to the superficial layers of MEC, closing the hippocampal-entorhinal loop. In the rat, we electrophysiologically and morphologically characterized RSC input into MEC and conclude that RSC provides an excitatory input to layer V pyramidal cells. Ultrastructural analyses of anterogradely labeled RSC projections showed that RSC axons in layer V of MEC form predominantly asymmetrical, likely excitatory, synapses on dendritic spines (90%) or shafts (8%), with 2% symmetrical, likely inhibitory, synapses on shafts and spines. The overall excitatory nature of the RSC input was confirmed by an optogenetic approach. Patterned laser stimulation of channelrhodopsin-expressing presynaptic RSC axons evoked exclusively EPSPs in recorded postsynaptic layer V cells. All responding layer V pyramidal cells had an axon extending toward the white matter. Half of these neurons also sent an axon to superficial layers. Confocal imaging of RSC synapses onto MEC layer V neurons shown to project superficially by way of retrogradely labeling from superficial layers confirmed that proximal dendrites of superficially projecting cells are among the targets of inputs from RSC. The excitatory RSC input thus interacts with both entorhinal-cortical and entorhinal-hippocampal circuits.
Journal of Neuroscience 10/2013; 33(40):15779-15792. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the hippocampus, spatial and non-spatial parameters may be represented by a dual coding scheme, in which coordinates in space are expressed by the collective firing locations of place cells and the diversity of experience at these locations is encoded by orthogonal variations in firing rates. Although the spatial signal may reflect input from medial entorhinal cortex, the sources of the variations in firing rate have not been identified. We found that rate variations in rat CA3 place cells depended on inputs from the lateral entorhinal cortex (LEC). Hippocampal rate remapping, induced by changing the shape or the color configuration of the environment, was impaired by lesions in those parts of the ipsilateral LEC that provided the densest input to the hippocampal recording position. Rate remapping was not observed in LEC itself. The findings suggest that LEC inputs are important for efficient rate coding in the hippocampus.
[show abstract][hide abstract] ABSTRACT: Representing an environment globally, in a coarse way, and locally, in a fine-grained way, are two fundamental aspects of how our brain interprets the world that surrounds us. The neural correlates of these representations have not been explicated in humans. In this study we used fMRI to investigate these correlates and to explore a possible functional segregation in the hippocampus and parietal cortex. We hypothesized that processing a coarse, global environmental representation engages anterior parts of these regions, whereas processing fine-grained, local environmental information engages posterior parts. Participants learned a virtual environment and then had to find their way during fMRI. After scanning, we assessed strategies used and representations stored. Activation in the hippocampal head (anterior) was related to the multiple distance and global direction judgments and to the use of a coarse, global environmental representation during navigation. Activation in the hippocampal tail (posterior) was related to both local and global direction judgments and to using strategies like number of turns. A structural shape analysis showed that the use of a coarse, global environmental representation was related to larger right hippocampal head volume and smaller right hippocampal tail volume. In the inferior parietal cortex, a similar functional segregation was observed, with global routes represented anteriorly and fine-grained route information such as number of turns represented posteriorly. In conclusion, moving from the anterior to the posterior hippocampus and inferior parietal cortex reflects a shift from processing coarse global environmental representations to processing fine-grained, local environmental representations.
Journal of Cognitive Neuroscience 06/2013; · 4.49 Impact Factor
[show abstract][hide abstract] ABSTRACT: Grid cells in layer II of the medial entorhinal cortex form a principal component of the mammalian neural representation of space. The firing pattern of a single grid cell has been hypothesized to be generated through attractor dynamics in a network with a specific local connectivity including both excitatory and inhibitory connections. However, experimental evidence supporting the presence of such connectivity among grid cells in layer II is limited. Here we report recordings from more than 600 neuron pairs in rat entorhinal slices, demonstrating that stellate cells, the principal cell type in the layer II grid network, are mainly interconnected via inhibitory interneurons. Using a model attractor network, we demonstrate that stable grid firing can emerge from a simple recurrent inhibitory network. Our findings thus suggest that the observed inhibitory microcircuitry between stellate cells is sufficient to generate grid-cell firing patterns in layer II of the medial entorhinal cortex.
[show abstract][hide abstract] ABSTRACT: Behavioral, anatomical, and gene expression studies have shown functional dissociations between the dorsal and ventral hippocampus with regard to their involvement in spatial cognition, emotion, and stress. In this study we examined the difference of the multisynaptic inputs to the dorsal and ventral dentate gyrus (DG) in the rat by using retrograde trans-synaptic tracing of recombinant rabies virus vectors. Three days after the vectors were injected into the dorsal or ventral DG, monosynaptic neuronal labeling was present in the entorhinal cortex, medial septum, diagonal band, and supramammillary nucleus, each of which is known to project to the DG directly. As in previous tracing studies, topographical patterns related to the dorsal and ventral DG were seen in these regions. Five days after infection, more of the neurons in these regions were labeled and labeled neurons were also seen in cortical and subcortical regions, including the piriform and medial prefrontal cortices, the endopiriform nucleus, the claustrum, the cortical amygdala, the medial raphe nucleus, the medial habenular nucleus, the interpeduncular nucleus, and the lateral septum. As in the monosynaptically labeled regions, a topographical distribution of labeled neurons was evident in most of these disynaptically labeled regions. These data indicate that the cortical and subcortical inputs to the dorsal and ventral DG are conveyed through parallel disynaptic pathways. This second-order input difference in the dorsal and ventral DG is likely to contribute to the functional differentiation of the hippocampus along the dorsoventral axis.
PLoS ONE 01/2013; 8(11):e78928. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The medial entorhinal cortex (MEC), presubiculum (PrS), and parasubiculum (PaS) are interconnected components of the hippocampal-parahippocampal spatial-representation system. Principal cells in all layers of MEC show signs of directional tuning, overt in head direction cells present in all layers except for layer II, and covert in grid cells, which are the major spatially modulated cell type in layer II. Directional information likely originates in the head direction-vestibular system and PrS and PaS are thought to provide this information to MEC. Efferents from PaS and PrS show a selective laminar terminal distribution in MEC superficial layers II and III, respectively. We hypothesized that this anatomically determined laminar distribution does not preclude monosynaptic interaction with neurons located in deeper layers of MEC in view of the extensive apical dendrites from deeper cells reaching layers II and III. This hypothesis was tested in the rat using tilted in vitro slices in which origins and terminations of PrS and PaS fibers were maintained, as assessed using anterograde anatomical tracing. Based on voltage-sensitive dye imaging, multipatch single-cell recordings, and scanning photostimulation of caged glutamate, we report first that principal neurons in all layers of MEC receive convergent monosynaptic inputs from PrS and PaS and second, that elicited responses show layer-specific decay times and frequency-dependent facilitation. These results indicate that regardless of their selective laminar terminal distribution, PrS and PaS inputs may monosynaptically convey directional information to principal neurons in all layers of MEC through synapses on their extensive dendritic arbors.
Journal of Neuroscience 12/2012; 32(49):17620-17631. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain.
Journal of Neurochemistry 09/2012; 123(4):532-41. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10-11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.
PLoS ONE 01/2012; 7(2):e31302. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The lateral entorhinal cortex (LEC) provides a major cortical input to the hippocampal formation, equaling that of the medial entorhinal cortex (MEC). To understand the functional contributions made by LEC, basic knowledge of individual neurons, in the context of the intrinsic network, is needed. The aim of this study is to compare physiological and morphological properties of principal neurons in different LEC layers in postnatal rats. Using in vitro whole cell current-clamp recordings from up to four post hoc morphologically identified neurons simultaneously, we established that principal neurons show layer specific physiological and morphological properties, similar to those reported previously in adults. Principal neurons in L(ayer) I, LII, and LIII have the majority of their dendrites and axonal collaterals alone in superficial layers. LV contains mainly pyramidal neurons with dendrites and axons extending throughout all layers. A minority of LV and all principal neurons in LVI are neurons with dendrites confined to deep layers and axons in superficial and deep layers. Physiologically, input resistances and time constants of LII neurons are lower and shorter, respectively, than those observed in LV neurons. Fifty-four percent of LII neurons have sag potentials, resonance properties, and rebounds at the offset of hyperpolarizing current injection, whereas LIII and LVI neurons do not have any of these. LV neurons show prominent spike-frequency adaptation and a decrease in spike amplitudes in response to strong depolarization. Despite the well-developed interlaminar communication in LEC, the laminar differences in the biophysical and morphological properties of neurons suggest that their in vivo firing patterns and functions differ, similar to what is known for neurons in different MEC layers.
[show abstract][hide abstract] ABSTRACT: Principal neurons in different medial entorhinal cortex (MEC) layers show variations in spatial modulation that stabilize between 15 and 30 days postnatally. These in vivo variations are likely due to differences in intrinsic membrane properties and integrative capacities of neurons. The latter depends on inputs and thus potentially on the morphology of principal neurons. In this comprehensive study, we systematically compared the morphological and physiological characteristics of principal neurons in all MEC layers of newborn rats before and after weaning. We recorded simultaneously from up to four post-hoc morphologically identified MEC principal neurons in vitro. Neurons in L(ayer) I-LIII have dendritic and axonal arbors mainly in superficial layers, and LVI neurons mainly in deep layers. The dendritic and axonal trees of part of LV neurons diverge throughout all layers. Physiological properties of principal neurons differ between layers. In LII, most neurons have a prominent sag potential, resonance and membrane oscillations. Neurons in LIII and LVI fire relatively regular, and lack sag potentials and membrane oscillations. LV neurons show the most prominent spike-frequency adaptation and highest input resistance. The data indicate that adult-like principal neuron types can be differentiated early on during postnatal development. The results of the accompanying paper, in which principal neurons in the lateral entorhinal cortex (LEC) were described (Canto and Witter,2011), revealed that significant differences between LEC and MEC exist mainly in LII neurons. We therefore systematically analyzed changes in LII biophysical properties along the mediolateral axis of MEC and LEC. There is a gradient in properties typical for MEC LII neurons. These properties are most pronounced in medially located neurons and become less apparent in more laterally positioned ones. This gradient continues into LEC, such that in LEC medially positioned neurons share some properties with adjacent MEC cells.
[show abstract][hide abstract] ABSTRACT: The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.
[show abstract][hide abstract] ABSTRACT: Navigation is mediated by a network of brain areas, and research has focused on the head-direction system in the presubiculum (PrS), the grid cell containing medial entorhinal cortex (EC) (MEC) and place cells in the hippocampus. Less research addressed the interactions of the retrosplenial cortex (RSC) and the navigational system, although it is well established that damage to the RSC leads to navigational deficits. We previously showed that RSC provides a dense input to deep layers of MEC and to superficial layers of PrS. In this study we use confocal microscopical analysis and show that the dense projection from the caudal part of the ventral retrosplenial granular cortex targets neurons in Layer III of PrS, which provide input to superficial layers of MEC. Our high resolution anatomical data indicate that sparsely spiny pyramidal neurons in Layer III of PrS that originate projections to Layer III of MEC are the main target of these retrosplenial projections. Retrosplenial axonal boutons were found to equally contact spines and shafts of basal dendrites in Layer III, but contacts on shafts are more prominent close to the soma, indicating the potential for efficient synaptic transfer. These observations suggest that neurons in Layer III of PrS have an important role in mediating RSC contributions to navigation.
[show abstract][hide abstract] ABSTRACT: Hippocampal changes may be a useful biomarker for Alzheimer's disease if they are specific to dementia sub-type. We compare hippocampal volume and shape in population-based incident cases of Alzheimer's disease and vascular dementia (VaD).
Participants are Japanese-American men from the Honolulu Asia Aging Study. The following analysis is based on a sub-group of men with mild incident Alzheimer's disease (n=24: age=82.5 ± 4.6) or incident VaD (n=14: age=80.5 ± 4.5). To estimate hippocampal volume, one reader, blinded to dementia diagnosis, manually outlined the left and right formation of the hippocampus using published criteria. We used 3-D mapping methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal width between dementia groups.
Hippocampal volume was about 5% smaller in the Alzheimer's disease group compared to the VaD group, but the difference was not significant. Hippocampal shape differed between the two case groups for the left (p<0.04) but not right (p<0.21) hippocampus. The specific region of the hippocampus that most consistently differed between the Alzheimer's disease and VaD cases was in the lateral portion of the left hippocampus. Our interpretation of this region is that it intersects the CA1 sub-region to a great extent but also includes the dentate gyrus (and hilar region) and subiculum.
As indicated by shape analysis, there are some differences in atrophy localisation between the Alzheimer's disease and VaD cases, despite the finding that volume of the hippocampi did not differ. These findings suggest hippocampal atrophy in Alzheimer's disease may be more focal than in VaD.
Journal of neurology, neurosurgery, and psychiatry 04/2011; 82(4):373-6. · 4.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: A connectome is an indispensable tool for brain researchers, since it quickly provides comprehensive knowledge of the brain's anatomical connections. Such knowledge lies at the basis of understanding network functions. Our first comprehensive and interactive account of brain connections comprised the rat hippocampal-parahippocampal network. We have now added all anatomical connections with the retrosplenial cortex (RSC) as well as the intrinsic connections of this region, because of the interesting functional overlap between these brain regions. The RSC is involved in a variety of cognitive tasks including memory, navigation, and prospective thinking, yet the exact role of the RSC and the functional differences between its subdivisions remain elusive. The connectome presented here may help to define this role by providing an unprecedented interactive and searchable overview of all connections within and between the rat RSC, parahippocampal region and hippocampal formation.