Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning

Grid cells recorded in the medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4 to 11 hertz). We analyzed grid cell spatial coding during reduction of network theta rhythm oscillations caused by medial septum (MS) inactivation with muscimol. During MS inactivation, grid cells lost their spatial periodicity, whereas head-direction cells maintained their selectivity. Conjunctive grid-by-head-direction cells lost grid cell spatial periodicity but retained head-direction specificity. All cells showed reduced rhythmicity in autocorrelations and cross-correlations. This supports the hypothesis that spatial coding by grid cells requires theta oscillations, and dissociates the mechanisms underlying the generation of entorhinal grid cell periodicity and head-direction selectivity.     

Major dissociation between medial and lateral entorhinal input to dorsal hippocampus

Hippocampal place cells are a model system of how the brain constructs cognitive representations and of how these representations support complex behavior, learning, and memory. There is, however, a lack of detailed knowledge about the properties of hippocampal afferents. We recorded multiple single units from the hippocampus and the medial and lateral entorhinal areas of behaving rats. Although many medial entorhinal neurons had highly specific place fields, lateral entorhinal neurons displayed weak spatial specificity. This finding demonstrates a fundamental dissociation between the information conveyed to the hippocampus by its major input streams, with spatial information represented by the medial and nonspatial information represented by the lateral entorhinal cortex.     

Spatial representation in the entorhinal cortex

As the interface between hippocampus and neocortex, the entorhinal cortex is likely to play a pivotal role in memory. To determine how information is represented in this area, we measured spatial modulation of neural activity in layers of medial entorhinal cortex projecting to the hippocampus. Close to the postrhinal-entorhinal border, entorhinal neurons had stable and discrete multipeaked place fields, predicting the rat's location as accurately as place cells in the hippocampus. Precise positional modulation was not observed more ventromedially in the entorhinal cortex or upstream in the postrhinal cortex, suggesting that sensory input is transformed into durable allocentric spatial representations internally in the dorsocaudal medial entorhinal cortex.     

Conjunctive representation of position, direction, and velocity in entorhinal cortex

Grid cells in the medial entorhinal cortex (MEC) are part of an environment-independent spatial coordinate system. To determine how information about location, direction, and distance is integrated in the grid-cell network, we recorded from each principal cell layer of MEC in rats that explored two-dimensional environments. Whereas layer II was predominated by grid cells, grid cells colocalized with head-direction cells and conjunctive grid x head-direction cells in the deeper layers. All cell types were modulated by running speed. The conjunction of positional, directional, and translational information in a single MEC cell type may enable grid coordinates to be updated during self-motion-based navigation.     

Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex

The hippocampus and entorhinal cortex play a pivotal role in spatial learning and memory. The two forebrain regions are highly interconnected via excitatory pathways. Using optogenetic tools, we identified and characterized long-range γ-aminobutyric acid-releasing (GABAergic) neurons that provide a bidirectional hippocampal-entorhinal inhibitory connectivity and preferentially target GABAergic interneurons. Activation of long-range GABAergic axons enhances sub- and suprathreshold rhythmic theta activity of postsynaptic neurons in the target areas.     

Internally generated reactivation of single neurons in human hippocampus during free recall

The emergence of memory, a trace of things past, into human consciousness is one of the greatest mysteries of the human mind. Whereas the neuronal basis of recognition memory can be probed experimentally in human and nonhuman primates, the study of free recall requires that the mind declare the occurrence of a recalled memory (an event intrinsic to the organism and invisible to an observer). Here, we report the activity of single neurons in the human hippocampus and surrounding areas when subjects first view cinematic episodes consisting of audiovisual sequences and again later when they freely recall these episodes. A subset of these neurons exhibited selective firing, which often persisted throughout and following specific episodes for as long as 12 seconds. Verbal reports of memories of these specific episodes at the time of free recall were preceded by selective reactivation of the same hippocampal and entorhinal cortex neurons. We suggest that this reactivation is an internally generated neuronal correlate for the subjective experience of spontaneous emergence of human recollection.     

The spatial periodicity of grid cells is not sustained during reduced theta oscillations

Grid cells in parahippocampal cortices fire at vertices of a periodic triangular grid that spans the entire recording environment. Such precise neural computations in space have been proposed to emerge from equally precise temporal oscillations within cells or within the local neural circuitry. We found that grid-like firing patterns in the entorhinal cortex vanished when theta oscillations were reduced after intraseptal lidocaine infusions in rats. Other spatially modulated cells in the same cortical region and place cells in the hippocampus retained their spatial firing patterns to a larger extent during these periods without well-organized oscillatory neuronal activity. Precisely timed neural activity within single cells or local networks is thus required for periodic spatial firing but not for single place fields.     

A major direct GABAergic pathway from zona incerta to neocortex

Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.     

仔猪海马结构及其周围皮质内生长抑素mRNA的分布

用原位杂交组织化学法研究了５头仔猪海马结构及其周围皮质内生长抑素ｍＲＮＡ的分布。结果表明生长抑素ｍＲＮＡ主要分布于海马的始层和齿状回的多形层，偶见于海马的辐射层和锥体细胞层，此外，在内溴区和海马旁回内也见到标记细胞，主要位于深层。     

Neural representations of location composed of spatially periodic bands

The mammalian hippocampal formation provides neuronal representations of environmental location, but the underlying mechanisms are poorly understood. Here, we report a class of cells whose spatially periodic firing patterns are composed of plane waves (or bands) drawn from a discrete set of orientations and wavelengths. The majority of cells recorded in parasubicular and medial entorhinal cortices of freely moving rats belonged to this class and included grid cells, an important subset that corresponds to three bands at 60° orientations and has the most stable firing pattern. Occasional changes between hexagonal and nonhexagonal patterns imply a common underlying mechanism. Our results indicate a Fourier-like spatial analysis underlying neuronal representations of location, and suggest that path integration is performed by integrating displacement along a restricted set of directions.     

Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning

The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex --> dentate gyrus --> CA3 --> CA1 --> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex --> CA1 --> entorhinal cortex). We developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion-based memory recall, and for spatial tuning of CA1 cells.     

Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat

The long-term effects of excitotoxic lesions in the nucleus basalis magnocellularis of the rat were found to mimic several neuropathological and chemical changes associated with Alzheimer's disease. Neuritic plaque-like structures, neurofibrillary changes, and neuronal atrophy or loss were observed in the frontoparietal cortex, hippocampus, amygdala, and entorhinal cortex 14 months after the lesions were made. Cholinergic markers in neocortex were reduced, while catecholamine and indoleamine metabolism was largely unaffected at this time. Bilateral lesions of the nucleus basalis magnocellularis increased somatostatin and neuropeptide Y in the cortex of the rat by at least 138 and 284 percent, respectively, suggesting a functional interaction between cholinergic and peptidergic neurons that may differ from that in Alzheimer's disease.     

Visual instruction of the neural map of auditory space in the developing optic tectum

Neural maps of visual and auditory space are aligned in the adult optic tectum. In barn owls, this alignment of sensory maps was found to be controlled during ontogeny by visual instruction of the auditory spatial tuning of neurons. Large adaptive changes in auditory spatial tuning were induced by raising owls with displacing prisms mounted in spectacle frames in front of the eyes; neurons became tuned to sound source locations corresponding to their optically displaced, rather than their normal, visual receptive field locations. The results demonstrate that visual experience during development calibrates the tectal auditory space map in a site-specific manner, dictating its topography and alignment with the visual space map.     

Plasticity of hippocampal circuitry in Alzheimer's disease

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.     

Encoding of spatial location by posterior parietal neurons

The cortex of the inferior parietal lobule in primates is important for spatial perception and spatially oriented behavior. Recordings of single neurons in this area in behaving monkeys showed that the visual sensitivity of the retinotopic receptive fields changes systematically with the angle of gaze. The activity of many of the neurons can be largely described by the product of a gain factor that is a function of the eye position and the response profile of the visual receptive field. This operation produces an eye position-dependent tuning for locations in head-centered coordinate space.     

Postlesion axonal growth produces permanent functional connections

Lesions of the entorhinal cortex in neonatal rats cause the commissural projections to the dentate gyrus to spread from their normal location in the inner molecular layer into the outer molecular layer, a region normally occupied by afferents from the entorhinal cortex. These lesions also cause the short-latency response to commissural stimulation to spread into the outer molecular layer, a result suggesting that these abnormally located connections are operative.     

Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory

Associating temporally discontinuous elements is crucial for the formation of episodic and working memories that depend on the hippocampal-entorhinal network. However, the neural circuits subserving these associations have remained unknown. The layer III inputs of the entorhinal cortex to the hippocampus may contribute to this process. To test this hypothesis, we generated a transgenic mouse in which these inputs are specifically inhibited. The mutant mice displayed significant impairments in spatial working-memory tasks and in the encoding phase of trace fear-conditioning. These results indicate a critical role of the entorhinal cortex layer III inputs to the hippocampus in temporal association memory.     

Spatial selectivity of rat hippocampal neurons: dependence on preparedness for movement

The mammalian hippocampal formation appears to play a major role in the generation of internal representations of spatial relationships. In rats, this role is reflected in the spatially selective discharge of hippocampal pyramidal cells. The principal metric for coding spatial relationships might be the organism's own movements in space, that is, the spatial relationship between two locations is coded in terms of the movements executed in getting from one to the other. Thus, information from the motor programming systems (or "motor set") may contribute to coding of spatial location by hippocampal neurons. Spatially selective discharge of hippocampal neurons was abolished under conditions of restraint in which the animal had learned that locomotion was impossible. Therefore, hippocampal neuronal activity may reflect the association of movements with their spatial consequences.     

Neural mechanisms of visual attention: how top-down feedback highlights relevant locations

Attention helps us process potentially important objects by selectively increasing the activity of sensory neurons that represent the relevant locations and features of our environment. This selection process requires top-down feedback about what is important in our environment. We investigated how parietal cortical output influences neural activity in early sensory areas. Neural recordings were made simultaneously from the posterior parietal cortex and an earlier area in the visual pathway, the medial temporal area, of macaques performing a visual matching task. When the monkey selectively attended to a location, the timing of activities in the two regions became synchronized, with the parietal cortex leading the medial temporal area. Parietal neurons may thus selectively increase activity in earlier sensory areas to enable focused spatial attention.