John O’Keefe

On the trail of the hippocampal engram

Recent ideas about hippocampal function in animals suggest that it may be involved in memory. A new test for rat memory is described (the despatch task). It has several properties which make it well suited for the study of one-trial, long-term memory. The information about the location of the goal is given to the rat when it is in the startbox. The memory formed is long lasting (>30 min), and the animals are remembering the location of the goal and not the response to be made to reach that goal. The spatial relations of the cues within the environment can be manipulated to bias the animals towards selection of a place hypothesis or a guidance hypothesis. The latter does not seem to support long-term memory formation in the way that the former does. Fornix lesions selectively disrupt performance of the place-biased task, a finding that is predicted by the cognitive map theory but not by other ideas about hippocampal involvement in memory.

Theta activity, virtual navigation and the human hippocampus

J.O’K. is supported by the Medical Research Council and N.B. by the Royal Society. We thank Mick Rugg for useful suggestions on an earlier draft and John Huxter for help with the figures.

Fully integrated silicon probes for high-density recording of neural activity

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal–oxide–semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-μm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

Models of grid cells and theta oscillations

Arising from M. M.Yartsev, M. P. Witter & N. Ulanovsky 479, 103–107 (2011)10.1038/nature10583Grid cells recorded in the medial entorhinal cortex (MEC) of freely moving rodents show a markedly regular spatial firing pattern whose underlying mechanism has been the subject of intense interest. Yartsev et al. report that the firing of grid cells in crawling bats does not show theta rhythmicity “causally disproving a major class of computational models” of grid cell firing that rely on oscillatory interference. However, their data may be consistent with these models, with the apparent lack of theta rhythmicity reflecting slow movement speeds and low firing rates. Thus, the conclusion of Yartsev et al. is not supported by their data.

The Development of the Head Direction System before Eye Opening in the Rat

Summary Head direction (HD) cells are neurons found in the hippocampal formation and connected areas that fire as a function of an animal’s directional orientation relative to its environment [1, 2]. They integrate self-motion and environmental sensory information to update directional heading [3]. Visual landmarks, in particular, exert strong control over the preferred direction of HD cell firing [4]. The HD signal has previously been shown to appear adult-like as early as postnatal day 16 (P16) in the rat pup, just after eye opening and coinciding with the first spontaneous exploration of its environment [5, 6]. In order to determine whether the HD circuit can begin its organization prior to the onset of patterned vision, we recorded from the anterodorsal thalamic nucleus (ADN) and its postsynaptic target in the hippocampal formation, the dorsal pre-subiculum (PrSd), before and after eye opening in pre-weanling rats. We find that HD cells can be recorded at the earliest age sampled (P12), several days before eye opening. However, this early HD signal displays low directional information content and lacks stability both within and across trials. Following eye opening, the HD system matures rapidly, as more cells exhibit directional firing, and the quality and reliability of the directional signal improves dramatically. Cue-rotation experiments show that a prominent visual landmark is able to control HD responses within 24 hr of eye opening. Together, the results suggest that the directional network can be organized independently of visual spatial information while demonstrating the importance of patterned vision for accurate and reliable orientation in space.

Local transformations of the hippocampal cognitive map

The mechanisms behind grid cell changes When grid cells were first discovered in the brain, the grids were considered to have rigid coordinates beyond the borders of the testing environments. However, recent findings suggest that the grid cell pattern can be altered easily by changing the space of the enclosure. But how? Krupic et al. discovered that local changes in the geometry of the environment shifted individual neighboring grid fields, while more distant fields remained unchanged. Thus, changes to the grid structure are localized. Stable landmarks continue to exert an effect on most grid cells, whereas the ones close to changed borders are modified. Science, this issue p. 1143 Individual grid fields in the brain shift by different amounts with changes in the geometry of the enclosure. Grid cells are neurons active in multiple fields arranged in a hexagonal lattice and are thought to represent the “universal metric for space.” However, they become nonhomogeneously distorted in polarized enclosures, which challenges this view. We found that local changes to the configuration of the enclosure induce individual grid fields to shift in a manner inversely related to their distance from the reconfigured boundary. The grid remained primarily anchored to the unchanged stable walls and showed a nonuniform rescaling. Shifts in simultaneously recorded colocalized grid fields were strongly correlated, which suggests that the readout of the animal’s position might still be intact. Similar field shifts were also observed in place and boundary cells—albeit of greater magnitude and more pronounced closer to the reconfigured boundary—which suggests that there is no simple one-to-one relationship between these three different cell types.

Toward a Mechanism for Navigation by the Rat Hippocampus

A simulation of the rat hippocampus as a mechanism for representing spatial information which is used to guide navigation is presented. A neuronal simulation of the firing patterns of four layers of cells: sensory, entorhinal, place and subicular cells, and a postulated set of goal cells form the basis of the model. Each cell type is characterised by the rat and timing of action potentials relative to the clock cycles provided by the hippocampal ? rhythm. Learning occurs in binary synapses, switched on by simultaneous pre- and post-synaptic activity. Activation spreads forward, through each layer in turn, to the goal cells which receive a reinforcement signal whenever a goal (e.g. food reward) is encountered. The ‘population vectors’ of sub-sets of goal cells code for the instantaneous direction of the rat from previously encountered rewards, allowing successful navigation in open fields.

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

A. H. Black 1929–1978

In this respect the pursuit of science seems to me to require particular courage. It is concerned with knowledge, achieved through doubt. Making knowledge about everything available for everybody, science strives to make sceptics of them all.