Distal CA1 Maintains a More Coherent Spatial Representation than Proximal CA1 When Local and Global Cues Conflict.

Entorhinal cortical projections show segregation along the transverse axis of CA1, with the medial entorhinal cortex (MEC) sending denser projections to proximal CA1 (pCA1) and the lateral entorhinal cortex (LEC) sending denser projections to distal CA1 (dCA1). Previous studies have reported functional segregation along the transverse axis of CA1 correlated with the functional differences in MEC and LEC. pCA1 shows higher spatial selectivity than dCA1 in these studies. We employ a double rotation protocol, which creates an explicit conflict between the local and the global cues, to understand the differential contributions of these reference frames to the spatial code in pCA1 and dCA1 in male Long-Evans rats. We show that pCA1 and dCA1 respond differently to this local-global cue conflict. pCA1 representation splits as predicted from the strong conflicting inputs it receives from MEC and dCA3. In contrast, dCA1 rotates more in concert with the global cues. In addition, pCA1 and dCA1 display comparable levels of spatial selectivity in this study. This finding differs from the previous studies, perhaps because of richer sensory information available in our behavior arena. Together, these observations indicate that the functional segregation along proximodistal axis of CA1 is not of the amount of spatial selectivity but that of the nature of the different inputs used to create and anchor spatial representations.SIGNIFICANCE STATEMENT Subregions of the hippocampus are thought to play different roles in spatial navigation and episodic memory. It was previously thought that the distal part of area CA1 of the hippocampus carries lesser information about space than proximal CA1 (pCA1). We report that distal CA1 (dCA1) spatial representation moves more in concert with the global cues than pCA1 when the local and the global cues conflict. We also show that spatial selectivity is comparable along the proximodistal axis in this experimental protocol. Thus, different parts of the brain receiving differential outputs from pCA1 and dCA1 receive spatial information in different spatial reference frames encoded using different sets of inputs, rather than different amounts of spatial information as thought earlier.

Differential propagation of ripples along the proximodistal and septotemporal axes of dorsal CA1 of rats.

The functional connectivity of the hippocampus with its primary cortical input, the entorhinal cortex, is organized topographically. In area CA1 of the hippocampus, this leads to different functional gradients along the proximodistal and septotemporal axes of spatial/sensory responsivity and spatial resolution respectively. CA1 ripples, a network phenomenon, allow us to test whether the hippocampal neural network shows corresponding gradients in functional connectivity along the two axes. We studied the occurrence and propagation of ripples across the entire proximodistal axis along with a comparable spatial range of the septotemporal axis of dorsal CA1. We observed that ripples could occur at any location, and their amplitudes were independent of the tetrode location along the proximodistal and septotemporal axes. When a ripple was detected on a particular tetrode ("reference tetrode"), however, the probability of cooccurrence of ripples and ripple amplitude observed on the other tetrodes decreased as a function of distance from the reference tetrode. This reduction was greater along the proximodistal axis than the septotemporal axis. Furthermore, we found that ripples propagate primarily along the proximodistal axis. Thus, over a spatial scale of ∼1.5 mm, the network is anisotropic along the two axes, complementing the topographically organized cortico-hippocampal connections.

Egocentric coding of external items in the lateral entorhinal cortex.

Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations.

Inexpensive, scalable camera system for tracking rats in large spaces.

Most studies of neural correlates of spatial navigation are restricted to small arenas (≤1 m2) because of the limits imposed by the recording cables. New wireless recording systems have a larger recording range. However, these neuronal recording systems lack the ability to track animals in large area, constraining the size of the arena. We developed and benchmarked an open-source, scalable multicamera tracking system based on low-cost hardware. This "Picamera system" was used in combination with a wireless recording system for characterizing neural correlates of space in environments of sizes up to 16.5 m2. The Picamera system showed substantially better temporal accuracy than a popular commercial system. An explicit comparison of one camera from the Picamera system with a camera from the commercial system showed improved accuracy in estimating spatial firing characteristics and head direction tuning of neurons. This improved temporal accuracy is crucial for accurately aligning videos from multiple cameras in large spaces and characterizing spatially modulated cells in a large environment. NEW & NOTEWORTHY Studies of neural correlates of space are limited to biologically unrealistically small spaces by neural recording and position tracking hardware. We developed a camera system capable of tracking animals in large spaces at a high temporal accuracy. Together with the new wireless recording systems, this system facilitates the study of neural correlates of space at biologically relevant scale. This increased temporal accuracy of tracking also improves the estimates of spatiotemporal correlates of neural activity.

Navigational Strategies and Their Neural Correlates.

Animals depend on navigation to find food, water, mate(s), shelter, etc. Different species use diverse strategies that utilise forms of motion- and location-related information derived from the environment to navigate to their goals and back. We start by describing behavioural studies undertaken to unearth different strategies used in navigation. Then we move on to outline what we know about the brain area most associated with spatial navigation, namely the hippocampal formation. While doing so, we first briefly explain the anatomical connections in the area and then proceed to describe the neural correlates that are considered to play a role in navigation. We conclude by looking at how the strategies might interact and complement each other in certain contexts.

Neural Population Evidence of Functional Heterogeneity along the CA3 Transverse Axis: Pattern Completion versus Pattern Separation.

Classical theories of associative memory model CA3 as a homogeneous attractor network because of its strong recurrent circuitry. However, anatomical gradients suggest a functional diversity along the CA3 transverse axis. We examined the neural population coherence along this axis, when the local and global spatial reference frames were put in conflict with each other. Proximal CA3 (near the dentate gyrus), where the recurrent collaterals are the weakest, showed degraded representations, similar to the pattern separation shown by the dentate gyrus. Distal CA3 (near CA2), where the recurrent collaterals are the strongest, maintained coherent representations in the conflict situation, resembling the classic attractor network system. CA2 also maintained coherent representations. This dissociation between proximal and distal CA3 provides strong evidence that the recurrent collateral system underlies the associative network functions of CA3, with a separate role of proximal CA3 in pattern separation.

Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames.

The hippocampus receives its major cortical input from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input. We review new data which suggest that this simple dichotomy between 'where' versus 'what' needs revision. We propose a refinement of this model, which is more complex than the simple spatial-non-spatial dichotomy. MEC is proposed to be involved in path integration computations based on a global frame of reference, primarily using internally generated, self-motion cues and external input about environmental boundaries and scenes; it provides the hippocampus with a coordinate system that underlies the spatial context of an experience. LEC is proposed to process information about individual items and locations based on a local frame of reference, primarily using external sensory input; it provides the hippocampus with information about the content of an experience.

Influence of local objects on hippocampal representations: Landmark vectors and memory.

The hippocampus is thought to represent nonspatial information in the context of spatial information. An animal can derive both spatial information as well as nonspatial information from the objects (landmarks) it encounters as it moves around in an environment. In this article, correlates of both object-derived spatial as well as nonspatial information in the hippocampus of rats foraging in the presence of objects are demonstrated. A new form of CA1 place cells, called landmark-vector cells, that encode spatial locations as a vector relationship to local landmarks is described. Such landmark vector relationships can be dynamically encoded. Of the 26 CA1 neurons that developed new fields in the course of a day's recording sessions, in eight cases, the new fields were located at a similar distance and direction from a landmark as the initial field was located relative to a different landmark. In addition, object-location memory in the hippocampus is also described. When objects were removed from an environment or moved to new locations, a small number of neurons in CA1 and CA3 increased firing at the locations where the objects used to be. In some neurons, this increase occurred only in one location, indicating object + place conjunctive memory; in other neurons, the increase in firing was seen at multiple locations where an object used to be. Taken together, these results demonstrate that the spatially restricted firing of hippocampal neurons encode multiple types of information regarding the relationship between an animal's location and the location of objects in its environment.

Perirhinal cortex represents nonspatial, but not spatial, information in rats foraging in the presence of objects: comparison with lateral entorhinal cortex.

The medial temporal lobe (MTL) is involved in mnemonic processing. The perirhinal cortex (PRC) plays a role in object recognition memory, while the hippocampus is required for certain forms of spatial memory and episodic memory. The lateral entorhinal cortex (LEC) receives direct projections from PRC and is one of the two major cortical inputs to the hippocampus. The transformations that occur between PRC and LEC neural representations are not well understood. Here, we show that PRC and LEC had similarly high proportions of neurons with object-related activity (PRC 52/94; LEC 72/153), as expected from their locations in the "what" pathway into the hippocampus. However, LEC unit activity showed more spatial stability than PRC unit activity. A minority of LEC neurons showed stable spatial firing fields away from objects; these firing fields strongly resembled hippocampal place fields. None of the PRC neurons showed this place-like firing. None of the PRC or LEC neurons demonstrated the high firing rates associated with interneurons in hippocampus or medial entorhinal cortex, further dissociating this information processing stream from the path-integration based, movement-related processing of the medial entorhinal cortex and hippocampus. These results provide evidence for nonspatial information processing in the PRC-LEC pathway, as well as showing a functional dissociation between PRC and LEC, with more purely nonspatial representations in PRC and combined spatial-nonspatial representations in LEC.

Hippocampus.

Damage to the hippocampus and related brain regions causes a profound amnesic syndrome, in which patients are unable to form new memories about their experiences and about facts about the world. A number of theories have been proposed to explain hippocampal function. The theories that are currently most influential propose that the hippocampus is the substrate of declarative or episodic memory and that the hippocampus is the neural locus of a cognitive map. Anatomical, physiological, and behavioral studies of the hippocampal system have enabled a rich understanding of a number of general principles of information processing and storage in the brain. In this article, we describe key anatomical and physiological features of hippocampal function as well as the most influential theories of hippocampal function. WIREs Cogn Sci 2012, 3:231-251. doi: 10.1002/wcs.1164 For further resources related to this article, please visit the WIREs website.

Representation of non-spatial and spatial information in the lateral entorhinal cortex.

Some theories of memory propose that the hippocampus integrates the individual items and events of experience within a contextual or spatial framework. The hippocampus receives cortical input from two major pathways: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). During exploration in an open field, the firing fields of MEC grid cells form a periodically repeating, triangular array. In contrast, LEC neurons show little spatial selectivity, and it has been proposed that the LEC may provide non-spatial input to the hippocampus. Here, we recorded MEC and LEC neurons while rats explored an open field that contained discrete objects. LEC cells fired selectively at locations relative to the objects, whereas MEC cells were weakly influenced by the objects. These results provide the first direct demonstration of a double dissociation between LEC and MEC inputs to the hippocampus under conditions of exploration typically used to study hippocampal place cells.

Theta modulation in the medial and the lateral entorhinal cortices.

Hippocampal neurons show a strong modulation by theta frequency oscillations. This modulation is thought to be important not only for temporal encoding and decoding of information in the hippocampal system, but also for temporal ordering of neuronal activities on timescales at which physiological mechanisms of synaptic plasticity operate. The medial entorhinal cortex (MEC), one of the two major cortical inputs to the hippocampus, is known to show theta modulation. Here, we show that the local field potentials (LFPs) in the other major cortical input to the hippocampus, the lateral entorhinal cortex (LEC), show weaker theta oscillations than those shown in the MEC. Neurons in LEC also show weaker theta modulation than that of neurons in MEC. These findings suggest that LEC inputs are integrated into hippocampal representations in a qualitatively different manner than the MEC inputs. Furthermore, MEC grid cells increase the scale of their periodic spatial firing patterns along the dorsoventral axis, corresponding to the increasing size of place fields along the septotemporal axis of the hippocampus. We show here a corresponding gradient in the tendency of MEC neural firing to skip alternate theta cycles. We propose a simple model based on interference of delta oscillations with theta oscillations to explain this behavior.

Representation of odor habituation and timing in the hippocampus.

We performed simultaneous single-neuron recordings from the hippocampus and the olfactory bulb of anesthetized, freely breathing rats. Odor response properties of neurons in the olfactory bulb and hippocampus were characterized as firing rate changes or respiration-coupled changes. A panel of five odors was used. The rats had not been exposed to the odors on the panel before the experiment. The olfactory bulb and hippocampal neurons responded to repeated odor presentations in two ways: first, by changes in firing rate, and second, by respiratory tuning changes. Approximately 60% of bulbar neurons, 48% of hippocampal CA1 neurons, and 12% of hippocampal CA3 neurons showed statistically significant responses. None of the odor-responsive neurons in either the bulb or hippocampus responded to all of the odors on the panel. Repeated 10 sec odor stimuli presented at the intervals of 20, 30, 60, 110, and 160 sec were used to analyze the effect of the interval on odor response properties of the recorded neurons. Bulbar neurons were relatively nonselective for odor interval. Hippocampal neurons showed unexpected selectivity for the interval between repeated odor presentations. CA1 and CA3 neurons responded to only one to three of the intervals in the range. On the basis of these findings, we postulate that the hippocampus has the ability to keep track of the time elapsed between consecutive odor stimuli. This may act as a neuronal substrate for habituation and for complex tasks such as odor-guided navigation.