Bruce L. McNaughton

Cortical connectivity maps reveal anatomically distinct areas in the parietal cortex of the rat.

A central feature of theories of spatial navigation involves the representation of spatial relationships between objects in complex environments. The parietal cortex has long been linked to the processing of spatial visual information and recent evidence from single unit recording in rodents suggests a role for this region in encoding egocentric and world-centered frames. The rat parietal cortex can be subdivided into four distinct rostral-caudal and medial-lateral regions, which includes a zone previously characterized as secondary visual cortex. At present, very little is known regarding the relative connectivity of these parietal subdivisions. Thus, we set out to map the connectivity of the entire anterior-posterior and medial-lateral span of this region. To do this we used anterograde and retrograde tracers in conjunction with open source neuronal segmentation and tracer detection tools to generate whole brain connectivity maps of parietal inputs and outputs. Our present results show that inputs to the parietal cortex varied significantly along the medial-lateral, but not the rostral-caudal axis. Specifically, retrosplenial connectivity is greater medially, but connectivity with visual cortex, though generally sparse, is more significant laterally. Finally, based on connection density, the connectivity between parietal cortex and hippocampus is indirect and likely achieved largely via dysgranular retrosplenial cortex. Thus, similar to primates, the parietal cortex of rats exhibits a difference in connectivity along the medial-lateral axis, which may represent functionally distinct areas.

Grids from bands, or bands from grids? An examination of the effects of single unit contamination on grid cell firing fields

Neural recording technology is improving rapidly, allowing for the detection of spikes from hundreds of cells simultaneously. The limiting step in multielectrode electrophysiology continues to be single cell isolation. However, this step is crucial to the interpretation of data from putative single neurons. We present here, in simulation, an illustration of possibly erroneous conclusions that may be reached when poorly isolated single cell data are analyzed. Grid cells are neurons recorded in rodents, and bats, that spike in equally spaced locations in a hexagonal pattern. One theory states that grid firing patterns arise from a combination of band firing patterns. However, we show here that summing the grid firing patterns of two poorly resolved neurons can result in spurious band-like patterns. Thus, evidence of neurons spiking in band patterns must undergo extreme scrutiny before it is accepted. Toward this aim, we discuss single cell isolation methods and metrics.

Nonuniform allocation of hippocampal neurons to place fields across all hippocampal subfields.

The mechanisms governing how the hippocampus selects neurons to exhibit place fields are not well understood. A default assumption in some previous studies was the uniform random draw with replacement (URDWR) model, which, theoretically, maximizes spatial “pattern separation”, and predicts a Poisson distribution of the numbers of place fields expressed by a given cell per unit area. The actual distribution of mean firing rates exhibited by a population of hippocampal neurons, however, is approximately exponential or log‐normal in a given environment and these rates are somewhat correlated across multiple places, at least under some conditions. The advantage of neural activity‐dependent immediate‐early gene (IEG) analysis, as a proxy for electrophysiological recording, is the ability to obtain much larger samples of cells, even those whose activity is so sparse that they are overlooked in recording studies. Thus, a more accurate representation of the activation statistics can potentially be achieved. Some previous IEG studies that examined behavior‐driven IEG expression in CA1 appear to support URDWR. There was, however, in some of the same studies, an under‐recruitment of dentate gyrus granule cells, indicating a highly skewed excitability distribution, which is inconsistent with URDWR. Although it was suggested that this skewness might be related to increased excitability of recently generated granule cells, we show here that CA1, CA3, and subiculum also exhibit cumulative under‐recruitment of neurons. Thus, a highly skewed excitability distribution is a general principle common to all major hippocampal subfields. Finally, a more detailed analysis of the frequency distributions of IEG intranuclear transcription foci suggests that a large fraction of hippocampal neurons is virtually silent, even during sleep. Whether the skewing of the excitability distribution is cell‐intrinsic or a network phenomenon, and the degree to which this excitability is fixed or possibly time‐varying are open questions for future studies.

Models of Path Integration in the Hippocampal Complex

Path integration is the process of summing up information about direction and distance traveled, in order to keep track of one’s relative position. Path integration is hypothesized to be the basis for the formation of the “place code” the hippocampus uses to encode spatial memories. In this chapter, we discuss models of how the hippocampal system may implement path integration. First, we explain the relationship of path integration to the hippocampal system, compare path integration to other navigation strategies, and discuss evidence for its use in creating the place cell code. Then, we examine path integration models for the creation and updating of a place cell map representation. We compare two major classes of such models and discuss experimental tests of their predictions to date. Finally, we briefly discuss the role of associations between place cell activity and sensory information in resetting the path integrator systems upon visits to familiar locations and how those associations can modify the structure of the hippocampal map with experience.

Evidence for an Evolutionarily Conserved Memory Coding Scheme in the Mammalian Hippocampus.

Decades of research identify the hippocampal formation as central to memory storage and recall. Events are stored via distributed population codes, the parameters of which (e.g., sparsity and overlap) determine both storage capacity and fidelity. However, it remains unclear whether the parameters governing information storage are similar between species. Because episodic memories are rooted in the space in which they are experienced, the hippocampal response to navigation is often used as a proxy to study memory. Critically, recent studies in rodents that mimic the conditions typical of navigation studies in humans and nonhuman primates (i.e., virtual reality) show that reduced sensory input alters hippocampal representations of space. The goal of this study was to quantify this effect and determine whether there are commonalities in information storage across species. Using functional molecular imaging, we observe that navigation in virtual environments elicits activity in fewer CA1 neurons relative to real-world conditions. Conversely, comparable neuronal activity is observed in hippocampus region CA3 and the dentate gyrus under both conditions. Surprisingly, we also find evidence that the absolute number of neurons used to represent an experience is relatively stable between nonhuman primates and rodents. We propose that this convergence reflects an optimal ensemble size for episodic memories. SIGNIFICANCE STATEMENT One primary factor constraining memory capacity is the sparsity of the engram, the proportion of neurons that encode a single experience. Investigating sparsity in humans is hampered by the lack of single-cell resolution and differences in behavioral protocols. Sparsity can be quantified in freely moving rodents, but extrapolating these data to humans assumes that information storage is comparable across species and is robust to restraint-induced reduction in sensory input. Here, we test these assumptions and show that species differences in brain size build memory capacity without altering the structure of the data being stored. Furthermore, sparsity in most of the hippocampus is resilient to reduced sensory information. This information is vital to integrating animal data with human imaging navigation studies.

Behavior-driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus

Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal–ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior‐driven cells across the dorsal–ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two‐ to‐threefold reduction in spatial behavior‐driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self‐motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non‐spatial information within the hippocampus along its dorso‐ventral axis.

A methodological pipeline for serial-section imaging and tissue realignment for whole-brain functional and connectivity assessment.

BACKGROUND Understanding the neurobiological basis of cognition and behavior, and disruptions to these processes following injury and disease, requires a large-scale assessment of neural populations, and knowledge of their patterns of connectivity. NEW METHOD We present an analysis platform for large-scale investigation of functional and neuroanatomical connectivity in rodents. Retrograde tracers were injected and in a subset of animals behavioral tests to drive immediate-early gene expression were administered. This approach allows users to perform whole-brain assessment of function and connection in a semi-automated quantitative manner. Brains were cut in the coronal plane, and an image of the block face was acquired. Wide-field fluorescent scans of whole sections were acquired and analyzed using Matlab software. RESULTS The toolkit utilized open-source and custom platforms to accommodate a largely automated analysis pipeline in which neuronal boundaries are automatically segmented, the position of segmented neurons are co-registered with a corresponding image acquired during sectioning, and a 3-D representation of neural tracer (and other products) throughout the entire brain is generated. COMPARISON WITH EXISTING METHODS Current whole brain connectivity measures primarily target mice and use anterograde tracers. Our focus on segmented units of interest (e.g., NeuN labeled neurons) and restricting measures to these units produces a flexible platform for a variety of whole brain analyses (measuring activation, connectivity, markers of disease, etc.). CONCLUSIONS This open-source toolkit allows an investigator to visualize and quantify whole brain data in 3-D, and additionally provides a framework that can be rapidly integrated with user-specific analyses and methodologies.

Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy

&NA; See Lenck‐Santini (doi:10.1093/awx205) for a scientific commentary on this article. Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast‐spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy.

Reactivation of Rate Remapping in CA3

The hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as “global” and “rate” remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific “index codes” to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience. SIGNIFICANCE STATEMENT The hippocampus is required for memory of events and their spatial contexts. The primary correlate of hippocampal activity is location in space, but multiple memories can occur in the same location. To be useful for distinguishing these memories, the hippocampus must be able, not only to express, but also to retrieve both spatial and nonspatial information about events. Whether it can retrieve nonspatial information has been challenged recently. We exposed rats to two different experiences (running in different directions) in the same locations and showed that even the nonspatial components of hippocampal cell firing are reactivated spontaneously during sleep, supporting the conclusion that both types of information about a recent experience can be retrieved.

Impaired Spatial Reorientation in the 3xTg-AD Mouse Model of Alzheimer's Disease

In early Alzheimer’s disease (AD) spatial navigation is impaired; however, the precise cause of this impairment is unclear. Recent evidence suggests that getting lost in new surroundings is one of the first impairments to emerge in AD. It is possible that getting lost in new surroundings represents a failure to use distal cues to get oriented in space. Therefore, we set out to look for impaired use of distal cues for spatial orientation in a mouse model of amyloidosis (3xTg-AD). To do this, we trained mice to shuttle to the end of a track and back to an enclosed start box to receive a water reward. Then, mice were trained to stop in an unmarked reward zone to receive a brain stimulation reward. The time required to remain in the zone for a reward was increased across training, and the track was positioned in a random start location for each trial. We found that 6-month female, but not male, 3xTg-AD mice were impaired. Male and female mice had only intracellular pathology and male mice had less pathology, particularly in the dorsal hippocampus. Thus, AD may cause spatial disorientation as a result of impaired use of landmarks.