Spatial disorientation is an early symptom of Alzheimer’s disease (AD). The hippocampus creates a cognitive map, wherein cells form firing fields in specific locations within an environment, termed place cells. Critically, place cells remain stable across visits to an environment, but change their firing rate or field location in a different environment. In rodent models of AD-like pathology, place cells exhibit broadened tuning and altered responses to environmental changes. Additionally, events known as sharp wave ripples (SWRs), coordinate the firing of hippocampal neurons, including place cells, and are disrupted in mouse models of AD. Our lab found that increasing cerebral blood flow (CBF) with anti-Ly6G antibody treatment improved performance on spatial memory tasks. Here, we investigate the effect of increased CBF on neural mechanisms associated with cognitive map stability across contexts. We investigated the association between CBF and cognitive map stability in 7-9-month-old APP/PS1 mice and wild-type controls by recording neural activity in hippocampus area CA1 using 64-channel silicon probes. Mice were recorded as they explored open field arenas with differing environmental contexts, A and B. Place cells were identified as neurons with significant spatial information in their firing rate maps. Local field potential recordings from pyramidal and stratum radiatum layers of CA1 were used to detect awake-SWRs (aSWRs). Place cells from APP/PS1 mice did not exhibit higher place field correlations within contexts (AA' or BB'), as compared to between (AB) contexts, suggesting these different contexts are not differentially encoded (Figure 1). In contrast, wild-type control mice showed higher within context correlation (Figure 1). APP/PS1 mice also had a reduced rate and duration of aSWR compared to controls (Figure 2). Following treatment with anti-Ly6G antibodies, both context discrimination by place cells and duration of aSWR increased in APP/PS1 mice (Figure 2). These results highlight the association between place cell stability and subsequent aSWR dynamics as a potential mechanism contributing to an impaired cognitive map in AD. Importantly, the rescue of behavioral features and aSWR physiological properties following anti-Ly6G antibody treatment suggests that increasing CBF may be a candidate therapy to mitigate spatial memory impairments in AD.

Alzheimer’s disease (AD) manifests with early spatial memory impairment and is linked to the degeneration of hippocampal circuits. Hippocampal sharp wave ripples (SWRs) are high-frequency population-burst events that coordinate the reactivation of neural assemblies (groups of neurons that become correlated in their firing patterns during learning) in post-learning sleep, which is the neural basis of memory consolidation. SWRs are reduced in the APP/PS1 mouse model of AD-like pathology. Previously, we showed that cerebral blood flow (CBF) decreases and memory deficits were rescued following treatment with anti-Ly6G antibodies. Here, we examine the potential normalization of hippocampal circuit activity with CBF increase. Male, 7-14-month-old APP/PS1 mice and wild-type controls were implanted with 64-channel silicon probes in hippocampal area CA1. Neural activity was recorded during sleep before and after the exploration of an open field. Putative cell types were identified using feature-based classification, and neural assemblies were detected using independent component analysis. APP/PS1 mice had reduced magnitude and duration of assembly reactivation in post-task sleep SWRs. After treatment with anti-Ly6G antibodies, which increase CBF and improve memory performance, we found increased reactivation of these assemblies in post-task sleep SWRs, relative to no-treatment controls (Figure 1). We found that increasing CBF normalizes neural mechanisms of memory consolidation that are altered in AD mouse models, supporting the development of treatment approaches to increase CBF in AD.

Small-animal virtual reality (VR) systems have become invaluable tools in neuroscience for studying complex behavior during head-fixed neural recording, but they lag behind commercial human VR systems in terms of miniaturization, immersivity and advanced features such as eye tracking. Here we present MouseGoggles, a miniature VR headset for head-fixed mice that delivers independent, binocular visual stimulation over a wide field of view while enabling eye tracking and pupillometry in VR. Neural recordings in the visual cortex validate the quality of image presentation, while hippocampal recordings, associative reward learning and innate fear responses to virtual looming stimuli demonstrate an immersive VR experience. Our open-source system's simplicity and compact size will enable the broader adoption of VR methods in neuroscience.

Prenatal alcohol exposure (PAE) is among the most common developmental insults to the nervous system and is characterized by memory disruption. There is a pressing need to identify physiological alterations that help explain this memory impairment. Hippocampal sharp-wave ripples (SPW-Rs) are a compelling candidate for this purpose as they are the electrophysiological signatures of memory consolidation. We report that rats exposed to moderate prenatal alcohol display abnormalities restricted to SPW-R episodes that manifest as decreased recruitment of CA1 pyramidal cells and interneurons to SPW-R events, altered excitation during SPW-Rs, and decreased cell assembly activation rate. These differences observed at the single neuron and the population level may limit the ability of memory trace reactivation during SPW-Rs through the disruption of the intrinsic structure of cell sequences. Together, our results suggest that alterations in hippocampal SPW-R spike dynamics may underlie alcohol exposure-related memory deficits.

Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus, called place cells, discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. We therefore tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in-vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Secondly, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between contexts in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to context provides a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.

Spatial disorientation is observed very early on in Alzheimer's disease (AD). Individuals with prodromal or early AD show progressive impairments in using environmental landmarks to navigate successfully within an environment. Noninvasive functional imaging techniques paired with virtual and real-world navigation tasks reveal a disruption of spatial navigation circuitry that emerges even in preclinical populations. Over time, functional differences increase while spatial navigation performance decreases. The use of animal models with AD-like pathology has provided some insight into possible mechanisms of impeded navigation ability. Functional cell types that fire relative to spatial features, such as place and grid cells, fire less precisely over time relative to control animals. Differences are also observed at the population level with evidence of functional connectivity disruption of the hippocampal–entorhinal circuits.

AbstractBackgroundSpatial navigation is impaired in the early stages of Alzheimer’s disease (AD) and may be a defining behavioral marker of preclinical AD. Head direction (HD) cells are cortical‐limbic neurons that discharge action potentials as a function of an animal’s spatial orientation in an environment. HD cells can maintain their orientation across repeated test sessions, in reference to salient landmarks, and are thought to play a critical role in guiding accurate spatial behavior. Thus, we tested the hypothesis that impairments in HD cell stability would be apparent in AD.MethodsTo test this hypothesis, we used the TgF344‐AD rat model of AD which exhibits progressive pathology in cortical‐limbic regions. Previously, we found that 10 month old TgF344‐AD rats make progressively fewer spatially and directionally precise movements during navigation. Thus, HD cells were characterized in the posterior cortex (retrosplenial, postsubiculum, and visual association area 2) and the anterior thalamus of 10 ‐ 13 month TgF344‐AD rats and age matched F344 controls. Rats performed a pellet chasing task within a cylinder fitted with a white cue card during recordings. In some sessions, the cue card was rotated to assess landmark control.ResultsHD cells were identified and were found to exhibit similar directional firing characteristics between TgF344‐AD and F344 groups. Further, we found that HD cells in TgF344‐AD rats demonstrated intact responses to cue manipulations. In contrast, we observed that HD cells exhibited more variability and instability in their directional orientation across repeated test sessions.ConclusionsThese results support the hypothesis that deficits in the stability of HD cells may underlie spatial impairments in AD.

•The consumption of alcohol during gestation is detrimental to spatial processing.•Alcohol negatively affects the hippocampus, thalamus, & entorhinal cortex.•Future work should explore alcohol’s effect on the thalamus & entorhinal cortex.•Representations within the hippocampal formation & thalamus should be investigated.

Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal's sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells.

Spatial navigation is impaired in early stages of Alzheimer’s disease (AD), and may be a defining behavioral marker of preclinical AD. Nevertheless, limitations of diagnostic criteria for AD and within animal models of AD make characterization of preclinical AD difficult. A new rat model (TgF344-AD) of AD overcomes many of these limitations, though spatial navigation has not been comprehensively assessed. Using the hidden and cued platform variants of the Morris water task, a longitudinal assessment of spatial navigation was conducted on TgF344-AD (n=16) and Fischer 344 (n=12) male and female rats at three age ranges: 4 to 5 months, 7 to 8, and 10 to 11 months of age. TgF344-AD rats exhibited largely intact navigation at 4-5 and 7-8 months of age, with deficits in the hidden platform task emerging at 10-11 months of age. In general, TgF344-AD rats displayed less accurate swim trajectories to the platform and a wider search area around the platform region compared to wildtype rats. Impaired navigation occurred in the absence of deficits in acquiring the procedural task demands or navigation to the cued platform location. Together, the results indicate that TgF344-AD rats exhibit comparable deficits to those found in individuals in the early stages of AD.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model.

The retrosplenial cortex is anatomically positioned to integrate sensory, motor, and visual information and is thought to have an important role in processing spatial information and guiding behavior through complex environments. Anatomical and theoretical work has argued that the retrosplenial cortex participates in spatial behavior in concert with its primary input, the parietal cortex. Although the nature of this interactions is unknown, the central position is that the functional connectivity is hierarchical with egocentric spatial information processed at parietal cortex, and higher-level allocentric mappings generated in the retrosplenial cortex. Here, we review the evidence supporting this proposal. We begin by summarizing the key anatomical features of the retrosplenial-parietal network, and then review studies investigating the neural correlates of these regions during spatial behavior. Our summary of this literature suggests that the retrosplenial-parietal circuitry does not represent a strict hierarchical parcellation of function between the two regions, but instead a heterogeneous mixture of egocentric-allocentric coding and integration across frames of reference. We also suggest that this circuitry should be represented as a gradient of egocentric-to-allocentric information processing from parietal to retrosplenial cortices, with more specialized encoding of global allocentric frameworks within the retrosplenial cortex and more specialized egocentric and local allocentric representations in parietal cortex. We conclude by identifying the major gaps in this literature and suggest new avenues of research.

Spatial navigation and memory are impaired in early stages of Alzheimer’s disease (AD), and may be a defining behavioral marker of preclinical AD. Nevertheless, limitations of diagnostic criteria for prodromal AD and within animal models of AD make characterization of preclinical AD difficult. A new rat model (TgF344-AD) of AD overcomes many of these limitations, though spatial navigation and memory has not been comprehensively assessed. This study aimed to characterize. Using three paradigms of the Morris Water Maze, spatial navigation and memory were assessed in TgF344-AD (n=16) and Fischer 344 (n=12) male and female rats over three time points. TgF344-AD females exhibited navigational deficits at 4.5 months while TgF344-AD males show impairment at 10.5 months. Furthermore, TgF344-AD males demonstrate acute reference memory impairment at 10.5 months whereas TgF344-AD females are unimpaired. Across all time points, cued navigation, spatial working memory and reference memory remain largely intact between subjects. Overall, these results indicated TgF344-AD rats exhibit comparable deficits to those found in individuals with MCI and provides further evidence of sexual dimorphisms of AD.

Animals occupy territories in which resources such as food and shelter are often distributed unevenly. While studies of exploratory behavior have typically involved the laboratory rodent as an experimental subject, questions regarding what constitutes exploration have dominated. A recent line of research has utilized a descriptive approach to the study of rodent exploration, which has revealed that this behavior is organized into movement subsystems that can be readily quantified. The movements include home base behavior, which serves as a central point of attraction from which rats and mice organize exploratory trips into the remaining environment. In this review, we describe some of the features of this organized behavior pattern as well as its modulation by sensory cues and previous experience. We conclude the review by summarizing research investigating the neurobiological bases of exploration, which we hope will stimulate renewed interest and research on the neural systems mediating these behaviors.

Head Direction (HD) cells of the rodent Papez circuit are thought to reflect the spatial orientation of the animal. Because NMDA transmission is important for spatial behavior, we sought to determine the effects of NMDA blockade on the basic directional signal carried by HD cells and on experience-dependent modification of this system. In Experiment 1, HD cells were recorded from the anterior dorsal thalamus in female Long-Evans rats while they foraged in a familiar enclosure following administration of the NMDA antagonist CPP or saline. While the drug produced a significant decrease in peak firing rates, it failed to affect the overall directional specificity and landmark control of HD cells. Experiment 2 took place over 2 days and assessed whether the NMDA antagonist would interfere with the stabilization of the HD network in a novel environment. On Day 1 the animal was administered CPP or saline and placed in a novel enclosure to allow the stabilization of the HD signal relative to the new environmental landmarks. On Day 2 the animal was returned to the formerly novel enclosure to determine if the enclosure specific direction-dependent activity established on Day 1 was maintained. In contrast to HD cells from control animals, cells from animals receiving CPP during the initial exposure to the novel enclosure did not maintain the same direction-dependent activity relative to the enclosure in the subsequent drug-free exposure. These findings demonstrate that plasticity in the HD system is dependent on NMDA transmission similar to many other forms of spatial learning.

Head direction (HD) cells, found in the rodent Papez circuit, are thought to form the neural circuitry responsible for directional orientation. Because NMDA transmission has been implicated in spatial tasks requiring directional orientation, we sought to determine if the NMDA antagonist dizocilpine (MK-801) would disrupt the directional signal carried by the HD network. Anterior thalamic HD cells were isolated in female Long-Evans rats and initially monitored for baseline directional activity while the animals foraged in a familiar enclosure. The animals were then administered MK-801 at a dose of .05 mg/kg or 0.1 mg/kg, or isotonic saline, and cells were re-examined for changes in directional specificity and landmark control. While the cells showed no changes in directional specificity and landmark control following administration of saline or the lower dose of MK-801, the higher dose of MK-801 caused a dramatic attenuation of the directional signal, characterized by decreases in peak firing rates, signal to noise, and directional information content. While the greatly attenuated directional specificity of cells in the high dose condition usually remained stable relative to the landmarks within the recording enclosure, a few cells in this condition exhibited unstable preferred directions within and between recording sessions. Our results are discussed relative to the possibility that the findings explain the effects of MK-801 on the acquisition and performance of spatial tasks.