Publications by authors named "Benjamin J Clark"

42 Publications

Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology.

Neurosci Biobehav Rev 2021 May 9;127:647-658. Epub 2021 May 9.

Department of Psychology, University of New Mexico, Albuquerque, NM, 87109, Mexico. Electronic address:

Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.005DOI Listing
May 2021

Age-Related Alterations in Prelimbic Cortical Neuron Expression Vary by Behavioral State and Cortical Layer.

Front Aging Neurosci 2020 28;12:588297. Epub 2020 Oct 28.

Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United States.

Prefrontal cortical and medial temporal lobe connectivity is critical for higher cognitive functions that decline in older adults. Likewise, these cortical areas are among the first to show anatomical, functional, and biochemical alterations in advanced age. The prelimbic subregion of the prefrontal cortex and the perirhinal cortex of the medial temporal lobe are densely reciprocally connected and well-characterized as undergoing age-related neurobiological changes that correlate with behavioral impairment. Despite this fact, it remains to be determined how changes within these brain regions manifest as alterations in their functional connectivity. In our previous work, we observed an increased probability of age-related dysfunction for perirhinal cortical neurons that projected to the prefrontal cortex in old rats compared to neurons that were not identified as projection neurons. The current study was designed to investigate the extent to which aged prelimbic cortical neurons also had altered patterns of expression during behavior, and if this was more evident in those cells that had long-range projections to the perirhinal cortex. The expression patterns of the immediate-early gene were quantified in behaviorally characterized rats that also received the retrograde tracer cholera toxin B (CTB) in the perirhinal cortex to identify projection neurons to this region. As in our previous work, the current study found that CTB+ cells were more active than those that did not have the tracer. Moreover, there were age-related reductions in prelimbic cortical neuron expression that correlated with a reduced ability of aged rats to multitask. Unlike the perirhinal cortex, however, the age-related reduction in expression was equally likely in CTB+ and CTB- negative cells. Thus, the selective vulnerability of neurons with long-range projections to dysfunction in old age may be a unique feature of the perirhinal cortex. Together, these observations identify a mechanism involving prelimbic-perirhinal cortical circuit disruption in cognitive aging.
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http://dx.doi.org/10.3389/fnagi.2020.588297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655965PMC
October 2020

The Neuroscience of Spatial Navigation and the Relationship to Artificial Intelligence.

Front Comput Neurosci 2020 28;14:63. Epub 2020 Jul 28.

Department of Psychology, Program in Neuroscience, Florida State University, Tallahassee, FL, United States.

Recent advances in artificial intelligence (AI) and neuroscience are impressive. In AI, this includes the development of computer programs that can beat a grandmaster at GO or outperform human radiologists at cancer detection. A great deal of these technological developments are directly related to progress in artificial neural networks-initially inspired by our knowledge about how the brain carries out computation. In parallel, neuroscience has also experienced significant advances in understanding the brain. For example, in the field of spatial navigation, knowledge about the mechanisms and brain regions involved in neural computations of cognitive maps-an internal representation of space-recently received the Nobel Prize in medicine. Much of the recent progress in neuroscience has partly been due to the development of technology used to record from very large populations of neurons in multiple regions of the brain with exquisite temporal and spatial resolution in behaving animals. With the advent of the vast quantities of data that these techniques allow us to collect there has been an increased interest in the intersection between AI and neuroscience, many of these intersections involve using AI as a novel tool to explore and analyze these large data sets. However, given the common initial motivation point-to understand the brain-these disciplines could be more strongly linked. Currently much of this potential synergy is not being realized. We propose that spatial navigation is an excellent area in which these two disciplines can converge to help advance what we know about the brain. In this review, we first summarize progress in the neuroscience of spatial navigation and reinforcement learning. We then turn our attention to discuss how spatial navigation has been modeled using descriptive, mechanistic, and normative approaches and the use of AI in such models. Next, we discuss how AI can advance neuroscience, how neuroscience can advance AI, and the limitations of these approaches. We finally conclude by highlighting promising lines of research in which spatial navigation can be the point of intersection between neuroscience and AI and how this can contribute to the advancement of the understanding of intelligent behavior.
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http://dx.doi.org/10.3389/fncom.2020.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399088PMC
July 2020

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure.

Curr Biol 2020 09 23;30(18):3556-3569.e5. Epub 2020 Jul 23.

Department of Psychology, University of New Mexico, 2001 Redondo S Drive, Albuquerque, NM 87106, USA; Department of Neurosciences, University of New Mexico, 900 Camino de Salud, Albuquerque, NM 87131, USA. Electronic address:

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. Therefore, we 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. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli 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 contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.
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http://dx.doi.org/10.1016/j.cub.2020.06.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511441PMC
September 2020

A Comparison of Neural Decoding Methods and Population Coding Across Thalamo-Cortical Head Direction Cells.

Front Neural Circuits 2019 10;13:75. Epub 2019 Dec 10.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States.

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.
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http://dx.doi.org/10.3389/fncir.2019.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914739PMC
May 2020

Moderate prenatal alcohol exposure reduces parvalbumin expressing GABAergic interneurons in the dorsal hippocampus of adult male and female rat offspring.

Neurosci Lett 2020 01 23;718:134700. Epub 2019 Dec 23.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States. Electronic address:

Prenatal alcohol exposure (PAE) negatively impacts hippocampal development and impairs hippocampal-sensitive learning and memory. However, hippocampal neural adaptations in response to moderate PAE are not completely understood. To explore the effects of moderate PAE on GABAergic interneuron expression, this study used a rat model of moderate PAE to examine the effects of PAE on parvalbumin (PARV)-positive cells in fields CA1, CA3 and the dentate gyrus (DG) of the dorsal hippocampus (dHC). Long-Evans dams were given daily access to 5 % (vol/vol) ethanol or saccharine (SAC) control solutions throughout the course of gestation. Offspring were divided into four separate groups: PAE (n = 7) or SAC (n = 7) males, or PAE (n = 8) or SAC (n = 8) females. All rats were aged to adulthood and, following testing in the Morris water task, their brains were analyzed for the expression of the GABAergic neuronal marker PARV. We report a main effect of PAE on GABAergic expression, with significant reductions in PARV-positive cells in area CA3 for males and the DG for females. There was also a trend for a reduction in PARV expressing neurons in fields CA1 and CA3 in females. The results are discussed in relation to hippocampal GABAergic interneuron function, PAE and behavior.
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http://dx.doi.org/10.1016/j.neulet.2019.134700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179818PMC
January 2020

The effects of developmental alcohol exposure on the neurobiology of spatial processing.

Neurosci Biobehav Rev 2019 12 14;107:775-794. Epub 2019 Sep 14.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States. Electronic address:

The consumption of alcohol during gestation is detrimental to the developing central nervous system. One functional outcome of this exposure is impaired spatial processing, defined as sensing and integrating information pertaining to spatial navigation and spatial memory. The hippocampus, entorhinal cortex, and anterior thalamus are brain regions implicated in spatial processing and are highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on spatial processing may be attributed to changes at the synaptic to circuit level. In this review, we first describe the impact of developmental alcohol exposure on spatial behavior followed by a summary of the development of brain areas involved in spatial processing. We then provide an examination of the consequences of prenatal and early postnatal alcohol exposure in rodents on hippocampal, anterior thalamus, and entorhinal cortex-dependent spatial processing from the cellular to behavioral level. We conclude by highlighting several unanswered questions which may provide a framework for future investigation.
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http://dx.doi.org/10.1016/j.neubiorev.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876993PMC
December 2019

Bilateral postsubiculum lesions impair visual and nonvisual homing performance in rats.

Behav Neurosci 2019 Oct 6;133(5):496-507. Epub 2019 Jun 6.

Department of Psychological and Brain Sciences.

Nearly all species rely on visual and nonvisual cues to guide navigation, and which ones they use depend on the environment and task demands. The postsubiculum (PoS) is a crucial brain region for the use of visual cues, but its role in the use of self-movement cues is less clear. We therefore evaluated rats' navigational performance on a food-carrying task in light and in darkness in rats that had bilateral neurotoxic lesions of the PoS. Animals were trained postoperatively to exit a refuge and search for a food pellet, and carry it back to the refuge for consumption. In both light and darkness, control and PoS-lesioned rats made circuitous outward journeys as they searched for food. However, only control rats were able to accurately use visual or self-movement cues to make relatively direct returns to the home refuge. These results suggest the PoS's role in navigation is not limited to the use of visual cues, but also includes the use of self-movement cues. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721993PMC
October 2019

Moderate prenatal alcohol exposure impairs performance by adult male rats in an object-place paired-associate task.

Behav Brain Res 2019 03 7;360:228-234. Epub 2018 Dec 7.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States. Electronic address:

Memory impairments, including spatial and object processing, are often observed in individuals with Fetal Alcohol Spectrum Disorders. The neurobiological basis of memory deficits after prenatal alcohol exposure (PAE) is often linked to structural and functional alterations in the medial temporal lobe, including the hippocampus. Recent evidence suggests that the medial temporal lobe plays a critical role in processing high-order sensory stimuli such as complex objects and their associated locations in space. In the first experiment, we tested male rat offspring with moderate PAE in a medial temporal-dependent object-place paired-associate (OPPA) task. The OPPA task requires a conditional discrimination between an identical pair of objects presented at two spatial locations 180° opposite arms of a radial arm maze. Food reinforcement is contingent upon selecting the correct object of the pair for a given spatial location. Adult rats were given a total of 10 trials per day over 14 consecutive days of training. PAE male rats made significantly more errors than male saccharin (SACC) control rats during acquisition of the OPPA task. In Experiment 2, rats performed an object-discrimination task in which a pair of objects were presented in a single arm of the maze. Moderate PAE and SACC control rats exhibited comparable performance. The results suggest that moderate PAE rats can learn to discriminate objects, but are impaired when required to discriminate between objects on the basis of spatial location in the environment.
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http://dx.doi.org/10.1016/j.bbr.2018.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324964PMC
March 2019

Progressive impairment of directional and spatially precise trajectories by TgF344-Alzheimer's disease rats in the Morris Water Task.

Sci Rep 2018 11 1;8(1):16153. Epub 2018 Nov 1.

1 University of New Mexico, Department of Psychology, University of New Mexico, Albuquerque, NM, 87131, United States.

Spatial navigation is impaired in early stages of Alzheimer's disease, and may be a defining behavioral marker of preclinical AD. A new rat model (TgF344-AD) of AD overcomes many limitations of other rodent models, 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 months, with deficits in the hidden platform task emerging at 7-8 months and becoming significantly pronounced at 10-11 months of age. In general, TgF344-AD rats displayed less accurate swim trajectories to the platform and searched a wider 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 navigational deficits to those found in individuals with preclinical-AD.
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http://dx.doi.org/10.1038/s41598-018-34368-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212523PMC
November 2018

Behavioral and Neural Subsystems of Rodent Exploration.

Learn Motiv 2018 Feb 13;61:3-15. Epub 2017 Apr 13.

Department of Psychology, University of New Mexico, Albuquerque, New Mexico.

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 rodent exploratory behavior.
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http://dx.doi.org/10.1016/j.lmot.2017.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159932PMC
February 2018

Immediate-early gene Homer1a intranuclear transcription focus intensity as a measure of relative neural activation.

Hippocampus 2019 06 16;29(6):481-490. Epub 2018 Nov 16.

Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada.

Immediate-early genes (IEGs) exhibit a rapid, transient transcription response to neuronal activation. Fluorescently labeled mRNA transcripts appear as bright intranuclear transcription foci (INF), which have been used as an all-or-nothing indicator of recent neuronal activity; however, it would be useful to know whether INF fluorescence can be used effectively to assess relative activations within a neural population. We quantified the Homer1a (H1a) response of hippocampal neurons to systematically varied numbers of exposures to the same places by inducing male Long-Evans rats to run laps around a track. Previous studies reveal relatively stable firing rates across laps on a familiar track. A strong linear trend (r  > 0.9) in INF intensity was observed between 1 and 25 laps, after which INF intensity declined as a consequence of dispersion related to the greater elapsed time. When the integrated fluorescence of the entire nucleus was considered instead, the linear relationship extended to 50 laps. However, there was only an approximate doubling of H1a detected for this 50-fold variation in total spiking. Thus, the intranuclear H1a RNA fluorescent signal does provide a relative measure of how many times a set of neurons was activated over a ~10 min period, but the dynamic range and hence signal-to-noise ratios are poor. This low dynamic range may reflect previously reported reductions in the IEG response during repeated episodes of behavior over longer time scales. It remains to be determined how well the H1a signal reflects relative firing rates within a population of neurons in response to a single, discrete behavioral event.
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http://dx.doi.org/10.1002/hipo.23036DOI Listing
June 2019

The retrosplenial-parietal network and reference frame coordination for spatial navigation.

Behav Neurosci 2018 Oct 9;132(5):416-429. Epub 2018 Aug 9.

Department of Psychology.

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 input from the parietal cortex. Although the nature of these interactions is unknown, a central position is that the functional connectivity is hierarchical with egocentric spatial information processed in the 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. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188841PMC
October 2018

Dissociable effects of advanced age on prefrontal cortical and medial temporal lobe ensemble activity.

Neurobiol Aging 2018 10 30;70:217-232. Epub 2018 Jun 30.

McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL; Institute on Aging, University of Florida, Gainesville, FL. Electronic address:

The link between age-related cellular changes within brain regions and larger scale neuronal ensemble dynamics critical for cognition has not been fully elucidated. The present study measured neuron activity within medial prefrontal cortex (PFC), perirhinal cortex (PER), and hippocampal subregion CA1 of young and aged rats by labeling expression of the immediate-early gene Arc. The proportion of cells expressing Arc was quantified at baseline and after a behavior that requires these regions. In addition, PER and CA1 projection neurons to PFC were identified with retrograde labeling. Within CA1, no age-related differences in neuronal activity were observed in the entire neuron population or within CA1 pyramidal cells that project to PFC. Although behavior was comparable across age groups, behaviorally driven Arc expression was higher in the deep layers of both PER and PFC and lower in the superficial layers of these regions. Moreover, age-related changes in activity levels were most evident within PER cells that project to PFC. These data suggest that the PER-PFC circuit is particularly vulnerable in advanced age.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829909PMC
October 2018

Linear Self-Motion Cues Support the Spatial Distribution and Stability of Hippocampal Place Cells.

Curr Biol 2018 06 17;28(11):1803-1810.e5. Epub 2018 May 17.

Department of Psychology, Indiana University-Purdue University Fort Wayne, Fort Wayne, IN 46805, USA. Electronic address:

The vestibular system provides a crucial component of place-cell and head-direction cell activity [1-7]. Otolith signals are necessary for head-direction signal stability and associated behavior [8, 9], and the head-direction signal's contribution to parahippocampal spatial representations [10-14] suggests that place cells may also require otolithic information. Here, we demonstrate that self-movement information from the otolith organs is necessary for the development of stable place fields within and across sessions. Place cells in otoconia-deficient tilted mice showed reduced spatial coherence and formed place fields that were located closer to environmental boundaries, relative to those of control mice. These differences reveal an important otolithic contribution to place-cell functioning and provide insight into the cognitive deficits associated with otolith dysfunction.
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http://dx.doi.org/10.1016/j.cub.2018.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988980PMC
June 2018

Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease.

Neurobiol Aging 2018 01 5;61:169-176. Epub 2017 Oct 5.

Department of Psychology, University of New Mexico, Albuquerque, NM, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944488PMC
January 2018

Age-related Changes in Lateral Entorhinal and CA3 Neuron Allocation Predict Poor Performance on Object Discrimination.

Front Syst Neurosci 2017 30;11:49. Epub 2017 Jun 30.

Department of Neuroscience, McKnight Brain Institute, University of FloridaGainesville, FL, United States.

Age-related memory deficits correlate with dysfunction in the CA3 subregion of the hippocampus, which includes both hyperactivity and overly rigid activity patterns. While changes in intrinsic membrane currents and interneuron alterations are involved in this process, it is not known whether alterations in afferent input to CA3 also contribute. Neurons in layer II of the lateral entorhinal cortex (LEC) project directly to CA3 through the perforant path, but no data are available regarding the effects of advanced age on LEC activity and whether these activity patterns update in response to environmental change. Furthermore, it is not known the extent to which age-related deficits in sensory discrimination relate to the inability of aged CA3 neurons to update in response to new environments. Young and aged rats were pre-characterized on a LEGO object discrimination task, comparable to behavioral tests in humans in which CA3 hyperactivity has been linked to impairments. The cellular compartment analysis of temporal activity with fluorescence hybridization for the immediate-early gene Arc was then used to identify the principal cell populations that were active during two distinct epochs of random foraging in different environments. This approach enabled the extent to which rats could discriminate two similar objects to be related to the ability of CA3 neurons to update across different environments. In both young and aged rats, there were animals that performed poorly on the LEGO object discrimination task. In the aged rats only, however, the poor performers had a higher percent of CA3 neurons that were active during random foraging in a novel environment, but this is not related to the ability of CA3 neurons to remap when the environment changed. Afferent neurons to CA3 in LEC, as identified with the retrograde tracer choleratoxin B (CTB), also showed a higher percentage of cells that were positive for Arc mRNA in aged poor performing rats. This suggests that LEC contributes to the hyperactivity seen in CA3 of aged animals with object discrimination deficits and age-related cognitive decline may be the consequence of dysfunction endemic to the larger network.
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http://dx.doi.org/10.3389/fnsys.2017.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491840PMC
June 2017

Spatial Navigation: Retrosplenial Cortex Encodes the Spatial Structure of Complex Routes.

Authors:
Benjamin J Clark

Curr Biol 2017 07;27(13):R649-R651

Department of Psychology, University of New Mexico, MSC03 2220, 1 University of New Mexico, Albuquerque, NM 87131, USA. Electronic address:

A new study in which recordings were made from the retrosplenial cortex while rats navigated through a complex environment has revealed populations of cells that encode route-segments as well as the relative position of these segments within an allocentric framework.
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http://dx.doi.org/10.1016/j.cub.2017.05.019DOI Listing
July 2017

Post-training Inactivation of the Anterior Thalamic Nuclei Impairs Spatial Performance on the Radial Arm Maze.

Front Neurosci 2017 6;11:94. Epub 2017 Mar 6.

Department of Psychology, University of New Mexico Albuquerque, NM, USA.

The limbic thalamus, specifically the anterior thalamic nuclei (ATN), contains brain signals including that of head direction cells, which fire as a function of an animal's directional orientation in an environment. Recent work has suggested that this directional orientation information stemming from the ATN contributes to the generation of hippocampal and parahippocampal spatial representations, and may contribute to the establishment of unique spatial representations in radially oriented tasks such as the radial arm maze. While previous studies have shown that ATN lesions can impair spatial working memory performance in the radial maze, little work has been done to investigate spatial reference memory in a discrimination task variant. Further, while previous studies have shown that ATN lesions can impair performance in the radial maze, these studies produced the ATN lesions prior to training. It is therefore unclear whether the ATN lesions disrupted acquisition or retention of radial maze performance. Here, we tested the role of ATN signaling in a previously learned spatial discrimination task on a radial arm maze. Rats were first trained to asymptotic levels in a task in which two maze arms were consistently baited across training. After 24 h, animals received muscimol inactivation of the ATN before a 4 trial probe test. We report impairments in post-inactivation trials, suggesting that signals from the ATN modulate the use of a previously acquired spatial discrimination in the radial-arm maze. The results are discussed in relation to the thalamo-cortical limbic circuits involved in spatial information processing, with an emphasis on the head direction signal.
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http://dx.doi.org/10.3389/fnins.2017.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337504PMC
March 2017

Influence of Proximal, Distal, and Vestibular Frames of Reference in Object-Place Paired Associate Learning in the Rat.

PLoS One 2016;11(9):e0163102. Epub 2016 Sep 22.

Department of Psychology, University of New Mexico, Albuquerque, New Mexico.

Object-place paired associate learning has been used to test hypotheses regarding the neurobiological basis of memory in rodents. Much of this work has focused on the role of limbic and hippocampal-parahippocampal regions, as well as the use of spatial information derived from allothetic visual stimuli to determine location in an environment. It has been suggested that idiothetic self-motion (vestibular) signals and internal representations of directional orientation might play an important role in disambiguating between spatial locations when forming object-place associations, but this hypothesis has not been explicitly tested. In the present study, we investigated the relationship between allothetic (i.e., distal and proximal cues) and vestibular stimuli on performance of an object-place paired-associate task. The paired-associate task was composed of learning to discriminate between an identical pair of objects presented in 180° opposite arms of a radial arm maze. Thus, animals were required to select a particular object on the basis of spatial location (i.e., maze arm). After the animals acquired the object-place rule, a series of probe tests determined that rats utilize self-generated vestibular cues to discriminate between the two maze arms. Further, when available, animals showed a strong preference for local proximal cues associated with the maze. Together, the work presented here supports the establishment of an object-place task that requires both idiothetic and allothetic stimulus sources to guide choice behavior, and which can be used to further investigate the dynamic interactions between neural systems involved in pairing sensory information with spatial locations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033391PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163102PLOS
September 2016

Do the anterior and lateral thalamic nuclei make distinct contributions to spatial representation and memory?

Neurobiol Learn Mem 2016 09 4;133:69-78. Epub 2016 Jun 4.

Department of Psychology, University of New Mexico, Albuquerque, NM, United States.

The anterior and lateral thalamus has long been considered to play an important role in spatial and mnemonic cognitive functions; however, it remains unclear whether each region makes a unique contribution to spatial information processing. We begin by reviewing evidence from anatomical studies and electrophysiological recordings which suggest that at least one of the functions of the anterior thalamus is to guide spatial orientation in relation to a global or distal spatial framework, while the lateral thalamus serves to guide behavior in relation to a local or proximal framework. We conclude by reviewing experimental work using targeted manipulations (lesion or neuronal silencing) of thalamic nuclei during spatial behavior and single-unit recordings from neuronal representations of space. Our summary of this literature suggests that although the evidence strongly supports a working model of spatial information processing involving the anterior thalamus, research regarding the role of the lateral thalamus is limited and requires further attention. We therefore identify a number of major gaps in this research and suggest avenues of future study that could potentially solidify our understanding of the relative roles of anterior and lateral thalamic regions in spatial representation and memory.
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http://dx.doi.org/10.1016/j.nlm.2016.06.002DOI Listing
September 2016

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

J Neurosci Methods 2016 06 31;266:151-60. Epub 2016 Mar 31.

Canadian Centre for Behavioural Neuroscience, The University of Lethbridge, Lethbridge, AB, Canada; Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

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.
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http://dx.doi.org/10.1016/j.jneumeth.2016.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695690PMC
June 2016

Passive Transport Disrupts Grid Signals in the Parahippocampal Cortex.

Curr Biol 2015 Oct 17;25(19):2493-502. Epub 2015 Sep 17.

Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA. Electronic address:

Navigation is usually thought of relative to landmarks, but neural signals representing space also use information generated by an animal's movements. These signals include grid cells, which fire at multiple locations, forming a repeating grid pattern. Grid cell generation depends upon theta rhythm, a 6-10 Hz electroencephalogram (EEG) oscillation that is modulated by the animals' movement velocity. We passively moved rats in a clear cart to eliminate motor related self-movement cues that drive moment-to-moment changes in theta rhythmicity. We found that passive movement maintained theta power and frequency at levels equivalent to low active movement velocity, spared overall head-direction (HD) cell characteristics, but abolished both velocity modulation of theta rhythmicity and grid cell firing patterns. These results indicate that self-movement motor cues are necessary for generating grid-specific firing patterns, possibly by driving velocity modulation of theta rhythmicity, which may be used as a speed signal to generate the repeating pattern of grid cells.
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http://dx.doi.org/10.1016/j.cub.2015.08.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596791PMC
October 2015

Maintained directional navigation across environments in the Morris water task is dependent on vestibular cues.

J Exp Psychol Anim Learn Cogn 2015 Jul 22;41(3):301-308. Epub 2015 Jun 22.

University of Lethbridge.

An experiment was designed to test the hypothesis that an internally generated sense of spatial orientation contributes to navigation by rats in the Morris water task and to determine whether this strategy is dependent on vestibular cues. Rats were trained in a standard hidden platform procedure in which they received 8 daily swim trials. In a probe test, rats were carried in an opaque box to a pool located in a novel adjacent environment. During transport, 1 cohort of rats received a disorientation procedure, composed of gentle rotation in the box, while a second cohort served as transport controls. Upon being placed in the pool in the novel room, controls displayed a preference for the pool quadrant predicted by a retained directional response across rooms, whereas disoriented rats failed to display a preference for the same quadrant. Furthermore, control rats swam faster and more directly toward the target quadrant. Together, these findings suggest that rats retain a directional response based on vestibular cues across environments, which can be used to disambiguate geometrically equivalent locations in a novel room and apparatus. (PsycINFO Database Record
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http://dx.doi.org/10.1037/xan0000066DOI Listing
July 2015

Spatial navigation. Disruption of the head direction cell network impairs the parahippocampal grid cell signal.

Science 2015 Feb 5;347(6224):870-874. Epub 2015 Feb 5.

Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA.

Navigation depends on multiple neural systems that encode the moment-to-moment changes in an animal's direction and location in space. These include head direction (HD) cells representing the orientation of the head and grid cells that fire at multiple locations, forming a repeating hexagonal grid pattern. Computational models hypothesize that generation of the grid cell signal relies upon HD information that ascends to the hippocampal network via the anterior thalamic nuclei (ATN). We inactivated or lesioned the ATN and subsequently recorded single units in the entorhinal cortex and parasubiculum. ATN manipulation significantly disrupted grid and HD cell characteristics while sparing theta rhythmicity in these regions. These results indicate that the HD signal via the ATN is necessary for the generation and function of grid cell activity.
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http://dx.doi.org/10.1126/science.1259591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476794PMC
February 2015

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

Front Neural Circuits 2014 5;8:146. Epub 2015 Jan 5.

Canadian Centre for Behavioural Neuroscience, The University of Lethbridge Lethbridge, AB, Canada ; Department of Neurobiology and Behavior, University of California Irvine, CA, USA.

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.
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http://dx.doi.org/10.3389/fncir.2014.00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283643PMC
July 2015

Interaction of egocentric and world-centered reference frames in the rat posterior parietal cortex.

J Neurosci 2014 Apr;34(16):5431-46

Canadian Centre for Behavioural Neuroscience, The University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4.

Navigation requires coordination of egocentric and allocentric spatial reference frames and may involve vectorial computations relative to landmarks. Creation of a representation of target heading relative to landmarks could be accomplished from neurons that encode the conjunction of egocentric landmark bearings with allocentric head direction. Landmark vector representations could then be created by combining these cells with distance encoding cells. Landmark vector cells have been identified in rodent hippocampus. Given remembered vectors at goal locations, it would be possible to use such cells to compute trajectories to hidden goals. To look for the first stage in this process, we assessed parietal cortical neural activity as a function of egocentric cue light location and allocentric head direction in rats running a random sequence to light locations around a circular platform. We identified cells that exhibit the predicted egocentric-by-allocentric conjunctive characteristics and anticipate orienting toward the goal.
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http://dx.doi.org/10.1523/JNEUROSCI.0511-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988403PMC
April 2014

Lesions of the dorsal tegmental nuclei disrupt control of navigation by distal landmarks in cued, directional, and place variants of the Morris water task.

Behav Neurosci 2013 Aug 3;127(4):566-81. Epub 2013 Jun 3.

Department of Psychological and Brain Sciences, Dartmouth College, NH, USA.

Navigation depends on a network of neural systems that accurately monitor an animal's spatial orientation in an environment. Within this navigation system are head direction (HD) cells which discharge as a function of an animal's directional heading, providing an animal with a neural compass to guide ongoing spatial behavior. Experiments were designed to test this hypothesis by damaging the dorsal tegmental nucleus (DTN), a midbrain structure that plays a critical role in the generation of the rodent HD cell signal, and evaluating landmark based navigation using variants of the Morris water task. In Experiments 1 and 2, shams and DTN-lesioned rats were trained to navigate toward a cued platform in the presence of a constellation of distal landmarks located outside the pool. After reaching a training criteria, rats were tested in three probe trials in which (a) the cued platform was completely removed from the pool, (b) the pool was repositioned and the cued platform remained in the same absolute location with respect to distal landmarks, or (c) the pool was repositioned and the cued platform remained in the same relative location in the pool. In general, DTN-lesioned rats required more training trials to reach performance criterion, were less accurate to navigate to the platform position when it was removed, and navigated directly to the cued platform regardless of its position in the pool, indicating a general absence of control over navigation by distal landmarks. In Experiment 3, DTN and control rats were trained in directional and place navigation variants of the water task where the pool was repositioned for each training trial and a hidden platform was placed either in the same relative location (direction) in the pool or in the same absolute location (place) in the distal room reference frame. DTN-lesioned rats were initially impaired in the direction task, but ultimately performed as well as controls. In the place task, DTN-lesioned rats were severely impaired and displayed little evidence of improvement over the course of training. Together, these results support the conclusion that the DTN is required for accurate landmark navigation.
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http://dx.doi.org/10.1037/a0033087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997071PMC
August 2013

Head direction cell activity in the anterodorsal thalamus requires intact supragenual nuclei.

J Neurophysiol 2012 Nov 8;108(10):2767-84. Epub 2012 Aug 8.

Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire 03755, USA.

Neural activity in several limbic areas varies as a function of the animal's head direction (HD) in the horizontal plane. Lesions of the vestibular periphery abolish this HD cell signal, suggesting an essential role for vestibular afference in HD signal generation. The organization of brain stem pathways conveying vestibular information to the HD circuit is poorly understood; however, recent anatomical work has identified the supragenual nucleus (SGN) as a putative relay. To test this hypothesis, we made lesions of the SGN in rats and screened for HD cells in the anterodorsal thalamus. In animals with complete bilateral lesions, the overall number of HD cells was significantly reduced relative to control animals. In animals with unilateral lesions of the SGN, directional activity was present, but the preferred firing directions of these cells were unstable and less influenced by the rotation of an environmental landmark. In addition, we found that preferred directions displayed large directional shifts when animals foraged for food in a darkened environment and when they were navigating from a familiar environment to a novel one, suggesting that the SGN plays a critical role in projecting essential self-motion (idiothetic) information to the HD cell circuit.
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http://dx.doi.org/10.1152/jn.00295.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545120PMC
November 2012

Vestibular and attractor network basis of the head direction cell signal in subcortical circuits.

Front Neural Circuits 2012 20;6. Epub 2012 Mar 20.

Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover NH, USA.

Accurate navigation depends on a network of neural systems that encode the moment-to-moment changes in an animal's directional orientation and location in space. Within this navigation system are head direction (HD) cells, which fire persistently when an animal's head is pointed in a particular direction (Sharp et al., 2001a; Taube, 2007). HD cells are widely thought to underlie an animal's sense of spatial orientation, and research over the last 25+ years has revealed that this robust spatial signal is widely distributed across subcortical and cortical limbic areas. The purpose of the present review is to summarize some of the recent studies arguing that the origin of the HD signal resides subcortically, specifically within the reciprocal connections of the dorsal tegmental and lateral mammillary nuclei. Furthermore, we review recent work identifying "bursting" cellular activity in the HD cell circuit after lesions of the vestibular system, and relate these observations to the long held view that attractor network mechanisms underlie HD signal generation. Finally, we summarize anatomical and physiological work suggesting that this attractor network architecture may reside within the tegmento-mammillary circuit.
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http://dx.doi.org/10.3389/fncir.2012.00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308332PMC
October 2012