Biomedical subjects

Robert J Sutherland

Publications and source records attributed to Robert J Sutherland.

At least 19 recordsLinked to original sources

PubMed2007

Adrenalectomy-induced granule cell degeneration in the hippocampus causes spatial memory deficits that are not reversed by chronic treatment with corticosterone or fluoxetine.

Long-term adrenalectomy (ADX) causes a nearly complete and selective loss of granule cells in the dentate gyrus (DG) of the hippocampus. Previously, learning and memory deficits have been observed following ADX-induced granule cell degeneration for tasks that require the hippocampus. Our objective here was to determine whether corticosterone (CORT) replacement and treatment with the neurogenic compound fluoxetine could reverse behavioral deficits after ADX. We trained ADX and control rats in a moving, hidden platform version of the Morris water task before chronic administration (6 weeks) of CORT and either fluoxetine or vehicle. After treatment, all rats were retested in the Morris water task. Brains were labeled for the endogenous neurogenic markers Ki67 and doublecortin. Here we provide evidence that neurogenesis persists at a normal rate in the hippocampus after long-term ADX. After 8 weeks of CORT and fluoxetine administration, ADX-fluoxetine rats did not differ significantly compared to ADX-vehicle rats receiving CORT or compared to control rats in the number of Ki67 or doublecortin labeled cells. ADX-fluoxetine rats also did not significantly differ from ADX-vehicle rats in regards to granule cell layer thickness. Our results indicate that long-term ADX is associated with impaired spatial ability in the Morris water task and that neither chronic treatment with CORT, nor with CORT and fluoxetine are capable of altering the Morris water task deficit.

Adrenalectomy↗

PubMed2006

Hippocampal evoked potentials in novel environments: a behavioral clamping method.

The hippocampus is involved in the detection of novelty and is essential for certain forms of learning about environmental events and relationships. The cellular and molecular mechanisms of one form of hippocampal synaptic plasticity, long-term potentiation (LTP), are thought to overlap significantly with the neural mechanisms of learning. In this study changes in hippocampal synaptic efficacy were measured in awake, freely behaving rats during exploration of novel environments. Because hippocampal physiology is modulated by on-going behavior, evoked potentials collected during Type 1 versus Type 2 behavior were evaluated separately. The effect of prior LTP induction at perforant path-dentate synapses on exploration-induced changes was evaluated. The results show that exploration causes an increase in population spike amplitude with no change in excitatory postsynaptic potential during Type 1 behavior that lasts longer than 5 min. Prior induction of hippocampal LTP occludes the change induced by exploration. This change is not likely to be due to a reduction of GABAergic inhibition induced by novelty.

Animals↗

PubMed2006

Interleukin-1beta induces anorexia but not spatial learning and memory deficits in the rat.

Sickness behaviors are a set of adaptive responses to infection that include lethargy, anorexia, and, of direct relevance to this work, learning and memory impairments. The proinflammatory cytokine, interleukin-1 beta (IL-1beta) has been proposed as the primary peripheral mediator of these sickness behaviors, though few studies have investigated the effects of peripheral IL-1beta on learning and memory. We used three different versions of the Morris water task (Morris water task), a spatial learning and memory task, to separately assess the effects of peripheral IL-1beta on acquisition, consolidation, and retention of spatial location information. Using a dose that induced anorexia, assessed as a significant reduction in body weight, we observed no performance impairments in the IL-1beta-treated rats across the different versions of the task, suggesting that peripheral IL-1beta alone is insufficient to induce spatial learning and memory impairments in the rat. The observed dissociation of anorexia and cognitive dysfunction suggests that, either spatial learning and memory are not principal components of the sickness response, or cognitive dysfunction requires different or additional peripheral mediator(s).

Analysis of Variance↗

PubMed2006

Cognitive deficits in rats after forebrain cholinergic depletion are reversed by a novel NO mimetic nitrate ester.

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons.

Acetylcholine↗

PubMed2006

Growth points in research on memory and hippocampus.

We present an overview of two of our on-going projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions.

Amnesia, Retrograde↗

PubMed2005

Seahorse wins all races: hippocampus participates in both linear and non-linear visual discrimination learning.

Consistent with configural/conjunctive theories of the hippocampus, we report that rats trained on the non-linear transverse patterning discrimination problem (A+ versus B-, B+ versus C-, and C+ versus A) displayed retrograde amnesia when the hippocampus was later damaged. They also failed to relearn the solution to this problem. Damage to the hippocampus following training also produced retrograde amnesia in rats trained on a set of elemental discrimination problems (A+ versus B-, C+ versus D-, and E+ versus F-) that could be solved based on the associative strengths of the individual choice cues. However, in contrast to transverse patterning, rats easily relearned and retained these elemental problems and learned a new set of elemental problems after the damage. These results support two theoretical conclusions: (a) elemental discriminations can be learned by both a system that depends on the hippocampus and a system that does not require the hippocampus, and (b) in the intact animal these two systems competitively interact with the hippocampal-dependent system inhibiting memory formation by the extra-hippocampal system.

Animals↗

PubMed2005

Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation.

Sickness behaviour is an adaptive response to infection that includes lethargy, anorexia and of direct relevance to this work, learning and memory impairments. It has been suggested that proinflammatory cytokines may disrupt learning and memory by interfering with memory consolidation [C.R. Pugh, K. Kumagawa, M. Fleshner, L.R. Watkins, S.F. Maier, J.R. Rudy, Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning, Brain Behav. Immun. 12 (1998) 212-229]. We tested whether systemic interleukin-1beta is sufficient to induce impairments in memory consolidation by comparing the effects of post-learning administration of interleukin-1beta with, the potent endotoxin, lipopolysaccharide; and saline, on retention of conditioned fear of a context. We administered an acute intraperitoneal injection of lipopolysaccharide, interleukin-1beta or saline immediately following a single conditioning episode in which rats received two tone-shock pairings. Two days following the learning episode, animals were tested for strength of conditioned responding to both the context and tone. Lipopolysaccharide-injected animals, but not interleukin-1beta-injected animals, exhibited less conditioned fear of context compared to saline-treated controls. All groups showed similar conditioned fear of tone. Our results suggest that systemic interleukin-1beta is not sufficient to disrupt memory consolidation, but rather, the synergistic actions of the proinflammatory cytokines released by lipopolysaccharide are required to disrupt memory consolidation.

Acoustic Stimulation↗

PubMed2005

Virtual navigation in humans: the impact of age, sex, and hormones on place learning.

Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age >60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.

Adult↗

PubMed2005

The aging hippocampus: navigating between rat and human experiments.

Aging is associated with impairments in certain aspects of cognition, especially learning and memory. The hippocampus is a structure intimately involved with certain aspects of learning and memory, and is especially vulnerable to the course of aging. Recent findings, primarily from cognitive, magnetic resonance imaging, and magnetic resonance spectroscopy studies, but also briefly physiology and neurogenesis work, are reviewed. Evidence suggests that age-related impairment of hippocampus-dependent cognition is associated with changes on various levels of investigation in both humans and non-human animals. Also, the emphasis is placed on tasks and techniques that can be used to test both non-human and human animals in an attempt to bridge the gulf between the vast bodies of knowledge about the hippocampus in different species. To the extent that changes with normal aging are understood, they may aid in diagnosis, prevention, and/or treatment of age-related learning and memory deficits in both normal and pathological aging. In addition, studies of the aging hippocampus may have a side-effect in leading to a better understanding of the mechanisms that underlie learning and memory in general.

Aging↗

PubMed2004

Rodent spatial navigation: at the crossroads of cognition and movement.

Tasks that measure spatial learning and navigation have become central to contemporary research programs concerned with identifying the neurobiological bases of learning and memory. Although the past three decades have seen an explosion of research reports on rodent navigation, only a small proportion of this research has been directly aimed at identifying the constituent psychological and behavioral processes involved in navigation. Such efforts are critical for establishing a complete neuroscientific explanation of spatial behavior and navigation, however, the majority of these research efforts have focused on identifying a single behavioral dissociation (e.g. place learning vs cued navigation). Experimental comparisons limited to only two possible alternatives can lead to erroneous or otherwise incomplete conclusions regarding how animals navigate. Because multiple sources of information may come to bear on an animal's behavior in spatial tasks, consideration of these sources and their interaction may avoid certain pitfalls inherent in the single dissociation approach. We offer a descriptive model of rodent navigation which includes three important dimensions: reference frame, information, and movement control. A variety of extant behavioral and neurophysiological data that support the basic utility of this conceptual framework are discussed.

Animals↗

PubMed2004

Damage to the hippocampal formation does not disrupt representational flexibility as measured by a novelty transfer test.

Rats were trained on a set of visual discrimination problems (A+B-, C+D-, E+F-). The choice stimuli were then recombined to create novel combination tests (A+D-, C+F-, E+B-). Rats with damage to the hippocampus showed perfect transfer on these tests, always choosing A, C, and E, but were not able to learn the spatial location of the platform, indicating that damage to the hippocampus was functional. These results question the generality of H. Eichenbaum, P. Mathews, and N. J. Cohen's (1989) findings and the theoretical claim that choice behavior with novel combinations is based on inferential-like hippocampus-dependent processes (H. Eichenbaum, 1992). They are consistent with the view that simple associative processes guide choice behavior in animals with hippocampal damage that are confronted with novel combinations.

Animals↗

PubMed2003

Functional organization of adult motor cortex is dependent upon continued protein synthesis.

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.

Age Factors↗

PubMed2003

Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task.

We employed a computerized (virtual) Morris water task (VMWT) to measure place learning and cued-navigation in eight adolescent males (9.5-16.5 years old) diagnosed with Fetal Alcohol Syndrome (FAS). Eight adolescent males matched for age and ethnicity with no history of prenatal alcohol exposure served as controls. Participants were trained to navigate to a hidden platform in a fixed location relative to a set of four conspicuous extramaze cues. After 20 hidden platform trials, a single no-platform probe trial was conducted, followed by 8 trials during which the platform was visible (cued-navigation). The FAS group traveled further than controls to navigate to the hidden platform during training. During the probe trial, controls navigated more directly to the platform region and persisted in searching where the platform had been more than the FAS group. Cued-navigation was comparable in both groups, suggesting that group differences in place learning were not attributable to visual-motor or motivational deficits in the FAS subjects. This pattern of impaired place learning and spared cued-navigation is similar to that reported in rats exposed to ethanol during periods of prenatal or early postnatal brain growth, as well as in animals with hippocampal damage.

Adolescent↗

PubMed2003

The aging hippocampus: cognitive, biochemical and structural findings.

Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampus-dependent cognition.

Adult↗

PubMed2002

Differential involvement of amygdala and hippocampus in responding to novel objects and contexts.

Different medial temporal lobe structures are involved in memory for different types of novel cues and novel relationships among familiar cues. We measured the behavior of rats with amygdala or hippocampal damage, when confronted with novelty in an incidental learning paradigm. We examined both direct and indirect measures of memory. Following habituation to an environment, proximal objects or distal cues were manipulated in several ways. We found that rats with hippocampal damage exhibited a deficit on direct measures of memory, but performed normally on all indirect measures. Rats with amygdala damage exhibited a deficit on a direct measure, and performed normally on an indirect measure, of memory for proximal object identity. Thus, the hippocampus may be necessary for success on direct measures of memory for distal cues and proximal objects and the relationships among them. Likewise, the amygdala may be necessary for success on some direct measures of memory, such as memory for aspects of proximal object identity. Neither the amygdala nor the hippocampus functions as a generalized novelty detection system. To the extent that we tap implicit and explicit knowledge using this paradigm, we suggest that in the rat, the amygdala and hippocampal systems are necessary for at least some types of explicit knowledge.

Amygdala↗

PubMed2002

Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task.

For nonhumans, it has been shown that the hippocampus (HPC) is critical for spatial memory. We tested patients with unilateral HPC resections on a virtual analogue of a classic spatial task to assess HPC functioning in nonhumans: the Morris water task. We found that when humans are required to use spatial cues to navigate to a hidden escape platform in a pool, patients with HPC resections display severe impairments in spatial navigation relative to age-matched controls and age-matched patients who have had extra-HPC resections. This effect occurred for every patient tested and was evident regardless of side of surgery. Hence, it is apparent across species and irrespective of which hemisphere is damaged that the human HPC is critical for spatial/relational memory.

Brain Damage, Chronic↗

PubMed2002

Human place learning in a virtual Morris water task: some important constraints on the flexibility of place navigation.

We investigated human place learning in a computerized version of the Morris water task (VMWT) under comparable conditions to those employed by Sutherland et al. (Sutherland et al. Psychobiology, 1987;15:48-57) with rats. Participants viewed a computer-generated environment and were trained to locate a hidden goal in one half of a circular pool (region 1). The opportunity to navigate in and view cues from region 2 was systematically varied during training. Participants were then started from region 2 to assess transfer. Accurate transfer performance was dependent upon prior experience viewing distal cues from region 2 while on a trajectory to the goal, a finding we interpret as inconsistent with the automatic formation and modification of a cognitive map (O'Keefe J, Nadel L. The Hippocampus as a cognitive map. Oxford, UK: Clarendon Press, 1978). Additionally, the transfer data reported here closely match the data obtained by Sutherland et al. with rats suggesting some generality in the principles involved in place learning.

Acoustic Stimulation↗

PubMed2002

A role for olfaction in object recognition by normal and hippocampal-damaged rats.

To examine how olfactory and visual factors affect object discriminations in rats with and without hippocampus damage, the authors trained Long-Evans rats on simple object discriminations. They then examined how these discriminations were affected by rotations of the objects, by coating the objects in a transparent acrylic coating, or by both rotating and coating the objects in acrylic. The rats displayed no impairments when the objects were only sprayed in acrylic, and they displayed minor impairments when the objects were rotated. However, when the objects were both rotated and acrylic coated, the rats displayed severe impairments. This suggests that the rats are solving the rotated-only phase based on surface features of the objects (probably odor) and not based on the visual information. Such species' biases for obtaining object information are important factors to consider when designing and interpreting visual memory experiments across species. There was no difference in performance between the rats with hippocampus damage and the sham rats, and this is consistent with the literature on similar tasks.

Animals↗