[Show abstract][Hide abstract] ABSTRACT: Behavior in the real world is rarely motivated by primary conditioned stimuli that have been directly associated with potent unconditioned reinforcers. Instead, motivation and choice behavior are driven by complex chains of higher-order associations that are only indirectly linked to intrinsic reward and often exert their influence outside awareness. Second-order conditioning (SOC)  is a basic associative-learning mechanism whereby stimuli acquire motivational salience by proxy, in the absence of primary incentives [2 and 3]. Memory-systems theories consider first-order conditioning (FOC) and SOC to be prime examples of hippocampal-independent nondeclarative memory [4 and 5]. Accordingly, neurobiological models of SOC focus almost exclusively on nondeclarative neural systems that support motivational salience and reward value. Transfer of value from a conditioned stimulus to a neutral stimulus is thought to require the basolateral amygdala [6 and 7] and the ventral striatum [2 and 3], but not the hippocampus. We developed a new paradigm to measure appetitive SOC of tones in rats. Hippocampal lesions severely impaired both acquisition and expression of SOC despite normal FOC. Unlike controls, rats with hippocampal lesions could not discriminate between positive and negative secondary conditioned tones, although they exhibited general familiarity with previously presented tones compared with new tones. Importantly, normal rats’ behavior, in contrast to that of hippocampal groups, also revealed different confidence levels as indexed by effort, a central characteristic of hippocampal relational memory. The results indicate, contrary to current systems models, that representations of intrinsic relationships between reward value, stimulus identity, and motivation require hippocampal mediation when these relationships are of a higher order.
[Show abstract][Hide abstract] ABSTRACT: Food combinations have been associated with lower incidence of Alzheimer’s disease (AD). We hypothesized that a combination whole-food diet (WFD) containing freeze-dried fish, vegetables and fruits would improve cognitive function in TgCRND8 mice by modulating brain insulin-signaling and neuroinflammation. Cognitive function was assessed by a comprehensive battery of tasks adapted to the Morris water maze. Unexpectedly, a ‘Diet x Transgene’ interaction was observed in which transgenic animals fed the WFD exhibited even worse cognitive function than their transgenic counterparts fed the control diet on tests of spatial memory (P<0.01) and strategic rule learning (P=0.034). These behavioural deficits coincided with higher hippocampal gene expression of tumor necrosis factor-α (P=0.013). There were no differences in cortical amyloid-β peptide species according to diet. These results indicate that a dietary profile identified from epidemiological studies exacerbated cognitive dysfunction and neuroinflammation in a mouse model of familial AD. We suggest that normally adaptive cellular responses to dietary phytochemicals were impaired by amyloid-beta deposition leading to increased oxidative stress, neuroinflammation, and behavioural deficits.
Neurobiology of Aging 08/2014; · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A well-documented dissociation between memory encoding and retrieval concerns the role of attention in the two processes. The typical finding is that divided attention (DA) during encoding impairs future memory, but retrieval is relatively robust to attentional manipulations. However, memory research in the past 20 years had demonstrated that retrieval is a memory-changing process, in which the strength and availability of information are modified by various characteristics of the retrieval process. Based on this logic, several studies examined the effects of DA during retrieval (Test 1) on a future memory test (Test 2). These studies yielded inconsistent results. The present study examined the role of memory consolidation in accounting for the after-effect of DA during retrieval. Initial learning required a classification of visual stimuli, and hence involved incidental learning. Test 1 was administered 24 hours after initial learning, and therefore required retrieval of consolidated information. Test 2 was administered either immediately following Test 1 or after a 24-hour delay. Our results show that the effect of DA on Test 2 depended on this delay. DA during Test 1 did not affect performance on Test 2 when it was administered immediately, but improved performance when Test 2 was given 24-hours later. The results are consistent with other findings showing long-term benefits of retrieval difficulty. Implications for theories of reconsolidation in human episodic memory are discussed.
PLoS ONE 03/2014; 9(3):e91309. · 3.53 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor.
The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity.
Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-flourouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus.
Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls.
Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Recent developments reveal that memories relying on the hippocampus are relatively resistant to interference, but sensitive to decay. The hippocampus is vital to recollection, a form of memory involving reinstatement of a studied item within its spatial-temporal context. An additional form of memory known as familiarity does not involve contextual reinstatement, but a feeling of acquaintance with the studied items. Familiarity depends more on extrahippocampal structures that do not have the properties promoting resistance to interference. These notions led to the novel hypothesis that the causes of forgetting depend on the memories' nature: memories depending on recollection are more vulnerable to decay than interference, whereas for memories depending on familiarity, the reverse is true. This review provides comprehensive evidence for this hypothesis.
Trends in Cognitive Sciences 11/2013; · 21.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review evaluates three current theories - Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace- Transformation (Winocur, Moscovitch, & Bontempi, 2010a) - in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed.
Neurobiology of Learning and Memory 10/2013; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relationship of higher order problem solving to basic neuropsychological processes likely depends on the type of problems to be solved. Well-defined problems (e.g., completing a series of errands) may rely primarily on executive functions. Conversely, ill-defined problems (e.g., navigating socially awkward situations) may, in addition, rely on medial temporal lobe (MTL) mediated episodic memory processes. Healthy young (N = 18; M = 19; SD = 1.3) and old (N = 18; M = 73; SD = 5.0) adults completed a battery of neuropsychological tests of executive and episodic memory function, and experimental tests of problem solving. Correlation analyses and age group comparisons demonstrated differential contributions of executive and autobiographical episodic memory function to well-defined and ill-defined problem solving and evidence for an episodic simulation mechanism underlying ill-defined problem solving efficacy. Findings are consistent with the emerging idea that MTL-mediated episodic simulation processes support the effective solution of ill-defined problems, over and above the contribution of frontally mediated executive functions. Implications for the development of intervention strategies that target preservation of functional independence in older adults are discussed. (JINS, 2013, 19, 1-10).
Journal of the International Neuropsychological Society 09/2013; · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:To determine the feasibility of recruitment and retention of healthy older adults and the effectiveness of an intervention designed to manage age-related executive changes.Design:A pilot randomized controlled trial.Setting:Research centre and participants' homes.Participants:Nineteen healthy, community dwelling older adults with complaints of cognitive difficulties and everyday problems, but no evidence of mild cognitive impairment, dementia or depression on objective testing.Interventions:Seventeen hours of group and individual training. Participants in the experimental arm received education about self-management, successful aging and an occupation-based meta-cognitive strategy-training program. Participants in the control arm received education about brain health and participated in cognitively stimulating exercises.Main measures:Changes on untrained, everyday life goals were identified using the Canadian Occupational Performance Measure. Generalization of benefits was measured using the Stanford Chronic Disease Questionnaire, general self-efficacy and changes in executive function (Delis-Kaplan Executive Function System Tower Test, Word Fluency and Trail-Making Test).Results:20% (19/96) of healthy older adults approached were eligible, consented and were enrolled in the study, 90% (17/19) were retained to three-month follow-up. Participants in the experimental arm reported significantly more improvement on untrained goals (11/22 compared with 9/46, χ(2)=4.92, p<0.05), maintenance of physical activity (p<0.05) and better preparation for doctors' visits (p<0.05) relative to the control group. There were no significant between group differences on objective measures of executive function.Conclusions:These data support the feasibility of a larger trial where a sample of 72 (36 participants in each arm) would be required to confirm or refute these findings.
[Show abstract][Hide abstract] ABSTRACT: In a prospective study of environmental factors affecting cognitive recovery from stroke, adult male rats were reared for 3 months in a high-risk (relatively isolated, low activity, high-fat diet, high-stress) or low-risk (social, healthy diet, low-stress, physically active) environment. They then received cognitive testing to assess various aspects of learning and memory before undergoing 2-vessel occlusion (2VO) of the carotid arteries, or sham surgery. Rats were returned to their respective environments post-operatively. Relative to pre-operative levels, 2VO rats exhibited significant cognitive losses that were consistently greater in the high-risk group than its low-risk counterpart. As well, the high-risk 2VO group was impaired, relative to the low-risk 2VO group on tests of new learning introduced post-operatively. At 3-month follow-up testing, rats that had undergone 2VO surgery exhibited further decline on some tests but recovery on others, with recovery generally slower in the high-risk 2VO group. The high-risk environment also affected rats' pre-operative cognitive performance and, to a lesser extent, their performance following sham surgery. Overall, the study shows that rats experiencing cerebral ischemia are more likely to experience severe cognitive deficits if exposed to a high-risk environment and recover more slowly than ischemic rats in a more favourable environment. The results underscore the importance of lifestyle factors with respect to the impact of stroke on cognition and in assessing prospects for recovery of function.
Behavioural brain research 06/2013; · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional magnetic resonance imaging (fMRI) was used to compare brain activity during the retrieval of coarse- and fine-grained spatial details and episodic details associated with a familiar environment. Long-time Toronto residents compared pairs of landmarks based on their absolute geographic locations (requiring either coarse or fine discriminations) or based on previous visits to those landmarks (requiring episodic details). An ROI analysis of the hippocampus showed that all three conditions activated the hippocampus bilaterally. Fine-grained spatial judgments recruited an additional region of the right posterior hippocampus, while episodic judgments recruited an additional region of the right anterior hippocampus, and a more extensive region along the length of the left hippocampus. To examine whole-brain patterns of activity, Partial Least Squares (PLS) analysis was used to identify sets of brain regions whose activity covaried with the three conditions. All three comparison judgments recruited the default mode network including the posterior cingulate/retrosplenial cortex, middle frontal gyrus, hippocampus, and precuneus. Fine-grained spatial judgments also recruited additional regions of the precuneus, parahippocampal cortex and the supramarginal gyrus. Episodic judgments recruited the posterior cingulate and medial frontal lobes as well as the angular gyrus. These results are discussed in terms of their implications for theories of hippocampal function and spatial and episodic memory.
[Show abstract][Hide abstract] ABSTRACT: Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model.
Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing.
The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment.
Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting.
Clinical Cancer Research 03/2012; 18(11):3112-21. · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ability to acquire and retain spatial memories in order to navigate in new environments is known to decline with age, but little is known about the effect of aging on representations of environments learned long ago, in the remote past. To investigate the status of remote spatial memory in old age, we tested healthy young and older adults on a variety of mental navigation tests based on a large-scale city environment that was very familiar to participants but rarely visited by the older adults in recent years. We show that whereas performance on a route learning test of new spatial learning was significantly worse in older than younger adults, performance was comparable or better in the older adults on mental navigation tests based on a well-known environment learned long ago. An exception was in the older adults' ability to vividly re-experience the well-known environment, and recognize and represent the visual details contained within it. The results are seen as analogous to the pattern of better semantic than episodic memory that has been found to accompany healthy aging.
Frontiers in Aging Neuroscience 01/2012; 4:25. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy has improved survival rates in patients with many of the common cancers. However, there is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years after the completion of chemotherapy. The etiology of this phenomenon is largely unknown, and currently there are no proven treatments. This article explores the clinical and preclinical literature on potential therapies for chemotherapy-induced cognitive impairments. Emerging results suggest that both pharmacological and behavioral approaches may offer patients some benefits. However, research in this area has been limited and is sometimes fraught with methodological flaws. As a result, it is difficult to draw definite conclusions regarding treatment efficacy. These issues, along with predictors of cognitive decline, are discussed in the light of possible interventions.
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation has been investigated as a treatment for memory disturbance but its mechanisms remain elusive. We show that anterior thalamic nucleus (ATN) stimulation administered to corticosterone-treated rats one month prior to testing improved performance on a delayed non-matching to sample task and increased hippocampal neurogenesis. In contrast, no behavioral changes were observed in animals that were tested a few days after surgery. Results of this study suggests that the behavioral effects of ATN stimulation in corticosterone-treated animals was likely dependent on long-term plastic changes, including the development of newly borne dentate gyrus cells of sufficient functional maturity.
[Show abstract][Hide abstract] ABSTRACT: Adjuvant cancer chemotherapy often causes cognitive impairment that can be long-lasting and adversely affect quality of life. The present study sought to determine if the cognitive enhancing drug, donepezil, can reduce cognitive impairment induced by a combination of methotrexate +5-fluorouracil, two drugs commonly used in cancer chemotherapy. Four groups of mice: (1) chemotherapy-only; (2) chemotherapy+donepezil; (3) saline-only; (4) saline+donepezil, were administered the following learning and memory tests: (1) standard spatial memory (SM); (2) non-spatial cued memory (CM); (3) non-matching-to-sample (NMTS) rule-learning; (4) delayed-NMTS (DNMTS). The chemotherapy-only group was impaired on the SM, NMTS, and DNMTS tasks. Chemotherapy-induced cognitive deficits were significantly reduced in the chemotherapy+donepezil group whose performance on some measures was very similar to that of the saline-only group. There was no evidence that donepezil improved the performance of saline-treated mice. The results confirm the adverse effects of chemotherapy on cognitive function and demonstrate that they can be ameliorated by donepezil, which is widely used to treat cognitive impairment in other clinical populations (e.g., Alzheimer's disease).