MESSIER, C. AND N. M. WHITE. Contingent and non-contingent actions of sucrose and saccharin reinf... more MESSIER, C. AND N. M. WHITE. Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preference and memory. PHYSIOL BEHAV 32(2) 195-203, 1984.--Preference curves were generated by comparing 14 concentrations each of sucrose and saccharin in a 20-minute test in which rats were presented with a choice of a sweet solution and water. The most preferred concentration and one concentration above and one below the most preferred for both substances were studied further. The sucrose and saccharin solutions were contingently paired with novel flavors in a conditioned taste preference (CTP) paradigm. All of the sweet solutions enhanced the animals' subsequent conditioned taste preferences for the flavors. The lack of difference between the effects of the solutions in this paradigm suggest that they had similar rewarding values and that CTP's are established mainly on the basis of taste cues. In another experiment, post-training ingestion of sucrose solutions, injection of glucose and, to a much lesser extent, ingestion of saccharin solutions retroactively and non-contingently improved retention of a previously formed, classically conditioned association. The results indicated that this effect was mainly due to the post-ingestional effects of the sucrose solutions, although taste factors also had a slight influence. This series of experiments parallels previous findings with self-stimulation as the reinforcer. The results support the hypothesis that reinforcers have a dual action on behavior: the elicitation of affective states that, when paired with environmental stimuli, can influence future behavior towards those stimuli; and a non-contingent retroactive enhancement of retention of previously formed associations.
The memory-improving action of post-training, noncontingent injections of glucose was investigate... more The memory-improving action of post-training, noncontingent injections of glucose was investigated in a series of experiments which examined the effects of several substances that interact with glucose metabolism on the retention of a conditioned emotional response and on blood glucose levels in male hooded rats. Although post-training glucose injections of 1, 2, and 3 g/kg all produced similar increases in blood glucose, only 2 g/kg improved retention, suggesting that attainment of a particular blood glucose level is not critical for memory improvement. Post-training injections of a range of insulin doses (0.25-4 IU/kg) failed to affect retention. Post-training injection of fructose (the same doses as were used for glucose) had no effect on blood glucose levels and, as with glucose, only the 2 g/kg dose improved retention. This finding suggests that blood glucose levels are not critical for the memory-improving effect, that glucose and fructose may act on the same substrate and, because fructose does not act directly on the brain, it raises the possibility that both substances act peripherally. Posttraining injections of 2-deoxyglucose and 3-O-methylglucose both improved retention. The fact that these mostly nonmetabolized glucose analogs were effective suggests that the memory-improving action of glucose may depend on the activation of a membrane glucose transport mechanism. The implications of the possible action of glucose on peripheral transport mechanisms for understanding the effect of reinforcers on memory are discussed. (1984) showed that post-trial, noncontingent ingestion of sucrose solutions or subcutaneous injection of glucose solutions could retroactively improve retention. The present experiments extend these previous findings by demonstrating that a specific physiological event such as an interaction with glucose transport could be the basis for the improvement in retention observed with glucose injections and sucrose ingestion.
Various types of learning, including operant conditioning, induce an increase in cellular activat... more Various types of learning, including operant conditioning, induce an increase in cellular activation concomitant with an increase in local cerebral glucose utilization (LCGU). This increase is mediated by increased cerebral blood flow or changes in brain capillary density and diameter. Because glucose transporters are ultimately responsible for glucose uptake, we examined their plastic expression in response to cellular activation. In vitro and in vivo studies have demonstrated that cerebral glucose transporter 1 (GLUT1) expression consistently parallels changes in LCGU. The present study is the first to investigate the effect of memory processing on glucose transporters expression. Changes in GLUT expression produced by training in an operant conditioning task were measured in the brain of CD1 mice. Using semi-quantitative immunohistochemistry, Western blot and real time RT-PCR the cerebral GLUT1 and GLUT3 expression was quantified immediately, 220 min and 24 h following training. Relative to sham-trained and naive controls, operant conditioning training induced an immediate increase in GLUT1 immunoreactivity level in the hippocampus CA1 pyramidal cells as well as in the sensorimotor cortex. At longer post-learning delays, GLUT1 immunoreactivity decreased in the sensorimotor cortex and putamen. Parallel to the changes in protein levels, hippocampus GLUT1 mRNA level also increased immediately following learning. No effect of learning was found on hippocampal GLUT3 protein or mRNA expression. Measures of changes in glucose transporters expression present a link between cellular activation and glucose metabolism. The learning-induced localized increases in GLUT1 protein as well as mRNA levels observed in the present study confirm the previous findings that GLUT1 expression is plastic and respond to changes in cellular metabolic demands.
Ins2 C96Y Akita mice represent a model of spontaneous early-onset diabetes mellitus, expressing a... more Ins2 C96Y Akita mice represent a model of spontaneous early-onset diabetes mellitus, expressing a mutant non-functional isoform of insulin. These mice are characterized by a reduced number of pancreatic  cells resulting in hypoinsulinemia and hyperglycemia. We obtained longitudinal measures of morning fasting blood glucose levels and gait performance. Sciatic nerve electrophysiology was also performed and the performance of these mice on spatial memory tasks was measured longitudinally. We observed a progressive increase in fasting blood glucose levels that was proportionally associated with increased gait disturbances. Diabetes induced a decrease in the sensory nerve conduction velocity up to the age of 40 weeks. Glucose transporter (GLUT) 3 levels were reduced in the hippocampus of the aged Ins2 C96Y Akita mice. However, we failed to detect any significant deficits during reference, reversal or probe tests in the Morris water maze or in a spontaneous alternation task up to the age of 34 weeks old. We found that, up to the age of 34 weeks old, uncontrolled hyperglycemia produced peripheral neuropathy and reduced hippocampal GLUT3 levels in the absence of any effect on spatial memory processing.
Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, partic... more Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, particularly, atherosclerosis of large blood vessels. Together with other risk factors such as dyslipidemia, atherosclerosis increases the risk for coronary heart disease and stroke. Most studies that have examined the impact of type 2 diabetes and other heart disease risk factors on cognitive functions do not provide evidence that heart disease risk factors (with the possible exception of triglycerides) further increase the likelihood of observing cognitive deficits in diabetic patients. However, none of these studies used imaging techniques to evaluate atherosclerosis or evidence of cerebrovascular disease, such as infarctions. The few studies that have included brain imaging suggest that evidence of cerebrovascular disease further increases the risk for dementia in diabetic patients. The results of longitudinal studies suggest that diabetes is an independent risk factor for cognitive decline and dementia. The pattern of neuropsychological performance observed in type 2 diabetic patients appears to be the result of multiple interacting processes developing over time. In addition to the detrimental effects of protracted impaired glucose regulation on the central nervous system, type 2 diabetes pathology also encompasses the detrimental effects of associated complications such as cerebrovascular disease, which is likely the main cause of the observed processing speed/reaction time decrements. [Neurol Res 2004; 26: 567-572]
Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiologica... more Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia and Alzheimer's disease. The current diagnostic practices that typically exclude from an AD diagnostic any patients with suspected vascular dementia, makes it very hard to resolve this issue and likely result in an underestimation of the number of people with Alzheimer's disease and diabetes. When people with cerebrovascular disease are included, diabetes is associated with an increased risk for Alzheimer's disease. Studies that have examined peripheral glucoregulation in Alzheimer's disease are not consistent but some show small to moderate impairments in insulin sensitivity. One recent study suggest that in people that have both diabetes and an ApoE4 allele, the risk of developing Alzheimer's disease is more than double the risk of people with an ApoE4 allele without diabetes. Although diabetes does not produce any of the usual brain pathology associated with Alzheimer's disease, one study has shown that diabetes dramatically increases the amyloid deposition and neurofibrillary tangles in people with the ApoE4 genotype. Taken together, the data available suggest that diabetes is probably a risk factor for Alzheimer's disease mainly through the cerebrovascular disease diabetes causes. In people with other risk factors such as ApoE4 allele, diabetes appears to lead to a more dramatic increase in Alzheimer's disease pathology. q
MESSIER, C., M. GAGNON AND V. KNOTT. Effect of glucose and peripheral glucose regulation on memor... more MESSIER, C., M. GAGNON AND V. KNOTT. Effect of glucose and peripheral glucose regulation on memory in the elderly. NEUROBIOL AGING 18(3) 297-304, 1997.-We examined changes in cognitive performance following the intake of a glucose (50 g) or saccharin solution (50 mg) in fasted elderly male and female subjects. Glucoregulation was estimated using a recovery index that was used to categorize subjects within each sex as having poor or good recovery. Elderly males with poor recovery performed worse on the Logical Memory subtest of the Wechsler Memory Scale and on the free recall or recognition parts of a word list task. The item analysis of the Logical Memory subtest showed that male subjects with poor recovery remembered less of the last items of the paragraphs after drinking saccharin while the first items were equally remembered by both groups. Glucose improved the performance of the males with good regulation for the first seven items while the performance of males with poor regulation decreased for those items under glucose. The present study support the notion that peripheral glucoregulation can influence memory performance and that the ingestion of glucose can influence certain aspects of memory functioning.
Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests t... more Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age ϭ 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
Journal of Clinical and Experimental Neuropsychology, 2004
The present review integrates findings of published studies that have evaluated the cognitive fun... more The present review integrates findings of published studies that have evaluated the cognitive function of treated and untreated type 2 diabetic patients and provides a detailed overview of the neuropsychological assessments conducted. Cognitive deficits are observed in older people with glucose intolerance or untreated diabetes but these deficits appear to be attenuated by treatments that improve glycemic control. Cognitive decrements in treated type 2 diabetic patients are most consistently observed on measures of verbal memory (35% of the measures) and processing speed (45% of the measures) while preserved function is observed on measures of visuospatial, attention, semantic and language function. Some studies suggest that deficits in cognitive functions are associated with poorer glycemic control. A number of other factors, such as depression, cardiovascular and cerebrovascular disease, increase these deficits. We conclude that, in diabetic patients who achieve and maintain good glycemic control, type 2 diabetes only has a small impact on cognitive functions before the age of 70 years. However, early onset of type 2 diabetes, poor glycemic control and the presence of micro-and macrovascular disease may interact to produce early cognitive deficits. In older adults (70 years and over), diabetes likely interacts with other dementing processes such as vascular disease and Alzheimer's disease to hasten cognitive decline.
The present single-case study examined functional brain imaging patterns in a participant that re... more The present single-case study examined functional brain imaging patterns in a participant that reported being able, at will, to produce somatosensory sensations that are experienced as her body moving outside the boundaries of her physical body all the while remaining aware of her unmoving physical body. We found that the brain functional changes associated with the reported extra-corporeal experience (ECE) were different than those observed in motor imagery. Activations were mainly left-sided and involved the left supplementary motor area and supramarginal and posterior superior temporal gyri, the last two overlapping with the temporal parietal junction that has been associated with out-of-body experiences. The cerebellum also showed activation that is consistent with the participant's report of the impression of movement during the ECE. There was also left middle and superior orbital frontal gyri activity, regions often associated with action monitoring. The results suggest that the ECE reported here represents an unusual type of kinesthetic imagery.
MESSIER, C. AND N. M. WHITE. Contingent and non-contingent actions of sucrose and saccharin reinf... more MESSIER, C. AND N. M. WHITE. Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preference and memory. PHYSIOL BEHAV 32(2) 195-203, 1984.--Preference curves were generated by comparing 14 concentrations each of sucrose and saccharin in a 20-minute test in which rats were presented with a choice of a sweet solution and water. The most preferred concentration and one concentration above and one below the most preferred for both substances were studied further. The sucrose and saccharin solutions were contingently paired with novel flavors in a conditioned taste preference (CTP) paradigm. All of the sweet solutions enhanced the animals' subsequent conditioned taste preferences for the flavors. The lack of difference between the effects of the solutions in this paradigm suggest that they had similar rewarding values and that CTP's are established mainly on the basis of taste cues. In another experiment, post-training ingestion of sucrose solutions, injection of glucose and, to a much lesser extent, ingestion of saccharin solutions retroactively and non-contingently improved retention of a previously formed, classically conditioned association. The results indicated that this effect was mainly due to the post-ingestional effects of the sucrose solutions, although taste factors also had a slight influence. This series of experiments parallels previous findings with self-stimulation as the reinforcer. The results support the hypothesis that reinforcers have a dual action on behavior: the elicitation of affective states that, when paired with environmental stimuli, can influence future behavior towards those stimuli; and a non-contingent retroactive enhancement of retention of previously formed associations.
The memory-improving action of post-training, noncontingent injections of glucose was investigate... more The memory-improving action of post-training, noncontingent injections of glucose was investigated in a series of experiments which examined the effects of several substances that interact with glucose metabolism on the retention of a conditioned emotional response and on blood glucose levels in male hooded rats. Although post-training glucose injections of 1, 2, and 3 g/kg all produced similar increases in blood glucose, only 2 g/kg improved retention, suggesting that attainment of a particular blood glucose level is not critical for memory improvement. Post-training injections of a range of insulin doses (0.25-4 IU/kg) failed to affect retention. Post-training injection of fructose (the same doses as were used for glucose) had no effect on blood glucose levels and, as with glucose, only the 2 g/kg dose improved retention. This finding suggests that blood glucose levels are not critical for the memory-improving effect, that glucose and fructose may act on the same substrate and, because fructose does not act directly on the brain, it raises the possibility that both substances act peripherally. Posttraining injections of 2-deoxyglucose and 3-O-methylglucose both improved retention. The fact that these mostly nonmetabolized glucose analogs were effective suggests that the memory-improving action of glucose may depend on the activation of a membrane glucose transport mechanism. The implications of the possible action of glucose on peripheral transport mechanisms for understanding the effect of reinforcers on memory are discussed. (1984) showed that post-trial, noncontingent ingestion of sucrose solutions or subcutaneous injection of glucose solutions could retroactively improve retention. The present experiments extend these previous findings by demonstrating that a specific physiological event such as an interaction with glucose transport could be the basis for the improvement in retention observed with glucose injections and sucrose ingestion.
Various types of learning, including operant conditioning, induce an increase in cellular activat... more Various types of learning, including operant conditioning, induce an increase in cellular activation concomitant with an increase in local cerebral glucose utilization (LCGU). This increase is mediated by increased cerebral blood flow or changes in brain capillary density and diameter. Because glucose transporters are ultimately responsible for glucose uptake, we examined their plastic expression in response to cellular activation. In vitro and in vivo studies have demonstrated that cerebral glucose transporter 1 (GLUT1) expression consistently parallels changes in LCGU. The present study is the first to investigate the effect of memory processing on glucose transporters expression. Changes in GLUT expression produced by training in an operant conditioning task were measured in the brain of CD1 mice. Using semi-quantitative immunohistochemistry, Western blot and real time RT-PCR the cerebral GLUT1 and GLUT3 expression was quantified immediately, 220 min and 24 h following training. Relative to sham-trained and naive controls, operant conditioning training induced an immediate increase in GLUT1 immunoreactivity level in the hippocampus CA1 pyramidal cells as well as in the sensorimotor cortex. At longer post-learning delays, GLUT1 immunoreactivity decreased in the sensorimotor cortex and putamen. Parallel to the changes in protein levels, hippocampus GLUT1 mRNA level also increased immediately following learning. No effect of learning was found on hippocampal GLUT3 protein or mRNA expression. Measures of changes in glucose transporters expression present a link between cellular activation and glucose metabolism. The learning-induced localized increases in GLUT1 protein as well as mRNA levels observed in the present study confirm the previous findings that GLUT1 expression is plastic and respond to changes in cellular metabolic demands.
Ins2 C96Y Akita mice represent a model of spontaneous early-onset diabetes mellitus, expressing a... more Ins2 C96Y Akita mice represent a model of spontaneous early-onset diabetes mellitus, expressing a mutant non-functional isoform of insulin. These mice are characterized by a reduced number of pancreatic  cells resulting in hypoinsulinemia and hyperglycemia. We obtained longitudinal measures of morning fasting blood glucose levels and gait performance. Sciatic nerve electrophysiology was also performed and the performance of these mice on spatial memory tasks was measured longitudinally. We observed a progressive increase in fasting blood glucose levels that was proportionally associated with increased gait disturbances. Diabetes induced a decrease in the sensory nerve conduction velocity up to the age of 40 weeks. Glucose transporter (GLUT) 3 levels were reduced in the hippocampus of the aged Ins2 C96Y Akita mice. However, we failed to detect any significant deficits during reference, reversal or probe tests in the Morris water maze or in a spontaneous alternation task up to the age of 34 weeks old. We found that, up to the age of 34 weeks old, uncontrolled hyperglycemia produced peripheral neuropathy and reduced hippocampal GLUT3 levels in the absence of any effect on spatial memory processing.
Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, partic... more Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, particularly, atherosclerosis of large blood vessels. Together with other risk factors such as dyslipidemia, atherosclerosis increases the risk for coronary heart disease and stroke. Most studies that have examined the impact of type 2 diabetes and other heart disease risk factors on cognitive functions do not provide evidence that heart disease risk factors (with the possible exception of triglycerides) further increase the likelihood of observing cognitive deficits in diabetic patients. However, none of these studies used imaging techniques to evaluate atherosclerosis or evidence of cerebrovascular disease, such as infarctions. The few studies that have included brain imaging suggest that evidence of cerebrovascular disease further increases the risk for dementia in diabetic patients. The results of longitudinal studies suggest that diabetes is an independent risk factor for cognitive decline and dementia. The pattern of neuropsychological performance observed in type 2 diabetic patients appears to be the result of multiple interacting processes developing over time. In addition to the detrimental effects of protracted impaired glucose regulation on the central nervous system, type 2 diabetes pathology also encompasses the detrimental effects of associated complications such as cerebrovascular disease, which is likely the main cause of the observed processing speed/reaction time decrements. [Neurol Res 2004; 26: 567-572]
Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiologica... more Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia and Alzheimer's disease. The current diagnostic practices that typically exclude from an AD diagnostic any patients with suspected vascular dementia, makes it very hard to resolve this issue and likely result in an underestimation of the number of people with Alzheimer's disease and diabetes. When people with cerebrovascular disease are included, diabetes is associated with an increased risk for Alzheimer's disease. Studies that have examined peripheral glucoregulation in Alzheimer's disease are not consistent but some show small to moderate impairments in insulin sensitivity. One recent study suggest that in people that have both diabetes and an ApoE4 allele, the risk of developing Alzheimer's disease is more than double the risk of people with an ApoE4 allele without diabetes. Although diabetes does not produce any of the usual brain pathology associated with Alzheimer's disease, one study has shown that diabetes dramatically increases the amyloid deposition and neurofibrillary tangles in people with the ApoE4 genotype. Taken together, the data available suggest that diabetes is probably a risk factor for Alzheimer's disease mainly through the cerebrovascular disease diabetes causes. In people with other risk factors such as ApoE4 allele, diabetes appears to lead to a more dramatic increase in Alzheimer's disease pathology. q
MESSIER, C., M. GAGNON AND V. KNOTT. Effect of glucose and peripheral glucose regulation on memor... more MESSIER, C., M. GAGNON AND V. KNOTT. Effect of glucose and peripheral glucose regulation on memory in the elderly. NEUROBIOL AGING 18(3) 297-304, 1997.-We examined changes in cognitive performance following the intake of a glucose (50 g) or saccharin solution (50 mg) in fasted elderly male and female subjects. Glucoregulation was estimated using a recovery index that was used to categorize subjects within each sex as having poor or good recovery. Elderly males with poor recovery performed worse on the Logical Memory subtest of the Wechsler Memory Scale and on the free recall or recognition parts of a word list task. The item analysis of the Logical Memory subtest showed that male subjects with poor recovery remembered less of the last items of the paragraphs after drinking saccharin while the first items were equally remembered by both groups. Glucose improved the performance of the males with good regulation for the first seven items while the performance of males with poor regulation decreased for those items under glucose. The present study support the notion that peripheral glucoregulation can influence memory performance and that the ingestion of glucose can influence certain aspects of memory functioning.
Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests t... more Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age ϭ 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
Journal of Clinical and Experimental Neuropsychology, 2004
The present review integrates findings of published studies that have evaluated the cognitive fun... more The present review integrates findings of published studies that have evaluated the cognitive function of treated and untreated type 2 diabetic patients and provides a detailed overview of the neuropsychological assessments conducted. Cognitive deficits are observed in older people with glucose intolerance or untreated diabetes but these deficits appear to be attenuated by treatments that improve glycemic control. Cognitive decrements in treated type 2 diabetic patients are most consistently observed on measures of verbal memory (35% of the measures) and processing speed (45% of the measures) while preserved function is observed on measures of visuospatial, attention, semantic and language function. Some studies suggest that deficits in cognitive functions are associated with poorer glycemic control. A number of other factors, such as depression, cardiovascular and cerebrovascular disease, increase these deficits. We conclude that, in diabetic patients who achieve and maintain good glycemic control, type 2 diabetes only has a small impact on cognitive functions before the age of 70 years. However, early onset of type 2 diabetes, poor glycemic control and the presence of micro-and macrovascular disease may interact to produce early cognitive deficits. In older adults (70 years and over), diabetes likely interacts with other dementing processes such as vascular disease and Alzheimer's disease to hasten cognitive decline.
The present single-case study examined functional brain imaging patterns in a participant that re... more The present single-case study examined functional brain imaging patterns in a participant that reported being able, at will, to produce somatosensory sensations that are experienced as her body moving outside the boundaries of her physical body all the while remaining aware of her unmoving physical body. We found that the brain functional changes associated with the reported extra-corporeal experience (ECE) were different than those observed in motor imagery. Activations were mainly left-sided and involved the left supplementary motor area and supramarginal and posterior superior temporal gyri, the last two overlapping with the temporal parietal junction that has been associated with out-of-body experiences. The cerebellum also showed activation that is consistent with the participant's report of the impression of movement during the ECE. There was also left middle and superior orbital frontal gyri activity, regions often associated with action monitoring. The results suggest that the ECE reported here represents an unusual type of kinesthetic imagery.
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Papers by Claude Messier