Quarterly Journal of Experimental Psychology Section B-comparative and Physiological Psychology, 1994
The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a s... more The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a series of 48 place-navigation trials in an open-field water-maze followed, either 3 days or 14 weeks later, by ibotenic acid lesions of the hippocampus (HPC) or subiculum (SUB), or by sham-surgery (SHAM). Two weeks after surgery they were given a retention test without a hidden escape platform. There was a significant decline in performance with time in the SHAM group, but with the 14-week SHAM group performing significantly better than chance levels, whereas both lesioned groups performed at chance at both retention intervals. All rats were then retrained for 24 trials. SHAM rats escaped rapidly within 2 trials, suggesting a reactivation of memory rather than relearning. The HPC groups were severely impaired during retraining, with a developing trend towards better performance in the 3-day group. After 24 trials of training with the escape platform placed in the opposite quadrant of the pool, this new location was learned successfully by SHAM and SUB rats, but not by HPC rats. These results indicate that selective hippocampal formation lesions can cause deficits in retrieval but do not reveal a time-dependent gradient of memory consolidation.
Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM)... more Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.▶ High fat feeding (HFF) reduces peripheral insulin sensitivity in out-bred rats. ▶ HFF impairs an operant, but not a watermaze, delayed matching to position task. ▶ Effect of HFF is greater when the rule is switched from matching to non-matching. ▶ Cognitive deficit correlates with insulin sensitivity but not body weight.
Rationale: Recent studies have implicated intracellular transduction pathways and neurotrophic fa... more Rationale: Recent studies have implicated intracellular transduction pathways and neurotrophic factors in the action of antidepressants. Adaptation in these pathways may ultimately affect electrophysiological and morphological properties of neurones. We have previously shown that repeated electroconvulsive stimulation, a safe and effective antidepressant treatment, has profound effects on hippocampal synaptic connectivity and plasticity in the rat. Here, we investigated whether these electrophysiological properties were shared by the chemical antidepressant, fluoxetine. Objectives: To compare the electrophysiological and cognitive effects of two very different antidepressant treatments: repeated electroconvulsive stimulation (rECS); and chronic administration of the serotonin specific re-uptake inhibitor (SSRI), fluoxetine. Methods: Rats were exposed to either rECS or daily fluoxetine administration for 15 days. The animals were then anaesthetised and dentate field excitatory post-synaptic potential (fEPSP) characteristics were measured before and after the induction of long-term potentiation (LTP) by high frequency perforant path stimulation. In a separate experiment, the effects of rECS and chronic fluoxetine administration on acquisition and retention of a spatial learning task in the Morris watermaze were determined. Results: Chronic fluoxetine administration and rECS produced equivalent increases in dentate fEPSP compared to respective control groups. LTP induction was attenuated in both groups. Spatial learning was, in contrast, unaffected by fluoxetine treatment but significantly impaired following rECS. Conclusions: Given that fluoxetine and rECS share antidepressant properties, but differ in their effects on learning and memory, we propose that the common effects on dentate connectivity and synaptic plasticity described here are more likely to relate to affective rather than cognitive function. This result is consistent with other experiments showing that a reduction in dentate connectivity correlates with stress susceptibility in animals.
The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest ... more The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest that the memory dysfunction may be caused by alterations in hippocampal synaptic efficacy [20]. In situ hybridization was used to examine the possible receptor mechanisms responsible for this effect. Repeated ECS markedly increased mRNA expression for the GluR1 subunit of the AMPA receptor, but not the NMDAR1A-G subtypes of the NMDA receptor, relative to control treatments. This effect was present 24 h after the last seizure and may be responsible for the expression of the ECS-induced increase in synaptic efficacy.
The effects of repeated, spaced, electroconvulsive stimulation (ECS) on rodent hippocampal synapt... more The effects of repeated, spaced, electroconvulsive stimulation (ECS) on rodent hippocampal synaptic plasticity was investigated in vivo. Long-term potentiation (LTP) was induced in intact rats using high-frequency perforant path stimulation, and measured by recording extracellular excitatory field potentials and population spikes evoked in the dentate gyrus by low-frequency stimulation before and after LTP induction. LTP induction appeared to be inhibited in animals which had received ECS. However, inspection and analysis of absolute excitatory postsynaptic potential and population spike size before LTP induction in ECS treated animals suggested that LTP may have already been induced as a consequence of seizure activity, reducing the degree to which further potentiation could be elicited experimentally.
Quarterly Journal of Experimental Psychology Section B-comparative and Physiological Psychology, 1994
The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a s... more The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a series of 48 place-navigation trials in an open-field water-maze followed, either 3 days or 14 weeks later, by ibotenic acid lesions of the hippocampus (HPC) or subiculum (SUB), or by sham-surgery (SHAM). Two weeks after surgery they were given a retention test without a hidden escape platform. There was a significant decline in performance with time in the SHAM group, but with the 14-week SHAM group performing significantly better than chance levels, whereas both lesioned groups performed at chance at both retention intervals. All rats were then retrained for 24 trials. SHAM rats escaped rapidly within 2 trials, suggesting a reactivation of memory rather than relearning. The HPC groups were severely impaired during retraining, with a developing trend towards better performance in the 3-day group. After 24 trials of training with the escape platform placed in the opposite quadrant of the pool, this new location was learned successfully by SHAM and SUB rats, but not by HPC rats. These results indicate that selective hippocampal formation lesions can cause deficits in retrieval but do not reveal a time-dependent gradient of memory consolidation.
Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM)... more Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.▶ High fat feeding (HFF) reduces peripheral insulin sensitivity in out-bred rats. ▶ HFF impairs an operant, but not a watermaze, delayed matching to position task. ▶ Effect of HFF is greater when the rule is switched from matching to non-matching. ▶ Cognitive deficit correlates with insulin sensitivity but not body weight.
Rationale: Recent studies have implicated intracellular transduction pathways and neurotrophic fa... more Rationale: Recent studies have implicated intracellular transduction pathways and neurotrophic factors in the action of antidepressants. Adaptation in these pathways may ultimately affect electrophysiological and morphological properties of neurones. We have previously shown that repeated electroconvulsive stimulation, a safe and effective antidepressant treatment, has profound effects on hippocampal synaptic connectivity and plasticity in the rat. Here, we investigated whether these electrophysiological properties were shared by the chemical antidepressant, fluoxetine. Objectives: To compare the electrophysiological and cognitive effects of two very different antidepressant treatments: repeated electroconvulsive stimulation (rECS); and chronic administration of the serotonin specific re-uptake inhibitor (SSRI), fluoxetine. Methods: Rats were exposed to either rECS or daily fluoxetine administration for 15 days. The animals were then anaesthetised and dentate field excitatory post-synaptic potential (fEPSP) characteristics were measured before and after the induction of long-term potentiation (LTP) by high frequency perforant path stimulation. In a separate experiment, the effects of rECS and chronic fluoxetine administration on acquisition and retention of a spatial learning task in the Morris watermaze were determined. Results: Chronic fluoxetine administration and rECS produced equivalent increases in dentate fEPSP compared to respective control groups. LTP induction was attenuated in both groups. Spatial learning was, in contrast, unaffected by fluoxetine treatment but significantly impaired following rECS. Conclusions: Given that fluoxetine and rECS share antidepressant properties, but differ in their effects on learning and memory, we propose that the common effects on dentate connectivity and synaptic plasticity described here are more likely to relate to affective rather than cognitive function. This result is consistent with other experiments showing that a reduction in dentate connectivity correlates with stress susceptibility in animals.
The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest ... more The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest that the memory dysfunction may be caused by alterations in hippocampal synaptic efficacy [20]. In situ hybridization was used to examine the possible receptor mechanisms responsible for this effect. Repeated ECS markedly increased mRNA expression for the GluR1 subunit of the AMPA receptor, but not the NMDAR1A-G subtypes of the NMDA receptor, relative to control treatments. This effect was present 24 h after the last seizure and may be responsible for the expression of the ECS-induced increase in synaptic efficacy.
The effects of repeated, spaced, electroconvulsive stimulation (ECS) on rodent hippocampal synapt... more The effects of repeated, spaced, electroconvulsive stimulation (ECS) on rodent hippocampal synaptic plasticity was investigated in vivo. Long-term potentiation (LTP) was induced in intact rats using high-frequency perforant path stimulation, and measured by recording extracellular excitatory field potentials and population spikes evoked in the dentate gyrus by low-frequency stimulation before and after LTP induction. LTP induction appeared to be inhibited in animals which had received ECS. However, inspection and analysis of absolute excitatory postsynaptic potential and population spike size before LTP induction in ECS treated animals suggested that LTP may have already been induced as a consequence of seizure activity, reducing the degree to which further potentiation could be elicited experimentally.
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Papers by Caroline Stewart