Donald P. Cain

Partial reversal of the effect of maternal care on cognitive function through environmental enrichment

Maternal care influences hippocampal development in the rat. The offspring of mothers that exhibit increased levels of pup licking/grooming and arched-back nursing (High LG-ABN mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) receptor binding and enhanced hippocampal-dependent spatial learning. In these studies we examined whether environmental enrichment from days 22-70 of life might reverse the effects of low maternal care. Environmental enrichment eliminated the differences between the offspring of High and Low LG-ABN mothers in both Morris water maze learning and object recognition. However, enrichment did not reverse the effect of maternal care on long-term potentiation in the dentate gyrus or on hippocampal NMDA receptor binding. In contrast, peripubertal enrichment did reverse the effects of maternal care on hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor binding. These findings provide evidence for the reversal of the effects of reduced maternal investment in early life on cognitive function in adulthood. Such effects might involve compensatory changes associated with peripubertal enrichment.

Long-term potentiation and kindling: How similar are the mechanisms?

Long-term potentiation (LTP) and kindling are strikingly similar in many respects. Both are believed to model CNS plasticity, both are induced by the localized application of brief, high-frequency trains of electrical pulses through implanted electrodes, and both result in a lasting increase in the response to a constant stimulus. In addition to these formal similarities, recent findings have indicated that the two models may share aspects of an underlying neural mechanism, and this has led to the suggestion that LTP may constitute the cellular mechanism of kindling. However, other findings have indicated two models. This article discusses the differences in mechanisms and the relations between LTP and kindling.

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism : Nonspatial pretraining eliminates spatial learning deficits

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performances and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.

Detailed behavioral analysis of water maze acquisition under APV or CNQX: Contribution of sensorimotor disturbances to drug-induced acquisition deficits.

N-methyl-D-aspartate (NMDA) receptor antagonists disrupt acquisition of the water maze and cause sensorimotor disturbances. In a detailed behavioral analysis in male rats, it was found that the NMDA antagonist DL-2-aminophosphonovaleric acid (APV) caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under APV. The results are consistent with the known role of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA may contribute to but does not appear to be essential for spatial learning in the water maze.

Contribution of sex differences in the acute stress response to sex differences in water maze performance in the rat.

Male rats outperform females in spatial tasks, such as the water maze (WM). Female rats are known to have higher basal serum corticosterone (CORT) levels and to manifest a more rapid and stronger CORT response to novel stressors. Sex differences in stress responses to the handling and forced swimming in the WM task might contribute to the sex difference in WM performance. In Experiment 1, naive females were found to be impaired relative to naive males in swimming to a visible platform in a WM pool due to strongly thigmotaxic swimming by females. In Experiment 2, serum CORT, a physiological measure of stress, was highly elevated during and after WM training, with female > male values and strong inverse correlations between CORT and measures of WM performance in females. Familiarization with the WM pool and test procedures by strategies pretraining prior to spatial training reduced or eliminated the sex differences in the stress response and WM performance. In Experiment 3, adrenalectomy to eliminate the stress response eliminated sex differences in WM performance. Taken together, the results suggest that male and female rats may harbor brain circuitry that is equally capable of accurate spatial navigation and memory in the WM but which may be impaired to different degrees by the differential stress responses triggered by WM testing.

Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder.

Recent evidence suggests that a variety of environmental factors, including dietary and gastrointestinal agents, may contribute to autism spectrum disorders (ASD). Here we administered propionic acid (PPA), a short chain fatty acid that is used as a food preservative and also is a metabolic end-product of enteric bacteria in the gut, to adolescent (41 ± 4 days) male rats in a study of restricted/repetitive behavior, social behavior, and cognition. The goal was to further evaluate the effects of PPA in young rodents. PPA (4 μl of 0.26 M solution) was administered intracerebroventricularly prior to each behavioral test. Rats treated with PPA displayed restricted behavioral interest to a specific object among a group of objects, impaired social behavior, and impaired reversal in a T-maze task compared to controls given phosphate buffered saline. Immunohistochemical analysis of brain tissue from PPA rats revealed reactive astrogliosis and activated microglia, indicating an innate neuroinflammatory response. These findings are consistent with our earlier findings of ASD-relevant behavioral and brain events in adult rats given PPA, and support further study of effects of PPA in young rodents by establishing similar effects in adolescent animals.

Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning.

The problems and issues associated with the use of pharmacological antagonists in studies on learning and memory are considered in a review of the role of N-methyl-D-aspartate (NMDA) receptors, NMDA receptor-mediated long-term potentiation (LTP), and muscarinic receptors in spatial learning in the water maze. The evidence indicates that neither NMDA nor muscarinic receptors, nor NMDA receptor-mediated LTP, are required for spatial learning, although they might normally contribute to it. Detailed behavioral analyses have indicated that the water maze task is more complex than generally has been appreciated, and has a number of dissociable components. Naive rats trained under NMDA or muscarinic antagonism display sensorimotor disturbances that interfere with their ability to acquire the task. Rats made familiar with the general requirements of the task can learn the location of a hidden platform readily under NMDA or muscarinic antagonism. The ability of a rat to acquire the water maze task depends on its ability to apply instinctive behaviors to performance of the task in an adaptive manner. The instinctive behaviors undergo modification as the rat learns the general strategies required in the task. The evidence suggests that at least some of the plastic changes involved in acquiring the task occur in existing neural circuits situated in widespread areas of the brain, including sensory and motor structures in the cortex and elsewhere, and are therefore difficult to distinguish from existing sensorimotor mechanisms. More generally, the findings indicate the difficulty of inferring the occurrence or nonoccurrence of learning from behavior, and the difficulty of causally linking the action of particular receptor populations with the formation of specific memories.

Retardation of amygdala kindling by antagonism of NMD-aspartate and muscarinic cholinergic receptors: evidence for the summation of excitatory mechanisms in kindling.

DL-2-amino-5-phosphonovaleric acid (APV), a specific antagonist of N-methyl-D-aspartate (NMDA) receptors, was administered alone and in combination with scopolamine (SCO), an antagonist of muscarinic cholinergic receptors, to different groups of rats undergoing electrical kindling of the amygdala. Both groups were significantly retarded in their rate of kindling during 15 drug sessions compared to controls, and the group receiving APV and SCO kindled significantly slower than the group receiving APV alone. These results indicate that both NMDA and muscarinic cholinergic receptors are involved in kindling of the amygdala, and implicate a mechanism involving the summation of excitatory neurotransmission in kindling of the amygdala.

Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801

Three doses of MK801 (0.05 mg/kg, 0.3 mg/kg and 1.0 mg/kg) were given systemically to adult male rats, which were then tested on a battery of previously learned, reactive and spontaneous behaviors. Hyperactivity, hyper-reactivity, reductions in rearing behavior and deficits in tongue extension were found at the 0.05 mg/kg dose. Similar, but more severe results were found at the 0.3 mg/kg dose, with the addition of difficulties in climbing, balancing on a beam, and abnormalities in orienting to tactile stimuli. A number of tasks could not be performed at the 1.0 mg/kg dose including tongue extension, orienting, balancing on a beam, and climbing. Additionally, abnormal postures, gaits, and swimming behaviors were observed at this dose. These results characterize the behavioral effects of MK801 as a syndrome of hyperactivity, hyper-reactivity, and sensorimotor deficits. Evidence of this syndrome was present at all three doses, including the 0.05 mg/kg dose, which previously has been claimed to induce deficits similar to hippocampal lesions. Learning literature employing MK801 is discussed in the context of the behavioral deficits found in this study.

Repeated Mild Lateral Fluid Percussion Brain Injury in the Rat Causes Cumulative Long-Term Behavioral Impairments, Neuroinflammation, and Cortical Loss in an Animal Model of Repeated Concussion

There is growing evidence that repeated brain concussion can result in cumulative and long-term behavioral symptoms, neuropathological changes, and neurodegeneration. Little is known about the factors and mechanisms that contribute to these effects. The current study addresses the need to investigate and better understand the effects of repeated concussion through the development of an animal model. Male Long-Evans rats received 1, 3, or 5 mild lateral fluid percussion injuries or sham injuries spaced 5 days apart. After the final injury, rats received either a short (24 h) or long (8 weeks) post-injury recovery period, followed by a detailed behavioral analysis consisting of tests for rodent anxiety-like behavior, cognition, social behavior, sensorimotor function, and depression-like behavior. Brains were examined immunohistochemically to assess neuroinflammation and cortical damage. Rats given 1, 3, or 5 mild percussion injuries displayed significant short-term cognitive impairments. Rats given repeated mild percussion injuries displayed significantly worse short- and long-term cognitive impairments. Rats given 5 mild percussion injuries also displayed increased anxiety- and depression-like behaviors. Neuropathological analysis revealed short-term neuroinflammation in 3-injury rats, and both short- and long-term neuroinflammation in 5-injury rats. There was also evidence that repeated injuries induced short- and long-term cortical damage. These cumulative and long-term changes are consistent with findings in human patients suffering repeated brain concussion, provide support for the use of repeated mild lateral fluid percussion injuries to study repeated concussion in the rat, and suggest that neuroinflammation may be important for understanding the cumulative and chronic effects of repeated concussion.