Francis Boon

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.

Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: Further development of a rodent model of autism

Propionic acid (PPA) is a dietary short chain fatty acid and a metabolic end-product of enteric bacteria. Intracerebroventricular (ICV) injections of PPA can result in brain and behavioral abnormalities in rats similar to those seen in humans suffering from autism. To evaluate cognition and sensorimotor ability in the PPA model, male Long-Evans hooded rats received ICV injection of PPA or control compounds prior to behavioral testing in water maze and beam tasks. Compared to controls, PPA-treated rats were impaired in the water maze task as indicated by an unusual pattern of mild or no impairment during spatial acquisition training, but marked impairment during spatial reversal training. PPA-treated rats were also impaired on the beam task. Neuropathological analysis from PPA-treated rats revealed an innate neuroinflammatory response. These findings add to evidence that PPA can change the brain and behavior in the laboratory rat consistent with symptoms of human autism.

Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA-mediated long-term potentiation.

The role of NMDA receptors and NMDA-mediated hippocampal long-term potentiation (LTP) in spatial learning was studied in rats using the competitive, systemically administered NMDA receptor antagonists CGS19755 ((+/-)-cis-4-phosphonomethyl-2-piperidine carboxylic acid) and NPC17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid). CGS19755 caused sensorimotor disturbances and disrupted acquisition of the water maze in naive rats. The sensorimotor disturbances were greatly reduced and maze learning was normal in spite of the blockade of dentate gyrus LTP by CGS19755 in rats that had first been familiarized with the general task requirements by non-spatial pretraining. In a second experiment, antagonism of NMDA receptors caused small, but reliable, impairments in Y-maze and visible platform visual discrimination tasks. The results indicate that NMDA receptors are not crucial for water maze acquisition using a spatial learning strategy, and that NMDA antagonists cause visual and other sensorimotor disturbances in naive rats that could help account for their poor performance in this task.

Methamphetamine exposure from postnatal day 11 to 20 causes impairments in both behavioral strategies and spatial learning in adult rats.

Spatial learning and memory deficits in a water maze have been observed in adult animals exposed to a regimen of 4 daily doses of d-methamphetamine (MA) at 2 h intervals from postnatal day 11 to 20. An interpretational issue for these long-term effects of MA is whether they are truly spatial deficits or are secondary to alterations in sensorimotor systems. In this experiment, we evaluated the effects of a pretraining procedure shown to minimize the influence of drug-induced sensorimotor deficits. Animals within a litter were treated with MA or saline. Animals were either pretrained for nonspatial task requirements in the water maze (i.e., swimming and platform climbing) or were nai;ve to the task. Animals that received the pretraining did better than the nai;ve animals. The nai;ve MA animals performed worse than the nai;ve control animals as previously observed. By contrast, no difference in search time was noted between pretrained MA- and SAL-treated animals during the acquisition phase of testing. When the platform was relocated in a novel position, spatial learning was impaired for MA animals, regardless of pretraining. No increase in the number of platform nonrecognition events (swimovers, deflections, or jump-offs) occurred among pretrained or nai;ve groups compared to controls. These data suggest that sensorimotor deficits do not account for the spatial learning and memory deficits in animals exposed neonatally to MA.

Thalamic and hippocampal mechanisms in spatial navigation: A dissociation between brain mechanisms for learning how versus learning where to navigate

Various studies of hippocampus and medial thalamus (MT) suggest that these brain areas play a crucial, marginal, or no essential role in spatial navigation. These divergent views were examined in experiments using electrolytic Lesions of fimbria-fornix (FF) or radiofrequency or neurotoxic Lesions of MT of rats subsequently trained to find a stable visible (experiment 1) or hidden platform (experiments 2 and 3) in a water maze (WM) pool. Rats with electrolytic Lesions of FF or radiofrequency Lesions of MT were impaired in swimming to a stable visible platform, particularly the MT Lesion Group, suggesting impairment of WM strategies acquisition. Additional Lesioned rats were then tested in a hidden platform version of the WM task. Some rats were given Morriss nonspatial pretraining prior to Lesioning to provide them with training in the required WM behavioral strategies. Nonspatially Pretrained rats with FF Lesions eventually were able to navigate to the hidden platform, but the accuracy of place responding was impaired. This impairment occurred without problems in the motoric control of swimming or the use of WM behavioral strategies, suggesting that these rats had a spatial mapping impairment. Radiofrequency MT Lesions blocked acquisition of WM behavioral strategies by Naive rats throughout 3 days of training, severely impairing performance on all aspects of the hidden platform task. Nonspatially Pretrained rats given the same MT Lesions readily learned the hidden platform location and were indistinguishable from controls throughout spatial training. Rats given neurotoxic Lesions of MT for removal of cells were only mildly impaired and improved considerably during training, suggesting an important role for fibers of passage in WM strategies learning. The results provide a clear dissociation between a role for MT in learning WM behavioral strategies and the hippocampal formation in spatial mapping and memory. This is the first identification of a brain area, MT, that is essential for learning behavioral strategies that by themselves do not constitute the solution to the task but are necessary for the successful use of an innate learning ability: place response learning using spatial mapping.

Retrosplenial cortex lesions impair water maze strategies learning or spatial place learning depending on prior experience of the rat

There has been debate whether lesions strictly limited to retrosplenial (RS) cortex impair spatial navigation, and how robust and reliable any such impairment is. The present study used a detailed behavioral analysis with naive or strategies-pretrained rats given RS lesions and trained in a water maze (WM). Naive RS lesioned rats failed to acquire the required WM strategies throughout training. Strategies-pretrained RS lesioned rats were specifically impaired in spatial place memory without a WM strategies impairment. Additional training overcame the spatial memory impairment. Thus the behavioral consequences of the lesion depend on the specific previous experience of the animal. The use of appropriate training and testing techniques has revealed experience-dependant dissociable impairments in WM strategies learning and in spatial memory, indicating that RS cortex is involved in both forms of learning.

Evidence for different neurochemical contributions to long-term potentiation and to kindling and kindling-induced potentiation: Role of NMDA and urethane-sensitive mechanisms

Long-term potentiation (LTP) and kindling share a number of features, and it has been suggested that LTP might constitute the cellular mechanism of kindling. This question was approached by assessing the effect of urethane anesthesia (0.75 or 1.5 g/kg) or blockade of NMDA receptors by local infusion of DL-2-amino-5-phosphonovaleric acid (APV; 7.5 micrograms) on LTP, partial kindling, and kindling-induced potentiation (KIP) in the perforant path-dentate gyrus circuit of the intact hooded rat. Urethane anesthesia attenuated but did not block LTP and completely blocked partial kindling and KIP. APV completely blocked LTP but did not block partial kindling or KIP in the unanesthetized rat. These results suggest that different neurochemical mechanisms can support LTP on the one hand, and kindling and KIP on the other. They are consistent with a contribution by NMDA-mediated LTP to kindling and KIP, but they indicate that this contribution is not crucial for kindling and KIP in this circuit.