Biomedical subjects

M G Baxter

Publications and source records attributed to M G Baxter.

At least 37 records · Page 2Linked to original sources

PubMed1998

Monkeys with rhinal cortex damage or neurotoxic hippocampal lesions are impaired on spatial scene learning and object reversals.

Rhesus monkeys (Macaca mulatta) with lesions of the rhinal cortex or parahippocampal gyrus (made by aspiration) or hippocampus (made with ibotenic acid) and unoperated controls were tested on object discrimination and reversal, place discrimination and reversal, and spatial scene learning to determine the contribution of these temporal lobe structures to these forms of learning and memory. Rhinal cortex lesions produced a severe deficit in object reversal learning; hippocampal lesions produced a milder deficit. Monkeys with rhinal cortex removals and those with hippocampal lesions were equally impaired on spatial scene learning. None of the lesions impaired place discrimination or reversal. These results argue against the idea that the mnemonic contributions of the rhinal cortex and hippocampus are limited to object and spatial domains, respectively.

Animals↗

PubMed1997

Disruption of decrements in conditioned stimulus processing by selective removal of hippocampal cholinergic input.

The attention directed to environmental stimuli can be modified by experience. For example, preexposure of a conditioned stimulus (CS) in the absence of reinforcement can retard subsequent conditioning of that stimulus when it is paired directly with an unconditioned stimulus, a phenomenon referred to as latent inhibition. Similarly, consistent pairings of a CS with another event can slow the acquisition of new information about that CS. Such phenomena suggest that reductions in the processing of CSs occur when they are made behaviorally irrelevant or consistent predictors of other events. On the basis of the observation that hippocampal lesions prevented such reductions in CS processing, we hypothesized that damage to basal forebrain cholinergic neurons that project to the hippocampus, using microinjections of the selective immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB), also would disrupt normal reductions in CS processing. Lesions of hippocampal cholinergic input disrupted decreases in CS processing, manifested in both an absence of latent inhibition and a lack of reduced processing of a CS that had been a consistent predictor of another CS. These results indicate that cholinergic neurons in the MS/VDB play a role in the regulation of CS processing. Furthermore, these findings (in conjunction with previous findings) implicate both rostral (hippocampal-projecting) and caudal (cortical-projecting) regions of the basal forebrain cholinergic system in the modulation of attention.

Animals↗

PubMed1997

Selective immunolesions of hippocampal cholinergic input fail to impair spatial working memory.

The septo-hippocampal cholinergic pathway has traditionally been thought of as essential for spatial memory. Recent studies have demonstrated intact spatial learning following removal of this pathway with an immunotoxin selective for cholinergic neurons. In the present experiment, rats with selective removal of hippocampal cholinergic input were tested in a delayed nonmatching-to-position task in a water version of the radial arm maze. This allowed us to increase and parametrically vary the memory load compared with the standard Morris water maze (by varying the delay between the initial four choices and the final four choices) to determine if this would reveal a deficit in rats with lesions of septo-hippocampal cholinergic projections. Male Long-Evans rats were given injections of 192 IgG-saporin, a selective immunotoxin for cholinergic neurons, into the medial septum/vertical limb of the diagonal band (MS/VDB) to remove cholinergic projections to the hippocampus, or a control surgery. The rats were trained on the radial maze task following surgery. An escape platform was located at the end of each arm of the maze and was removed after an arm was utilized for escape. After initial training, a delay was interposed between the first four trials and the second four trials. Errors during the second four-trial component were scored in two categories: retroactive (reentering an arm chosen before the delay) and proactive (reentering an arm chosen after the delay). Retroactive errors increased as delay increased (from 60 s to 6 h) but were equivalent in control and MS/VDB-lesion groups. Proactive errors did not vary with delay and were also unaffected by the lesion. Radioenzymatic assays for choline acetyltransferase activity in the hippocampus of lesioned rats confirmed a significant loss of cholinergic input from the MS/VDB. These results indicate that normal spatial working memory is possible after substantial loss of septo-hippocampal cholinergic projections.

Acetylcholine↗

PubMed1996

Intact spatial learning following lesions of basal forebrain cholinergic neurons.

The role of the basal forebrain cholinergic system in learning and memory has held considerable interest since the discovery of cholinergic neurodegeneration in the basal forebrain in Alzheimer's disease. Contrary to expectation, selective removal of basal forebrain cholinergic neurons projecting to either hippocampus or neocortex fails to impair learning in a spatial task widely used to study hippocampal/cortical function. If cholinergic neurons contribute to learning and memory by integrated regulation of hippocampal and cortical processing, combined removal of hippocampal and cortical cholinergic projections might be necessary to produce impairment. However, this combined lesion failed to impair spatial learning. These data argue against the view that basal forebrain cholinergic deficiency plays a prominent role in disorders of learning and memory.

Acetylcholine↗

PubMed1996

Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input.

Studies using the selective cholinergic immunotoxin 192 IgG-saporin have demonstrated that lesions of the cholinergic input to the hippocampus from the medial septum/vertical limb of the diagonal band (MS/VDB) do not disrupt spatial learning in the water maze in young rats. However, age-related deficits in spatial learning correlate with the integrity of cholinergic neurons in the MS/VDB, suggesting that these neurons may be more crucial for spatial learning in aged rats. To investigate this hypothesis directly, we selectively lesioned these neurons in aged rats that demonstrated relatively intact spatial learning in an initial screening as well as in a comparison set of young rats. Intact and lesioned rats of both ages rapidly acquired a new place discrimination in a different spatial environment. These results indicate that the cholinergic input to the hippocampus is not differentially involved in spatial learning in aged rats.

Aging↗

PubMed1996

Spatial orienting of attention in adult and aged rhesus monkeys.

Aging produces changes in a variety of neural systems that result in a distinct neuropsychological profile of cognitive deficits. To determine the extent of functional decline in cognition with aging, the authors assessed attentional ability in adult (10-15 years old) and aged (28-33 years old) rhesus monkeys (Macaca mulatta) in 3 experiments, using a paradigm adapted from M. I. Posner, J. A. Walker, F. J. Friedrich, and R. D. Rafal (1984), in which a peripheral cue indicates the probable location of a target. Orienting of attention was not disrupted in aged monkeys. Response times of aged monkeys were comparable with adult monkeys' both in the attention task and in a simple reaction time task. These results suggest that the neural systems that subserve spatial orienting of attention remain intact in aged nonhuman primates.

Aging↗

PubMed1995

Nitric oxide synthase inhibition does not impair visual or spatial discrimination learning.

Nitric oxide (NO) is a candidate retrograde messenger involved in synaptic plasticity, and is linked to the cholinergic system in the brain. We examined the role of NO in the acquisition of visual and spatial discriminations by daily administration of either saline or 1-nitroarginine methyl ester (L-NAME), an NO synthase inhibitor. Brains were assayed for NO synthase activity and two presynaptic cholinergic markers: hemicholinium-3 (HC-3) binding, which determines the number of sodium-dependent high-affinity choline uptake sites, and activity of choline acetyltransferase (ChAT), which is the synthetic enzyme for acetylcholine. In both behavioral tasks, the acquisition rate was not different between groups. L-NAME reduced NO synthase activity by 85% in all brain areas assayed and HC-3 binding by 38% in hippocampus and 48% in posterior cortex. ChAT activity was not different between groups in any region assayed. These data suggest that NO does not play a role in visual or spatial discrimination learning. However, NO synthase inhibition may play a role in the regulation of cholinergic activity.

Animals↗

PubMed1995

Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats.

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory.

Acetylcholinesterase↗

PubMed1991

Neurochemical and behavioral aspects of lamotrigine.

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.

Animals↗

PubMed1978