Trond Myhrer

Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks

From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.

Exploratory behavior and reaction to novelty in rats with hippocampal perforant path systems disrupted

In this article, exploratory behavior and reaction to novelty were investigated in rats with either disruption of the total hippocampal perforant path projection (TPP), the medial perforant path (MPP), or lateral perforant path (LPP). All three experimental groups displayed increased locomotor activity, and the LPP group was even more active than the TPP and MPP groups. The TPP and LPP animals made more rearings than the control rats. The MPP and LPP groups exhibited less exploration of familiar objects than the TPP and control groups. TPP animals appeared unable to recognize novelty, LPP rats showed decreased preference for novelty, and MPP rats had only a slight deficit in recognition of novelty. It is suggested that perforant path disruptions reduce the hippocampal formations access to sensory information of neocortical origin.

Memory dysfunction following disruption of glutamergic systems in the temporal region of the rat: effects of agonistic amino acids

It has previously been shown that disruptions of fiber connections between the temporal cortex (TC) and the lateral entorhinal cortex (LEC) in rats result in severely impaired retention of a simultaneous brightness discrimination task. This memory impairment is accompanied by reduced high affinity D-aspartate uptake in both TC and LEC. The purpose of this study was to investigate whether systemic administration of glutamergic agonists might ameliorate the mnemonic dysfunction seen to follow TC/LEC transections. The results from Experiment 1 show that agonists acting selectively at the NMDA receptors (NMDA and glycine) or the quisqualate receptors (AMPA) produced complete amelioration of the memory deficit. Injection of kainic acid only produced a slight improvement of memory. The results from Experiment 2 show that the positive effects of agonists are probably not attributable to peripheral adrenergic mechanisms, because blockade of sympathetic terminal release did not prevent mitigating effect of glycine. The results are discussed in terms of possible central nervous mechanisms interfered with by the various agonists.

Effects of scopolamine and d-cycloserine on non-spatial reference memory in rats

The aim of the present work was to use a three-choice simultaneous brightness discrimination test to examine the retention of non-spatial reference memory in rats treated with scopolamine (0.5 mg/kg) alone and in combination with various concentrations of D-cycloserine (DCS) (5, 15 and 50 mg/kg). Scopolamine given 1 h before testing for retention was found to increase both the number of errors and the number of trials necessary to reach criterion. The three doses of DCS reduced this increase significantly and resulted in a U-shaped dose-response curve, where 15 mg/kg had a stronger compensatory effect than both 5 and 50 mg/kg. Control experiments were performed to confirm that the observed response was not due to non-mnemonic factors. Our results indicate that scopolamine and DCS affect non-spatial reference memory in a similar manner as shown for spatial reference memory.

Animal models of Alzheimer's disease: Glutamatergic denervation as an alternative approach to cholinergic denervation

Alzheimers disease (AD) is a neurodegenerative disorder that severely reduces lifespan. In this article, a new, glutamatergic denervation model of AD is presented as a supplement to the well known cholinergic one, because these models are trying to mimic different aspects of the pathology in AD. Impaired memory and disorientation are prominent features in the symptomatology of AD. In searching for neurochemical systems associated with the initial cognitive disorders of AD, a reorientation from cholinergic to glutamatergic systems is suggested. Results from recent behavioral studies of damage to the temporal and entorhinal cortices in rats imply that these structures are strongly involved in mnemonic function. Findings from Alzheimer brains and laboratory animals indicate that major losses of glutamatergic receptors may underly the cognitive impairment seen in AD patients. A growing body of evidence appears to support a glutamatergic hypothesis of AD. Possible pharmacological approaches are suggested.

Adverse psychological impact, glutamatergic dysfunction, and risk factors for Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by cell loss and pathological changes in neuronal transmission. In particular, malfunction in glutamatergic activity may be associated with the impairment of memory seen in Alzheimer patients. Both hypoactivation and hyperactivation of glutamatergic systems seem to cause impeded cognitive processing in animals. Rats subjected to rearing in isolation display reduced levels of glutamate in temporal regions accompanied by impaired learning and memory. Similar cognitive deficits are also seen in animals exposed to behavioral stress. Stress appears to have deleterious effects on cognition caused by glutamate neurotoxicity leading to attenuated synaptic activity. It is suggested that stress may represent a potential risk factor for AD. The known risk factors for AD (age, heredity, head trauma, low education, depression) may all be related to glutamatergic dysfunction. Some difficulties with pharmacological approaches based on glutamatergic agonists are discussed. It is suggested that optimal glutamate-mediated neurotransmission throughout life may prevent the occurrence of mental decline associated with AD.

Exploratory behavior, reaction to novelty, and proactive memory in rats with temporo-entorhinal connections disrupted

The parahippocampal cortex is ascribed a key function in mediating reciprocal connections between neocortical association areas and the hippocampal formation. Within this complex the lateral entorhinal cortex (LEC) seems to stand out as an important interface exerting modulating influence upon cognition and memory by way of its connections with the hippocampal formation and temporal cortex (TC), respectively. The purpose of the present study was to compare effects of TC/LEC disruptions in a novelty test with results previously obtained in the same test following lateral perforant path (LPP) disruptions. Further, effects of TC/LEC lesions on proactive memory were examined, since a profound impairment in retroactive memory has previously been found. Rats bearing TC/LEC lesions or LPP lesions behaved differently in the novelty test. It was also shown that the impairment in proactive memory was less severe than the one seen in retroactive memory following TC/LEC lesions. The results are discussed in terms of a highly integrative role of LEC.

Pharmacological Agents, Hippocampal EEG, and Anticonvulsant Effects on Soman-Induced Seizures in Rats

Changes in the hippocampal theta rhythm were used as a model in which anticonvulsant drugs may be screened for their potential to antagonize soman-induced (1xLD(50)) seizures. The zinc chelator, ethylenediaminetetra acetic acid (EDTA) (300mg/kg), and the NMDA receptor antagonist, HA-966 (60mg/kg), both disrupted the theta rhythm, but did not antagonize soman-induced seizures, neither separately, nor in combination. The anticholinergic and antiglutamatergic procyclidine (6mg/kg) did not influence the theta activity. The GABAergic agonists, diazepam (10mg/kg) and pentobarbital (30mg/kg), both reduced the theta frequency. Procyclidine, diazepam, and pentobarbital did not stop soman-induced seizures when administered separately, but both convulsions and seizure activity terminated when these agents were given together, and the rats slept through the critical convulsion period. This triple therapy was 100% effective, when administered 30-40min following onset of convulsions, and the rats displayed apparently normal behavior the next day. A screening model of potential anticonvulsants cannot be based on alterations in hippocampal EEG activity. Procyclidine, diazepam, and pentobarbital in combination disrupted the theta rhythm like the combination of EDTA and HA-966, but the latter combination did not have anticonvulsant effect. It is concluded that a triple regimen consisting of procyclidine, diazepam, and pentobarbital can effectively terminate soman-induced seizures that have lasted 30min or more.

Selective lesions in the temporal-hippocampal region of the rat : effects on acquisition and retention of a visual discrimination task

The first purpose of this study was to investigate whether lesions in the temporal region may affect acquisition or retention of a discrimination task. In Experiment 1, rats with lesions of the temporal cortex (TC), the lateral entorhinal cortex (LEC), or their interconnections were tested postoperatively in simultaneous brightness discrimination. The results show that neither TC lesions nor LEC lesions affected acquisition of the task, and only LEC lesions impaired retention. TC/LEC transections impaired both acquisition and retention. The second purpose was to investigate effects of hippocampal lesions and perforant path transections on the discrimination task (Experiment 2). Both hippocampal and perforant path lesions impaired acquisition of the task, whereas retention was unaffected. It is suggested that TC and LEC are primarily involved in information storing and that hippocampal function is primarily involved in information processing.

Impaired reference memory and reduced glutamergic activity in rats with temporo-entorhinal connections disrupted

SummaryThe purpose of the present study was to investigate whether effects of temporo-entorhinal disconnections on acquisition and retention of a visual discrimination task might be associated with neurochemical dysfunctions. The results revealed that the present lesions impaired both acquisition and retention of the discrimination task. This impairment was accompanied by decreased glutamergic activity in both temporal and entorhinal cortices. No changes were seen in levels of acetylcholine or GABA. Further, the distribution of glutamate/ aspartate was related to both regional and hemispheric differences. The results are discussed in terms of a highly integrative role of the lateral entorhinal cortex and in terms of other putative neurotransmitter systems involved in the function of memory.