Maintenance Of Spatial Memory Research Articles

Cytoplasmic Polyadenylation Element Binding Proteins CPEB1 and CPEB3 Regulate the Translation of FosB and Are Required for Maintaining Addiction-Like Behaviors Induced by Cocaine.

A recurrent and devastating feature of addiction to a drug of abuse is its persistence, which is mediated by maladaptive long-term memories of the highly pleasurable experience initially associated with the consumption of the drug. We have recently found that members of the CPEB family of proteins (Cytoplasmic Polyadenylation Element-Binding Proteins) are involved in the maintenance of spatial memory. However, their possible role in the maintenance of memories that sustain addictive behavior has yet to be explored. Little is known about any of the mechanisms for maintaining memories for addictive behavior. To address the mechanisms whereby addictive behavior is maintained over time, we utilized a conditional transgenic mouse model expressing a dominant-negative version of CPEB1 that abolishes the activity in the forebrain of two of the four CPEB isoforms (CPEB1 and CPEB3). We found that, following cocaine administration, these dominant-negative (DN) CPEB mice showed a significant decrease, when compared to wild type (WT) mice, in both locomotor sensitizations and conditioned place preference (CPP), two indices of addictive behavior. Supporting these behavioral results, we also found a difference between WT and DN-CPEB1-3 mice in the cocaine-induced synaptic depression in the core of the Nucleus Accumbens (NAc). Finally, we found that (1) CPEB is reduced in transgenic mice following cocaine injections and that (2) FosB, known for its contribution to establishing the addictive phenotype, when its expression in the striatum is increased by drug administration, is a novel target of CPEBs molecules. Thus, our study highlights how CPEB1 and CPEB3 act on target mRNAs to build the neuroadaptative implicit memory responses that lead to the development of the cocaine addictive phenotypes in mammals.

Suppressive effect of triadimefon, a triazole fungicide, on spatial learning and reference memory in rats

Although some central effects of triadimefon, a triazole fungicide, have been reported, its effects on spatial memory have not been examined. In this study, we used the Morris water maze to study the effect of triadimefon on spatial learning and memory in rats. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in the hippocampus by high-performance liquid chromatography. Our data showed that triadimefon inhibited spatial learning and impaired spatial reference memory, and decreased hippocampal retinoic acid concentration. There is evidence that triadimefon can regulate the metabolism of retinoic acid, which serves a critical function in the development and maintenance of spatial memory. Therefore, we speculate that the reduction in hippocampal retinoic acid concentration induced by triadimefon might be responsible for its suppressive effect on spatial learning and reference memory.

Biphasic effect of citral, a flavoring and scenting agent, on spatial learning and memory in rats

Although some central effects of citral have been reported, cognitive effects on spatial memory have not been investigated. The evidence showed that citral can regulate the synthesis of retinoic acid (RA), which exerts a vital function in the development and maintenance of spatial memory. In this study, we applied Morris water maze to test the effect of citral on animals' spatial learning and memory. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in rats' hippocampus by high performance liquid chromatography (HPLC). Our data implied biphasic effects of citral. The low dose (0.1 mg/kg) of citral improved the spatial learning capability, and enhanced the spatial reference memory of rats, whereas the high dose (1.0 mg/kg) was like to produce the opposite effects. Meanwhile, the low dose of citral increased the hippocampal retinoic acid concentration, while the high dose decreased it. Due to the quick elimination and non-bioaccumulation in the body, effects of citral on spatial memory in this study seemed to be indirect actions. The change in hippocampal retinoic acid concentration induced by different doses of citral might be responsible for the biphasic effect of citral on spatial learning and memory.

Circadian rhythms and memory: not so simple as cogs and gears

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

Age-Dependent Spatial Memory Loss Can Be Partially Restored by Immune Activation

Aging is often associated with a decline in hippocampus-dependent spatial memory. Here, we show that functional cell-mediated immunity is required for the maintenance of hippocampus-dependent spatial memory. Sudden imposition of immune compromise in young mice caused spatial memory impairment, whereas immune reconstitution reversed memory deficit in immune-deficient mice. Analysis of hippocampal gene expression suggested that immune-dependent spatial memory performance was associated with the expression of insulin-like growth factor (Igf1) and of genes encoding proteins related to presynaptic activity (Syt10, Cplx2). We further showed that memory loss in aged mice could be attributed to age-related attenuation of the immune response and could be reversed by immune system activation. Homeostatic-driven proliferation of lymphocytes, which expands the existing T cell repertoire, restored spatial memory deficits in aged mice. Thus, our results identify a novel function of the immune system in the maintenance of spatial memory and suggest an original approach for arresting or reversing age-associated memory loss.

Chronic exposure to low-intensity magnetic field improves acquisition and maintenance of memory

Although past research has suggested that acute exposure to extremely low-frequency magnetic field (ELF MF) impairs learning and memory function, data on chronic exposure remain scarce. In this study, we examined the changes in spatial learning and memory by the Morris water maze test after 4 weeks of daily exposure of rats to a 50-Hz magnetic field of 2 mT for either 1 or 4 h. We found that chronic exposure to ELF MF reduced the latency to find the hidden platform and improved long-term memory of former location of platform without affecting the short-term memory and motor activity. These findings for the first time indicate that chronic exposure to ELF MF exerts a positive effect on the acquisition and maintenance of spatial memory.

The Ins and Outs of Hippocampal Circuits

The anatomy of the entorhinal-hippocampal circuit suggests how spatial information may flow into and out of the CA1 region. In this issue of Neuron, two groups use in vivo physiology to make predictions about the circuit mechanisms involved in the encoding and maintenance of spatial memory. Brun et al. show that lesions of the cells providing direct input from the mEC to CA1 lead to a decrease in spatial tuning, while Cheng and Frank report that the exploration of novel space leads to a transient increase in the temporally correlated firing of pairs of CA1 cells outside of their place fields specifically during ripple-like high-frequency events in the local field potential.

Effects of Gaze Shifts on Maintenance of Spatial Memory in Macaque Frontal Eye Field

The activity of 91 neurons in the frontal eye fields (FEFs) of two macaque monkeys was recorded while the animals performed a delayed spatial match-to-sample task. During the delay, the animals were required to shift their gaze to one of four eccentric locations. Neuronal activity during the delay was analyzed for sensitivity to cue location and eye position. One-third of the neurons showed significant delay activity selective for cue location, whereas slightly more than one-half of the neurons showed significant modulation of delay activity when the gaze was shifted to an eccentric location. Despite this modulation, the neurons continued to signal their preferred cue location during most of the delay. However, after recentering saccades, the memory signal was temporarily abolished and then reemerged over a period of few hundred milliseconds. This is consistent with the idea that spatial working memory is buffered outside of the FEF. For most neurons, delay activity tended to increase when the gaze was shifted away from the preferred location and to decrease when the gaze was shifted toward the preferred location. This pattern of modulation is consistent with a vector subtraction mechanism that allows for the superposition of multiple saccade plans.

Differential effects of physostigmine and pilocarpine on the spatial memory deficits produced by two septo-hippocampal deafferentations in rats

Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity. An intraperitoneal injection of physostigmine (0.0032–0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032–3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats. These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.

Reversible inactivation of the medial septum differentially affects two forms of learning in rats

The contribution of the medial septum to different aspects of spatial information processing was assessed by examining the effects of reversible septal inactivation on radial maze performance of rats. In addition, the selectivity with which the medial septum affects learning was studied by testing the effects of septal inactivation on the acquisition of non-spatial information. Rats were first trained according to a spatial working memory procedure that included a 30-min delay between the first 4 (forced) choices and subsequent test (free) choices. The forced choices comprised the sample phase of the experiment while the free choices comprised the test phase. Saline or tetracaine (a local anesthetic) was injected into the medial septal area either before the sample phase, after the sample phase (i.e. at the beginning of the delay period), or just before the test phase. In contrast to the saline injections, tetracaine injected just before the samole or test phases produced a significant increase in errors at test. Tetracaine injection at the beginning of the delay period did not affect test choice accuracy. EEG records showed that septal inactivation drastically, yet temporarily, reduced the hippocampal Θ rhythm. Thus, when septal inactivation occurred either before the sample phase or at the beginning of the delay period, hippocampal Θ recovered by the time of the test phase. Septal inactivation also produced a significant retardation of learning on a non-spatial reference memory task, although clear improvement over trials did occur. Moreover, the results of subsequent saline injections suggest that at least some of the performance deficit was due to variables other than learning per se. Although such performance effects could at least in part account for the errors made when septal inactivation occurred before the test phase of the spatial task, it could not account for errors made when septal inactivation occurred before the sample phase. This result, together with the finding that septal inactivation drastically alters hippocampal single unit activity 27, 28, is consistent with the hypothesis that normal septal activation (of perhaps the hippocampus) is required for acquisition of spatial information. Maintenance of spatial memory, on the other hand, may not rely on such activity.

Differential effects of drugs on the behaviour of rats with selective fimbria-fornix lesions and intrahippocampal septal cell transplants

Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity.An intraperitoneal injection of physostigmine (0.0032–0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032–3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats.These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.

Learning and Memory Deficits After Ibotenate Lesions of the Nucleus Basalis: Reversal by Cholinomimetics

Abstract:The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesioned animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks. They also suggest that degeneration of cholinergic neurons in the basal forebrain contributes significantly to the learning and memory deficits observed in Alzheimer's disease.

Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis.

The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesion animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks.