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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disconnection of the amygdala central nucleus and the substantia innominata/nucleus basalis magnocellularis disrupts performance in a sustained attention task.

The basal forebrain cholinergic system is broadly implicated in the regulation of attention. Disruptions in the function of this system produce impairments in many attentional functions, including the performance of well-learned responses under increased attentional load and the surprise-induced enhancement of learning rate. Similarly, lesions of the amygdala central nucleus (CeA) have been found to impair attentional function in some circumstances. In the present article, the effects of lesions that disconnected CeA from the cholinergic substantia innominata/nucleus basalis magnocellularis (SI/nBM) on performance are examined in a modified 5-choice serial reaction time (5CSRT) task, thought to assess selective or sustained attention. The lesions impaired performance under conditions of increased attentional load, suggesting that a circuit that includes CeA and SI/nBM regulates these aspects of attention. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: II. Cortical morphology

Previous studies in the mouse have shown that neonatal lesions to the cholinergic basal forebrain (nBM) areas result in transient cholinergic depletion of neocortex and precipitate altered cortical morphogenesis. Lesion-induced morphological alterations in cortex persist into adulthood and are accompanied by behavioral changes, including spatial memory deficits. The current study investigated whether neonatal nBM lesions affect male and female mice differently in adulthood. Quantitative morphometry of cortical layer width was employed to assess alterations in cytoarchitecture in neonatally nBM-lesioned and littermate control mice of both sexes following behavioral testing. Our results showed significant decreases in cortical layer IV and V widths across somato/motor cortex in neonatally nBM lesioned mice of both sexes. Sexually dimorphic responses were observed in cortical layer II/III and total cortical width, limited to the area containing the "barrel cortex" representation of the whisker hairs. In lesioned females, layer II/III and total cortical width were decreased relative to female controls, and in lesioned males, layer II/III was increased relative to controls, whereas total cortical width was unchanged. In male but not female mice we observed significant correlations between decreased widths in layer IV and V and impaired performance on a spatial memory task. The current data further support a role of developing cholinergic cortical afferents in the modulation of cortical morphogenesis and cortical circuits involved in cognitive behaviors. In addition, our observations provide further evidence for sexually dimorphic development and function in cognitive centers of the rodent brain.     

Contribution of the cholinergic basal forebrain to proactive interference from stored odor memories during associative learning in rats.

E. De Rosa and M. E. Hasselmo (see record 2000-13470-003) demonstrated that 0.25 mg/kg scopolamine (SCOP) selectively increased proactive interference (PI) from stored odor memories during learning. In the present study, rats with bilateral cholinergic lesions limited to the horizontal limb of the diagonal band of Broca, made with 192 IgG-saporin, were not impaired in acquiring the same olfactory discrimination task relative to control rats. Rats with bilateral IgG-saporin lesions to all basal forebrain cholinergic nuclei (BF) also showed no impairment in acquisition of this task. However, the BF-saporin rats were hypersensitive to oxotremorine-induced hypothermia and demonstrated an increased sensitivity to PI following a low dose of SCOP (0.125 mg/kg) relative to control rats. The results suggest that weaker cholinergic modulation after cholinergic BF lesions makes the system more sensitive to PI during blockade of the remaining cholinergic elements. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: I. Behavior and neurochemistry

The nucleus basalis magnocellularis (nBM) provides the primary source of cholinergic input to the cortex. Neonatal lesions of the nBM produce transient reductions in cholinergic markers, persistent abnormalities in cortical morphology, and spatial navigation impairments in adult mice. The present study examined sex differences in the effects of an electrolytic nBM lesion on postnatal day 1 (PND 1) in mice on behavior and neurochemistry in adulthood. Mice were lesioned on PND 1 and tested at 8 weeks of age on a battery of behavioral tests including passive avoidance, cued and spatial tasks in the Morris water maze, simple and delayed nonmatch to sample versions of an odor discrimination task, and locomotor activity measurements. Following behavioral testing, mice were sacrificed for either morphological assessment or neurochemical analysis of a cholinergic marker or catecholamines. There were no lesion or sex differences in acquisition or retention of passive avoidance, performance of the odor discrimination tasks, or activity levels. Control mice showed a robust sex difference in performance of the spatial water maze task. The lesion produced a slight cued but more dramatic spatial navigation deficit in the water maze which affected only the male mice. Neurochemical analyses revealed no lesion-induced changes in either choline acetyltransferase activity or levels of norepinephrine or serotonin at the time of testing. The subsequent report shows a sex difference in lesion-induced changes in cortical morphology which suggests that sexually dimorphic cholinergic influences on cortical development are responsible for the behavioral deficits seen in this study.     

Animal models of memory impairment

Memory impairment in the elderly resembles a mild temporal lobe dysfunction. Alterations in the hippocampal formation are also a probable basis for cognitive deficits in some animal models of ageing. For example, aged rats are impaired in hippocampal-dependent tests of spatial memory. Recent studies have revealed considerable structural integrity in the aged hippocampus, even in aged rats with the most impaired spatial memory. In contrast, atrophy/loss of cholinergic neurons in the basal forebrain and deficiency in cholinergic transduction in hippocampus correlate with the severity of spatial memory impairment in aged rats. This evidence supports the longstanding view that age-related loss of memory has a cholinergic basis. In this context, it is somewhat surprising that the use of a selective cholinergic immunotoxin in young rats to further test this hypothesis has revealed normal spatial memory after removing septo-hippocampal cholinergic neurons. Young rats with immunotoxic lesions, however, have other behavioural impairments in tests of attentional processing. These lines of research have implications for understanding the neurobiological basis of memory deficits in ageing and for selecting an optimal behavioural setting in which to examine therapies aimed at restoring neurobiological function.     

Transfer Effects and Conditional Learning in Rats With Selective Lesions of Medial Septal/Diagonal Band Cholinergic Neurons.

The authors examined visual-spatial conditional learning with automated touchscreen tasks in male Long-Evans rats with selective lesions of medial septal/vertical limb of diagonal band (MS/VDB) cholinergic neurons produced by 192 IgG-saporin. Performance on a conditional task, in which 1 of 2 centrally displayed stimuli directed the rat to respond to an illuminated panel on the left or right, depended on training history: Control rats with experience on other visual tasks performed better than MS/VDB-lesioned rats with similar training histories, whereas this effect was reversed in naive rats. This difference appears to reflect transfer effects present in the control rats that are absent in the MS/VDB-lesioned rats. These findings may suggest that MS/VDB cholinergic neurons play a particular role in the transfer of behavioral experience and flexibility of application of behavioral rules in memory, rather than a role in conditional learning per se. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of hippocampal and parietal cortex lesions on memory for egocentric distance and spatial location information in rats

To assess the working memory system for egocentric distance and place information, delayed matching-to-sample (DMTS) go/no-go tasks were run for each rat. To assess the reference memory system, and to serve as a control for nonmemory deficits, successive discrimination go/no-go tasks were then conducted using the same rats. Rats with hippocampal, but not parietal cortex, lesions were impaired relative to controls in the working memory (DMTS) task for both egocentric distance and place information, although the deficit observed in the working memory task for egocentric distance information by rats with hippocampal lesions was mild. Neither hippocampal nor parietal cortex lesioned rats were impaired relative to controls in the reference memory (successive discrimination) task for either cue. The hippocampus appears to be involved in working memory for egocentric distance and in spatial location information, whereas the parietal cortex is not.     

Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease.

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cholinergic blockade effects on spatial integration versus cue discrimination performance.

Conducted a within-Ss investigation to determine the effects of central vs peripheral cholinergic blockade in 20 male Long-Evans hooded rats tested either on a spatial integration task in which the possibility of rule learning was also available or on a visual discrimination task in which the daily location of food was marked by a distinctive visual stimulus pattern. All testing was conducted on the Maier 3-table apparatus. The only effect of peripheral cholinergic blockade, produced by intraperitoneal atropine methylnitrate (50 mg/kg), was a decrease in exploratory behavior. In contrast, central cholinergic blockade by means of atropine sulfate (50 mg/kg) markedly impaired spatial integration performance. However, it did not impair Ss' ability in rule learning or visual discrimination learning. Central cholinergic blockade impaired Ss' tendency to enter all tables before reentering a given table during the exploratory phase of the daily session. This finding suggests an impairment of working memory for spatial information rather than a general impairment in working memory; this interpretation is applied to the explanation of the deficit in the spatial integration performance. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity.

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen to control rats but not in nBM-lesioned rats in the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impariment after nBM lesions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of repeated exposure to forced swimming on extracellular levels of 5-hydroxytryptamine in the rat

The present study examined the effects of electrolytic lesions of the Medial Septum/Vertical Diagonal Band of Broca (MS/VDBB), the Globus Pallidus (GP) and the Substantia- Innominata/Ventral Pallidum (SI/VP) on the performance of rats in object-recognition memory and radial-maze learning tests. In the latter test, subgroups of sham-operated, MS/VDBB, SI/VP and GP rats were treated with saline, amphetamine or physostigmine. (1) In the object recognition task, the level of discrimination wa s significantly lower in GP compared to SI/VP and in both GP and SI/VP compared to Control and MS/VDBB groups, however, only GP did not discriminate between new and familiar objects; (2) in the radial-maze task, GP and SI/VP lesions produced weak and tran sient impairment whereas MS/VDBB lesions produced a large deficit; (3) in the radial-maze task, performance of normal rats was improved with physostigmine and impaired with amphetamine. The effect of amphetamine was significant on non-memory measures only; (4) neither amphetamine nor physostigmine improved memory performances of lesioned rats. These results suggest that the septo-hippocampal projections are involved in spatial memory but not in object recognition whereas the integrity of Substantia Inno minata/Ventral Pallidum does not seem critical for either task. The cholinergic nature of the deficit produced by the medial septal lesion remains in question because of improvements seen in sham-operated rats but not in lesioned rats.     

Lack of task specificity and absence of posttraining effects of atropine on learning.

Three experiments, with 91 male Lister rats, examined the effect of the cholinergic antagonist atropine on the acquisition of learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions, on the retention of performance acquired in the absence of the drug, and on memory consolidation immediately after daily training trials. In Exp I, intraperitoneal atropine sulfate (10 or 50 mg/kg) injected 30 min prior to training severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Exp II, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in Ss previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects of gross sensorimotor impairments. In Exp III, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in Ss trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypotheses that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Results demonstrate dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.

The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquisition, retention, and extinction of operant discriminations in rats with nucleus basalis magnocellularis lesions.

Effects of bilateral ibotenic acid lesions of nucleus basalis magnocellularis (NBM) and scopolamine treatment on different aspects of learning and memory in an operant discrimination task were assessed. In Experiment 1, NBM lesions impaired acquisition performance. In Experiment 2, scopolamine lowered response rates but did not affect discrimination accuracy in lesioned or control rats. In Experiment 3, although pretrained rats showed transient increases in commission errors, percentage correct responding remained above chance levels after lesion. During extinction in Experiment 4, operant responding diminished more quickly in pretrained NBM-lesioned rats than in controls, but subsequent reacquisition performance was equivalent in both groups. Results suggest the NBM is importantly involved in discrimination learning, but cholinergic activity may be less critical for memory retention than for acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Entorhinal-perirhinal lesions impair performance of rats on two versions of place learning in the Morris water maze.

The effects of entorhinal–perirhinal lesions in rats were studied with 2 versions of a place learning task in the Morris water maze. These lesions impaired performance on a multiple-trial task (3 days of 6 trials and a probe trial). This assessment was followed by a task in which rats were repeatedly trained to find novel locations with a variable delay (30 sec or 5 min) imposed between each sample trial and retention test. Entorhinal–perirhinal damage produced a delay-dependent deficit in spatial memory: Rats with lesions were impaired at the 5-min delay relative to the control group and to their own performance at 30 sec. These findings are discussed in relationship to memory impairment after entorhinal damage and spatial learning deficits observed after hippocampal damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolism of 4,7,10,13,16,19-docosahexaenoic acid in isolated perfused adult and newborn pig eyes

In rats, hippocampal lesions result in impairment of spatial navigation, although other learning abilities remain unaltered. When learning a left/right discrimination task, rats can use a spatial strategy (with external maze landmarks-Situation 1) or are forced to use an egocentric strategy (without external or internal maze cues-Situation 2). Little is known about the extrahippocampal systems involved in the utilization of egocentric strategy. It is suggested that striatum could play an important role in the learning abilities that are spared after hippocampal lesion. The aim of our study was to investigate which strategy is used by rats bearing hippocampal or caudate-putamen lesions in the acquisition of a left/right discrimination task in an elevated T-maze in both Situations 1 and 2. We also investigated the effect of each lesion on the reversal of discrimination in both situations. Acquisition was not altered in any of the situations; however, a transfer test showed that hippocampal-lesioned rats used a different strategy (egocentric) from control animals (spatial) in Situation 1. In addition, reversal of the discrimination was impaired in Situation 2. Caudate-putamen lesion produced a transient effect on reversal of discrimination only in the egocentric task (Situation 2), but did not impair acquisition of the task in either situation, thus suggesting that the animals were able to use either strategy.     

Evolution of time coding systems

The neurotrophin receptor p75 is a low-affinity receptor that binds neurotrophins. To investigate the role of p75 in the survival and function of central neurons, p75 null-mutant and wild type litter mate mice were tested on behavioral tasks. Null mutants showed significant performance deficits on water maze, inhibitory avoidance, motor activity, and habituation tasks that may be attributed to cognitive dysfunction or may represent a global sensorimotor impairment. The p75 null-mutant and wild type litter mate mice were assessed for central cholinergic deficit by using quantitative stereology to estimate the total neuronal number in basal forebrain and striatum and for subpopulations expressing the high-affinity tyrosine receptor kinase A (trkA) neurotrophin receptor and choline acetyltransferase (ChAT). In the adult brain, cholinergic neurons of the basal forebrain receive target-derived trophic support, whereas cholinergic striatal neurons do not. Adult p75 null-mutant mice had significant reduction of basal forebrain volume by 25% and had a corresponding significant loss of 37% of total basal forebrain neurons. The basal forebrain population of ChAT-positive neurons in p75-deficient mice declined significantly by 27%, whereas the trkA-positive population did not change significantly. There was no significant change in striatal volume or in striatal neuronal number either in total or by cholinergic subpopulation. These results demonstrate vulnerability to the lack of p75 in adult central neurons that are neurotrophin dependent. In addition, the loss of noncholinergic central neurons in mice lacking p75 suggests a role for p75 in cell survival by an as yet undetermined mechanism. Possible direct and indirect effects of p75 loss on neuronal survival are discussed.     

Cholinergic mediation of spatial memory in the preweanling rat: Application of the radial arm maze paradigm.

In 2 experiments with 70 Sprague-Dawley rats, Ss were trained and tested in the maze from 16 to 25 days of age. Results show that Ss that received training performed significantly better than those naive to the task and better than chance, which suggests an early capacity for this type of learning. To distinguish between the working and the reference memory components of the task, a modification of the basic radial arm maze paradigm was used. Ss trained from 16 days received drug injections of saline, methscopolamine bromide, scopolamine hydrobromide, or arecoline hydrobromide prior to testing at 25 days. Results indicate that central cholinergic antagonism severely impaired working memory while sparing reference memory. This finding is consistent with a role for acetylcholine in adult learning and memory, specifically in working memory. Findings document that (a) the radial-arm-maze paradigm can be used effectively for the developmental study of learning and memory in the rat and (b) cholinergic system(s) mediates working memory at an early age. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deletion of glycine transporter 1 (GlyT1) in forebrain neurons facilitates reversal learning: Enhanced cognitive adaptability?

Local availability of glycine near N-methyl-D-aspartate receptors (NMDARs) is partly regulated by neuronal glycine transporter 1 (GlyT1), which can therefore modulate NMDAR function because binding to the glycine site of the NMDAR is necessary for channel activation. Disrupting GlyT1 in forebrain neurons has been shown to enhance Pavlovian conditioning and object recognition memory. Here, the authors report that the same genetic manipulation facilitated reversal learning in the water maze test of reference memory, but did not lead to any clear improvement in a working memory version of the water maze test. Facilitation in a nonspatial discrimination reversal task conducted on a T maze was also observed, supporting the conclusion that forebrain neuronal GlyT1 may modulate the flexibility in (new) learning and relevant mnemonic functions. One possibility is that these phenotypes may reflect reduced susceptibility to certain forms of proactive interference. This may be relevant for the suggested clinical application of GlyT1 inhibitors in the treatment of cognitive deficits, including schizophrenia, which is characterized by cognitive inflexibility in addition to the positive symptoms of the disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)