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)     

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

Different effects on learning ability after injection of the cholinergic immunotoxin ME20.4IgG-saporin into the diagonal band of Broca, basal nucleus of Meynert, or both in monkeys.

Immunotoxic lesions of the diagonal band of Broca (VDB) in monkeys disrupted cholinergic input to the hippocampus, producing impaired learning of visuospatial conditional discriminations but not simple visual discriminations. Immunotoxic lesions of the basal nucleus of Meynert (NBM) deprived the cortex of most of its cholinergic input, producing impaired learning of simple visual discriminations but not visuospatial conditional discriminations. Combined lesions of the NBM?+?VDB resulted in impaired learning of both types of task. The impairment after NBM lesions ameliorated with time but could be reinstated by a low dose of the glutamate blocking drug MK801, which, at this dose, did not impair simple visual discrimination learning in normal monkeys. The cholinergic projections from the NBM and VDB may sustain the function of the glutamatergic pyramidal cell pathways within the cortex and hippocampus, respectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

The regulation of hippocampal dynorphin by neural/neuroendocrine pathways: models for effects of aging on an opioid peptide system

Previous research has demonstrated increased messenger RNA expression and peptide content in an opioid system localized to hippocampal dentate granule cells in aged rats. This altered regulation of dynorphin was correlated with the emergence of an age-related impairment in spatial learning. Considerable evidence exists for additional effects of aging on systems that provide input to the dynorphin-containing dentate granule cells. Such changes have been well documented for loss of perforant path innervation from entorhinal cortex, deterioration in septohippocampal cholinergic neurons, and high amounts of glucocorticoids that have, among their targets, receptors located in the dentate gyrus. Similar to the effects of aging on hippocampal dynorphin, age-related changes in each of these systems correlate with the severity of spatial learning impairment in aged rats. This raises the possibility that dysregulation of dynorphin in the aged brain is a reactive response to antecedant change(s) in this circuitry, a hypothesis that was examined by separately manipulating in young rats the three neural/neuroendocrine systems identified above. Of the three models examined only removal of the perforant path reproduced the effect of aging on dynorphin in the hippocampal formation. An immunotoxin was used in Experiment 1 to selectively remove septo-hippocampal cholinergic neurons in young rats. No alteration in hippocampal opioid peptides was produced by this treatment. Experiment 2 examined effects of exposure to excess corticosterone. Adrenalectomized rats exhibited a significant decrease in hippocampal dynorphin-A (1-8) content, which was reversed by corticosterone replacement at a concentration approximating normal basal levels. Dynorphin-A (1-8) content, however, was not reliably increased by exposure to excess corticosterone. In contrast, perforant path removal was found to reproduce the effect of aging on dynorphin content; either aspiration of the entorhinal cortex or knife-cut transections of the perforant path reliably increased hippocampal dynorphin content. These results support the conclusion that age-related deterioration in the septohippocampal cholinergic system and evaluated exposure to corticosterone are not sufficient to induce an elevation in hippocampal dynorphin content. Only removal of the perforant path innervation was found to reproduce the elevation in hippocampal dynorphin content observed in aged rats with hippocampal-dependent learning impairment.     

Loss of rhythmically bursting neurons in rat medial septum following selective lesion of septohippocampal cholinergic system

The medial septum contains cholinergic and GABAergic neurons that project to the hippocampal formation. A significant proportion of the septohippocampal neurons (SHN) exhibit a rhythmically bursting (RB) activity that is involved in the generation of the hippocampal theta rhythm. The neurochemical nature of septal RB neurons is not firmly established. To address this question, the septal unit activity has been recorded in rats after selective destruction of the cholinergic septal neurons by the immunotoxin 192 IgG-saporin. Experiments have been performed in urethan-anesthetized and unanesthetized rats, 14-21 days after lesion. Acetylcholinesterase (AChE) histochemistry revealed a near-complete loss of cholinergic septal neurons and of cholinergic fibers in the hippocampus. The recorded neurons were located in the medial septum-diagonal band of Broca area. A number of these neurons were identified as projecting to the hippocampus (SHN) by their antidromic response to the electrical stimulation of the fimbria-fornix. In urethan-anesthetized lesioned rats, the percentage of RB neurons decreased significantly as compared with controls (17 vs. 41% for SHNs and 5 vs. 19% for unidentified septal neurons). The axonal conduction velocity and the burst frequency of the SHNs that retained a RB activity were higher in lesioned as compared with control rats. The number of spikes per burst was lower and the burst duration was shorter in lesioned rats as compared with controls. The urethan-resistant hippocampal theta was altered both in terms of frequency and amplitude. In unanesthetized lesioned rats, no RB septal neurons were found during arousal, as compared with 25% in controls. Their number was also markedly reduced during paradoxical sleep (9.7 vs. 38.5%). Histochemistry in 192 IgG-saporin-treated rats showed that RB neurons were found in areas devoid of AChE-positive neurons but containing parvalbumine-positive (presumably GABAergic) neurons. These data show that RB activity is considerably reduced after selective lesion of the cholinergic medial septal neurons. They suggested that the large majority of the RB septal neurons are cholinergic and that the few neurons that display RB activity in lesioned rats are GABAergic.     

Individual differences in spatial memory and striatal ChAT activity among young and aged rats

Individual differences in spatial memory among young and aged rats were assessed using memory tasks related to integrity of the hippocampus and the neostriatum. Relationships were then examined between measures of spatial memory and regional choline acetyltransferase (ChAT) activity, a marker for cholinergic integrity. Twenty-four-month-old Long-Evans rats were impaired in comparisons with 6-month-old rats on measures of place learning, working memory, reference memory, and perseveration in water-maze tasks. Aged rats that were impaired on one measure of memory, however, were not necessarily impaired on other measures. ChAT activity in the ventromedial and dorsolateral neostriatum of aged rats was significantly reduced in comparisons with young rats whereas no difference was found in the hippocampus. Aged rats with the most ChAT activity in the anterior ventromedial neostriatum performed best on the place-learning and reference memory tasks but also made the most perseverative errors on the working memory task. In addition, young and aged rats with the most ChAT activity in the anterior dorsolateral neostriatum were those with the least accurate working memory. No relationships were found between ChAT activity in the hippocampus and spatial memory. Thus age-related memory impairment has components that can be segregated by measuring relationships between cholinergic integrity in subregions of the anterior neostriatum and memory tasks with different strategic requirements.     

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

Three experiments, with 63 male Long-Evans rats, investigated the effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (NBM) on the acquisition and retention of several spatial memory tasks. 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, but not the acquisition of a position habit, was also significantly impaired in Ss with these lesions. In several of the tasks, there was evidence of some learning in the lesioned Ss after substantial training, although they were significantly deficient when compared with controls. Intraperitoneal administration of the cholinergic agonists physostigmine sulfate (0.5 mg/kg) or pilocarpine nitrate (3 mg/kg) prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesioned Ss. Lesions significantly reduced the activity of choline acetyltransferase in the anterior and the posterior neocortex but not the hippocampus. Results indicate that the cholinergic projections originating in the NBM are involved in the learning and memory of spatial tasks. (48 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blocking can occur without losses in attention in rats with selective removal of hippocampal cholinergic input.

Prior studies showed that 192 IgG-saporin lesions of cholinergic input to the hippocampus disrupted reductions in processing of uninformative stimuli. In 2 experiments in this study, the performance of rats with these lesions was examined in blocking procedures. In both lesioned and normal rats, previous pairing of one conditioned stimulus (CS) with food blocked conditioning of a 2nd CS when a compound of both CSs was paired with food. However, in subsequent savings tests, lesioned rats showed faster learning than did normal rats when the blocked CS was established as a signal for either reinforcement or nonreinforcement. Thus, the reduced attention to the blocked CS found in normal but not lesioned rats was not essential for the occurrence of blocking. Although rats with selective removal of hippocampal cholinergic input may be unable to reduce attention to redundant stimuli, other mechanisms of stimulus selection remain available to them. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain aging: changes in the nature of information coding by the hippocampus

Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information.     

Preserved neuron number in the hippocampus of aged rats with spatial learning deficits

Hippocampal neuron loss is widely viewed as a hallmark of normal aging. Moreover, neuronal degeneration is thought to contribute directly to age-related deficits in learning and memory supported by the hippocampus. By taking advantage of improved methods for quantifying neuron number, the present study reports evidence challenging these long-standing concepts. The status of hippocampal-dependent spatial learning was evaluated in young and aged Long-Evans rats using the Morris water maze, and the total number of neurons in the principal cell layers of the dentate gyrus and hippocampus was quantified according to the optical fractionator technique. For each of the hippocampal fields, neuron number was preserved in the aged subjects as a group and in aged individuals with documented learning and memory deficits indicative of hippocampal dysfunction. The findings demonstrate that hippocampal neuronal degeneration is not an inevitable consequence of normal aging and that a loss of principal neurons in the hippocampus fails to account for age-related learning and memory impairment. The observed preservation of neuron number represents an essential foundation for identifying the neurobiological effects of hippocampal aging that account for cognitive decline.     

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.     

Reduction in the number of NADPH-diaphorase-positive cells in the cerebral cortex and striatum in aged rats

Nitric oxide (NO) plays an important role as a diffusible messenger in learning and memory. To determine whether changes in NO production in the brain may be involved in aging-associated brain dysfunction, we measured the performance of aged rats in a radial arm maze task, and carried out histochemical examination of the changes in NADPH diaphorase (NADPH-d)-containing neurons in the brains of aged rats. The performance of aged rats (30 months old) in a radial arm maze task was significantly impaired compared to the performance of young rats (3 months old). The number of neurons containing NADPH-d reactivity in the cerebral cortex and striatum of aged rats was significantly reduced, by approximately 50 and 30 percent, respectively, compared to that in young rats. NO synthase activity in discrete brain regions of aged rats, i.e., in the cerebral cortex, striatum and hippocampus was not different from that in young rats, although the activity in the cerebellum of aged rats was significantly lower than that in young rats. These results suggest that the reduction in the number of NADPH-d-positive cells in the brains of aged rats may be involved in aging-associated learning impairment in rats.     

Neonatal 192 IgG-saporin lesions of basal forebrain cholinergic neurons selectively impair response to spatial novelty in adult rats.

The role of the developing cholinergic basal forebrain system on cognitive behaviors was examined in 7 day-old rats by giving lesions with intraventricular injections of 192 IgG-saporin or saline. Rats were subjected to passive avoidance on postnatal days (PND) 22–23, water maze testing on PND 50–60, and a open-field test (in which reactions to spatial and object novelty were measured) on PND 54. Behavioral effects of the lesions were evident only in the open-field test with 5 objects. Unlike controls, the lesioned rats did not detect a spatial change after a displacement of 2 of the 5 objects. Control and lesioned rats, however, showed comparable novelty responses to an unfamiliar object. Lesion effectiveness was confirmed by 75% and 84% decreases in choline acetyltransferase activity in cortex and hippocampus. These results suggest that the developing cholinergic system may be involved in spatial information processing or attention to spatial modifications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Maze learning and morphology of frontal cortex in adult and aged basal forebrain-lesioned rats

Maze performance and morphology of frontal cortex were assessed in young adult, middle-aged, and aged rats with and without lesions of the nucleus basalis magnocellularis. Although maze performance did not vary with age, neuron number and the thickness of superficial laminae were reduced in aged rats. Lamina II-III neurons were hypertrophied in middle-aged rats relative to both younger and older groups. At all ages, lesions significantly impaired maze performance. In young adult rats, lesions moderately reduced the size of lamina II-III neurons. This effect was more pronounced in middle-aged rats. Lesions in aged rats did not affect neuron size. The neuronal changes seen in middle-aged rats may reflect a compensatory response to the expression of other age-related neuronal changes, which may affect the ability of cortical neurons to respond to lesion-induced loss of cholinergic input.     

Immunohistochemical study of Ulex europaeus agglutinin 1 (UEA-1) binding of megakaryocytes in bone marrow biopsy specimens: demonstration of heterogeneity in staining pattern reflecting the stages of differentiation

Age-related spatial memory deficits are correlated with septohippocampal cholinergic system degeneration. The present study examined the effect of intraseptal infusions of the cholinergic agonist, oxotremorine, on spatial reference memory in middle-aged rats using place discrimination in the water maze, and on cholinergic activity using choline acetyltransferase (ChAT) activity. Oxotremorine mildly improved the rate of place discrimination acquisition of middle-aged rats during initial sessions only, but did not affect asymptotic levels of performance achieved. Of the brain regions assayed, ChAT activity increased with age in the temporal cortex and dorsal CA2/3 region of the hippocampus. Oxotremorine significantly decreased ChAT activity in the dorsal hippocampus. In contrast to our previous results in aged rats indicating a more robust effect of oxotremorine on spatial working memory, the present results suggest a modest effect of intraseptal oxotremorine on the acquisition of a spatial reference memory task.     

CD28-costimulation activates cyclic AMP-responsive element-binding protein in T lymphocytes

The retrosplenial cortex (RSC) receives cholinergic afferent fibers from the medial septal nucleus and diagonal band of Broca (DBB) by way of the cingulate bundle and the fornix. Bilateral lesions of both the cingulate and fornix pathways result in a complete depletion of cholinergic input to the RSC. In the present study we have examined the effects of transplanting cholinergic neurons from fetal rat pups to the RSC of adult rats following lesions of the cingulate bundle and fornix. The animals with lesions exhibited severe spatial memory impairments with a complete loss of extrinsic cholinergic afferents to the RSC. Animals with intraretrosplenial cortical transplants exhibited significant improvements in learning and memory performance as revealed by decreased escape latencies in spatial reference memory tests, increased numbers of platform crossings in spatial navigation tests, and a higher percentage of correct choices in a spatial working memory task. These improvements appeared to be cholinergically mediated because atropine administration significantly disrupted spatial navigation performance. The survival of the transplanted cholinergic neurons and their innervation of the RSC were characterized using a monoclonal antibody to choline acetyltransferase (ChAT). The staining of graft-derived ChAT-positive fibers also revealed a pattern of innervation that mimicked that of the cholinergic input in normal animals. These results indicate that intraretrosplenial cortical transplants of cholinergic neurons can rectify spatial memory deficits produced by the loss of intrinsic cholinergic afferents from the medial septal nucleus.     

Muscarinic receptors involved in hippocampal plasticity

The cholinergic septohippocampal system has been associated with learning and memory, as evidenced by the severe loss of these functions in lesioned animals as well as in senile demented patients. In an attempt to comprehend the physiological basis of the cholinergic innervation for hippocampal functions, numerous studies employed the in-vitro hippocampal slice preparation and analyzed the consequences of exposing the cells to cholinergic ligands. Many effects of activating a cholinergic receptor in the hippocampus were thus described, including blockade of several types of potassium conductances, yet few of these effects are intuitively related to the involvement of the cholinergic system in hippocampal plasticity. An alternative approach involves focusing on the possible effect of low concentration of cholinergic ligands on reactivity of the hippocampus to afferent stimulation. We found two new actions of acetylcholine (ACh); The first one is a fast onset, short lived increase in cellular responses to activation of the N-methyl-D-aspartate (NMDA) receptor, and the second one is a slow onset, long lasting increase in reactivity to afferent stimulation, resembling that produced by a tetanic stimulation, which we called muscarinic long term potentiation (LTPm). The latter effect is mediated by a postsynaptic M2 receptor, and it shares several properties with the more familiar tetanic LTP. In addition, LTPm involves a rise of intracellular calcium concentration and an activation of both a tyrosine kinase and a serine/threonine kinase. Intuitively, LTPm is better related to hippocampal plasticity than the other reported effects of ACh in the hippocampus. Indeed, aged rats, which are cognitively impaired, lack LTPm while they do express other muscarinic actions. It is proposed that LTPm is an important link between the cholinergic action and function in the hippocampus.     

Demonstration of cytoplasmic CD32 (Fc gamma RII) within human lymphocytes following microwave treatment

The effects of a novel prolyl endopeptidase inhibitor (PEP), (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)- 1-pyrrolidinecar-boxamide (JTP-4819), on performance of the Morris water maze task and on central cholinergic function were investigated in aged rats. Spatial memory (escape latency, path length, and swimming speed to the platform) was impaired in aged rats performing the Morris water maze task when compared to young rats. Administration of JTP-4819 (1 mg/kg, p.o.) for 14 days improved this memory deficit in aged rats, as shown by the decrease in escape latency and path length. In addition, when JTP-4819 (at doses of 1 and 3 mg/kg, p.o.) was administered for 3 wk, it reversed the age-related increase of ChAT activity in the cerebral cortex and the decrease of 3H-choline uptake in the hippocampus. These data suggest that JTP-4819 ameliorates age-related impairment of spatial memory and partly reverses central cholinergic dysfunction, possibly due to the enhancement of neuropeptide function by inhibition of PEP mediated degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone.