Cholinergic lesion of the striatum impairs acquisition and retention of a passive avoidance response.

Significant impairments in the acquisition and retention of a step-down passive avoidance task were found in Sprague-Dawley rats with striatal lesions induced by the cholinergic neurotoxin AF64A. No significant differences between control and AF64A-injected Ss were found in sensitivity to electric shock or in various measures of spontaneous locomotor activity. Striatal choline acetyltransferase (CAT) activity was significantly decreased in AF64A-treated Ss compared to controls, whereas glutamic acid decarboxylase (GAD) activities were not. Furthermore, there were no significant differences between groups in CAT and GAD in either the cortex or the hippocampus, supporting the specificity of the lesion to the striatum. The passive avoidance deficits support a role for the striatal cholinergic system in complex behavioral processes. (14 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Faster acquisition of discriminated lever-press avoidance by hippocampectomized rats.

Reports that 10 male albino rats with bilateral hippocampal destruction produced by aspiration acquired a discriminated lever-press avoidance task faster than, and exhibited avoidance levels consistently superior to 10 unoperated Ss and 10 Ss with neocortical destruction. Destruction of the hippocampus in Ss with extensive previous experience on the task resulted in improved avoidance performance, but the improvement was not significantly superior to the performance of controls. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of prefrontal lesions and combined prefrontal and limbic lesions on subsequent learning performance in the cat.

15 cats were given lesions in either the prefrontal cortex alone (n?=?7) or in the prefrontal cortex, anterior thalamus, mamillary bodies, and subiculum (n?=?8) before being tested in the acquisition of visual-reversal, delayed-alternation, and 2-way active-avoidance tasks. Lesioned Ss were compared to 6 unoperated and 4 sham-operated controls. As an extension of E. Irle and H. J. Markowitsch's (see record 1984-19842-001) study, in which triple limbic lesions failed to impair learning behavior of cats, the present study examined the effects of a lesion in the 4th brain structure (in addition to the original triple lesions). Results indicate that, compared with controls, Ss with prefrontal lesions were impaired in the acquisition of the avoidance task. In contrast, Ss with combined lesions were unimpaired in the acquisition of the visual-reversal task, facilitated in the acquisition of the avoidance task, but impaired in the acquisition of the delayed-alternation task. The superior performance Ss with combined lesions is interpreted as due to a lesion-induced functional shift acting on intact brain structures which, prior to massive limbic lesions, remained inhibited. (56 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine), a new noradrenaline neurotoxin, and stimulus conditions affecting acquisition of two-way active avoidance.

Several CS and UCS variables known to affect the rate of acquisition of the 2-way active avoidance task were investigated in rats treated with the novel selective noradrenaline neurotoxin DSP4 (50 mg/kg, ip). 234 male Sprague-Dawley rats were used in 6 experiments. Although the DSP4 Ss did not demonstrate the linear relation between CS duration and avoidance acquisition to the same extent as controls, their avoidance performance was as drastically disrupted as that of the controls both by preexposure to the CS and by increasing levels of shock intensity. DSP4 Ss also evidenced fear retention for the shuttle box cues previously associated with inescapable shocks to as marked a degree as control Ss. Biochemical data indicated profound noradrenaline depletion in the cortex and hippocampus and a lesser depletion in the hypothalamus. Findings offer a behavioral characterization of the consistent DSP4-induced impairment of 2-way active avoidance acquisition. (46 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Introduction to molecular biology and its application to pediatrics (3): restriction enzymes. Polymerase chain reaction. Ways to study mutations

Central cholinergic neurons play an important role in learning and memory functions. The present study was undertaken to elucidate the pathological changes in learning function and acetylcholine metabolism of the cerebral cortex and hippocampus, following microsphere embolism in rats. Microspheres (48 microns) were injected into the right internal carotid artery of the rats. Learning function was determined using a passive avoidance task on the seventh day after the embolism. In the biochemical study, acetylcholine and choline contents, and choline acetyltransferase activity were measured in the cerebral cortex and hippocampus. Cortical acetylcholinesterase-containing fibers were quantitatively estimated in the embolized rat. Passive avoidance was impaired in the microsphere-embolized rat. Microsphere embolism decreased the acetylcholine concentration and choline acetyltransferase activity in the cerebral cortex and hippocampus. In the histochemical study, the length of cortical acetylcholinesterase-containing fibers was decreased, but cell density was unchanged in the ipsilateral hemisphere of the microsphere-embolized rat. The results suggest that microsphere embolism induces severe damage to cholinergic neurons, which may be related to the impairment of learning function in the ischemic brain.     

Different effects of postnatal day 1 versus 7 192 immunoglobulin G-saporin lesions on learning, exploratory behaviors, and neurochemistry in juvenile rats.

Passive avoidance learning and retention, as well as locomotor and exploratory behaviors, were assessed in rats after intraventricular 192 immunoglobulin G-saporin injections on either Postnatal Day 1 (PND1) or PND7. PND1-lesioned rats were not significantly impaired on acquisition or retention of passive avoidance. PND7-lesioned rats acquired the task slower than controls, but retention was not affected. PND7-lesioned rats were less exploratory than controls and showed reduced wall rearing. Histological analysis of PND1- and PND7-lesioned rats revealed no neuronal degeneration in hippocampus or cortex. There was a marked reduction of choline acetyltransferase (ChAT) activity in the hippocampus, cortex, and septum in the PND7-lesioned rats and a slight but significant ChAT depletion in the cortex of PND1-lesioned rats. These data suggest that the cholinergic system is critical for the learning of passive avoidance and exploratory behavior in the developing rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparisons of behavioral effects of hippocampal and prefrontal cortex lesions in the rat.

5 groups of 5 male Wistar rats each, with aspiration lesions of dorsomedial frontal cortex, ventrolateral frontal cortex, hippocampus, or posterior cortex, or with sham operations, were tested in 5 behavioral situations: emotionality assessment, serial spatial reversals, 70:30 spatial probability, differential reinforcement of low rates (DRL), and barpress extinction. Ss with posterocortical lesions did not differ from operated controls on any task. The effects of lesions in the 2 anatomically defined frontal subfields were clearly dissociated on spatial reversals, spatial probability, and DRL. Lesions in either subfield produced a significant increase in emotionality relative to controls, and neither lesion affected barpress extinction. Results suggest that both frontal subfields may be functionally related to the hippocampus but in different ways. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Characterization of perforant path lesions in rodent models of memory and attention

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.     

Role of olfactory bulbectomy and DSP4 treatment in avoidance learning in the rat.

In 3 experiments with 101 male Sprague-Dawley rats, olfactory bulbectomized Ss and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)-treated Ss were studied on a 2-way active avoidance task as well as on step-down passive avoidance and fear conditioning and retention tasks. The DSP4-treated, but not olfactory bulbectomized, Ss were impaired in acquiring 2-way avoidance; bulbectomized, but not DSP4-treated, Ss showed notable passive avoidance and fear retention deficits. Bulbectomized Ss treated with DSP4 did not show passive avoidance and fear retention deficits, nor did these Ss evidence the 2-way avoidance impairment of the DSP4-treated Ss. No alteration of dopamine-beta-hydroxylase activity in the frontal cortex and hippocampus as a result of the bulbectomy operation was indicated. The double dissociation between bulbectomized and DSP4-treated Ss is discussed in terms of opponent behavioral processes, influenced by olfactory bulbectomy and DSP4, which may permit insights into experimental investigations of stress, anxiety, and depression. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some behavioral effects of entorhinal cortex lesions in the albino rat.

Performed 7 experiments on groups of adult male albino Sprague-Dawley rats (N = 74). Ss with lesions in the entorhinal cortex (a) were hyperactive in a novel open field and in activity wheels, (b) were less responsive to punishment than controls, and (c) showed complex changes in several avoidance behaviors. Mild hyperphagia was observed only when the lesions extended into the subiculum. Results support the idea that the entorhinal cortex may relay information from the cingulate cortex and olfactory areas to the hippocampus. It is suggested that entorhinal-midbrain connections demonstrated in other species may serve important functions in the rat. (36 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of dentate gyrus cells in retention of a radial arm maze task and sensitivity of rats to cholinergic drugs.

Male rats that received bilateral injections of colchicine into 2 rostrocaudal sites showed relatively long-lasting alterations in a previously acquired radial arm maze task and specific destruction of dentate granule cells. Subsequent experiments with cholinergic drugs indicate that physostigmine or nicotine had no effect on number of errors made in the maze, although other signs of cholinergic or pharmacological activity were present. RS-86, an analog of arecoline, decreased errors in colchicine-treated Ss, but effects were associated with signs of parasympathetic overstimulation and behavioral sedation. Pretreatment with scopolamine increased errors in controls but had no effect in colchicine-treated Ss. Colchicine-treated Ss were less sensitive to the motor stimulant effect of scopolamine. Effects appeared to be associated with increased levels of choline acetyltransferase in the hippocampus and a down regulation of muscarinic postsynaptic receptors. Intradentate colchicine may destroy granule cells, leading to compensatory reinnervation of cholinergic nerve terminals having cell bodies in the septum. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

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.     

Estrogen and basal forebrain cholinergic neurons: implications for brain aging and Alzheimer's disease-related cognitive decline

Recent studies suggest that estrogen replacement therapy can reduce the risk and severity of Alzheimer's disease (AD)-related dementia in postmenopausal women. Many different mechanisms by which estrogen therapy may help to reduce the risk and severity of AD-related pathophysiology have been proposed. Recent animal studies suggest that one way in which estrogen replacement may help to reduce cognitive deficits associated with aging and AD is by enhancing the functional status of cholinergic projections to the hippocampus and cortex. Here we review the evidence that estrogen is important in the maintenance of cholinergic neurons projecting to the hippocampus and cortex and that estrogen replacement can enhance the functional status of these neurons, as well as reduce cognitive deficits associated with muscarinic cholinergic impairment. Based on these studies, we conclude that, in animals, short-term treatment with physiological levels of estrogen, or estrogen and progesterone, has significant positive effects on cholinergic neurons in the medial septum and nucleus basalis magnocellularis and on their projections to the hippocampus and cortex. We hypothesize that similar effects in humans may help delay the decline in basal forebrain cholinergic function associated with aging and AD and thereby reduce the risk and severity of AD-related dementia in postmenopausal women.     

Neonatal monoaminergic depletion in mice (Mus musculus) improves performance of a novel odor discrimination task

This experiment examined behavior and neurochemistry in adult mice (Mus musculus) after neonatal depletion of monoaminergic fibers projecting to the neocortex and hippocampus. Lesions were made on Postnatal Day 1; mice developed to adulthood and were assessed on simple odor discrimination (SOD) and odor delayed nonmatch-to-sample (DNMS) tasks, passive avoidance (PA), and locomotor activity. On SOD, lesioned mice performed faster than controls but with similar accuracy. On the DNMS task, the lesioned mice performed faster and more accurately than controls. On PA, the lesioned mice exhibited a retention deficit relative to controls. Locomotor activity was similar in the 2 groups. Postmortem analyses revealed that the lesions reduced significantly norepinephrine and serotonin levels in both the neocortex and hippocampus. The data suggest that cortically projecting monoaminergic fibers play an important role in normal cognitive development.     

Semantic fluency in Alzheimer's, Parkinson's, and Huntington's disease: Dissociation of storage and retrieval failures.

Patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and normal controls were compared on 2 versions of a semantic fluency task: a standard, uncued version and a version in which Ss were cued with subordinate categories. All patients were impaired relative to controls on the standard version. On the cued version, PD and HD patients improved significantly, but AD patients did not. AD patients' fluency, but not PD or HD patients', correlated significantly with confrontation naming ability. Impairment exhibited by PD and HD patients on standard semantic fluency tasks may be due to a retrieval deficit, whereas that of AD patients may be due to degradation of semantic memory stores. In addition, the pattern of performance exhibited by a nonaphasic patient with bilateral frontal lobe lesions suggests that the retrieval functions involved may depend on integrity of the prefrontal cortex. (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)     

Differential effects of double and triple lesions of the cat's limbic system on subsequent learning behavior.

Investigated the effects of multiple lesions of the chain-linked subicular cortex, mamillary bodies, and anterior thalamus on the acquisition of a visual reversal and an active 2-way avoidance task by 45 cats. Compared with controls, Ss with lesions of the anterior thalamus and the mamillary bodies (Group AT/MM), of the anterior thalamus and the subiculum (Group AT/SUB), or of the mamillary bodies and the subiculum (Group MM/SUB) were strongly impaired in acquiring the reversal task; Ss with lesions of all 3 structures (Group AT/MM/SUB) were unimpaired. Similarly, in the active avoidance task, 2 of the 3 groups with double lesions (MM/SUB and AT/SUB) were impaired, but Groups AT/MM and AT/MM/SUB were not, compared with the control group. It is suggested that lesion-induced shifts possibly act on intact cortical and/or thalamic structures that, prior to massive limbic lesion, remained inhibited or otherwise suppressed. It is assumed that the influence of 1 of the 3 core regions of the modified Papez-circuit is sufficient for inhibiting the action of such structures, which, following a complete lesion of the system, may control essential parts of the behaviors tested. (60 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective hippocampal lesions and behavior: Effects of kainic acid lesions on performance of place and cue tasks.

Used kainic acid (KA; 1 and 2 μg/μl) lesions to study the effects of damage to the CA3 cell field and subiculum on performance of complex place and cue tasks by 54 male albino rats. In Exp I, neuroanatomical techniques determined the selectivity of the lesions. In a within-Ss design, Ss in Exp II were trained before the operations to run on an 8-arm radial maze with procedures that involved 2 kinds of learning (place and cue) and 2 memory functions (reference memory and working memory). Interrupting the intrahippocampal circuit by damaging the CA3 cell field with KA had minimal effects on performance; injections into subiculum and complete aspiration lesions of hippocampus resulted in impairments on the place but not the cue task. Only intraventricular injections of KA affected performance on both tasks. Results fail to support either the cognitive map or the working memory theory of hippocampal function. It is suggested that distant damage beyond the immediate area of injection complicates interpretation of the results and may limit the usefulness of KA as a neurotoxin in behavioral investigations. (57 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)