The Effects of Muscarinic Cholinergic Receptor Blockade in the Rat Anterior Cingulate and Prelimbic/Infralimbic Cortices on Spatial Working Memory

Previous findings indicate that cholinergic input to the medial prefrontal cortex may modulate mnemonic processes. The present experiment determined whether blockade of muscarinic cholinergic receptors in the rodent anterior cingulate and prelimbic/infralimbic cortices impairs spatial working memory. In a 12-arm radial maze, a working memory for spatial locations task was employed using a continuous recognition go/no-go procedure. Rats were allowed to enter 12 arms for a reinforcement. Of the 12 arm presentations, 3 or 4 arms were presented for a second time in a session that did not contain a reinforcement. The number of trials between the first and second presentations of an arm ranged from 0 to 6 (lags). Infusions of scopolamine (1, 5, and 10 μg), a muscarinic cholinergic antagonist, into the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, significantly impaired spatial working memory in a lag- and dose-dependent manner. The deficit induced by scopolamine (10 μg) was attenuated by concomitant intraprelimbic/infralimbic injections of oxotremorine (2 μg), a muscarinic cholinergic agonist. A separate group of rats was tested on a successive spatial discrimination task. Injections of scopolamine (1, 5, and 10 μg) into the prelimbic/infralimbic cortices did not impair performance on the spatial discrimination task. These findings suggest that muscarinic transmission in the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, is important for spatial working memory.     

Differential effects of m1 and m2 receptor antagonists in perirhinal cortex on visual recognition memory in monkeys

Microinfusions of the nonselective muscarinic antagonist scopolamine into perirhinal cortex impairs performance on visual recognition tasks, indicating that muscarinic receptors in this region play a pivotal role in recognition memory. To assess the mnemonic effects of selective blockade in perirhinal cortex of muscarinic receptor subtypes, we locally infused either the m1-selective antagonist pirenzepine or the m2-selective antagonist methoctramine in animals performing one-trial visual recognition, and compared these scores with those following infusions of equivalent volumes of saline. Compared to these control infusions, injections of pirenzepine, but not of methoctramine, significantly impaired recognition accuracy. Further, similar doses of scopolamine and pirenzepine yielded similar deficits, suggesting that the deficits obtained earlier with scopolamine were due mainly, if not exclusively, to blockade of m1 receptors. The present findings indicate that m1 and m2 receptors have functionally dissociable roles, and that the formation of new visual memories is critically dependent on the cholinergic activation of m1 receptors located on perirhinal cells.     

Effects of gonadectomy and androgen supplementation on attention in male rats

Androgens are hypothesized to enhance aspects of mnemonic processing. However, it is unclear whether the memory improvement is associated with changes in earlier aspects of information processing, such as attention. The present experiments examined the effects of gonadectomy or supplementation with testosterone or dihydrotestosterone on performance of male rats in a two-lever attention task that required discrimination of visual signals and non-signals. In Experiment 1, Long-Evans rats were trained in the attention task and then underwent gonadectomy or sham-surgery. Postsurgically, animals were tested for 20 sessions in the attention task and then received manipulations designed to increase attentional demands. Gonadectomized and sham-treated animals performed similarly during immediate postsurgical testing and across all manipulations. Finally, the effects of administering the muscarinic receptor antagonist scopolamine (0, 0.1, and 0.2 mg/kg) on attentional performance were assessed for all animals. Scopolamine decreased accuracy of signal detection but did not differentially affect gonadectomized and sham-treated animals. In Experiment 2, a new group of rats (not gonadectomized) was trained to perform the attention task and subsequently administered testosterone (0, 0.1, and 0.5 mg/kg) or dihydrotestosterone (0, 0.1, and 0.5mg/kg) prior to performing the standard version of the attention task and in the presence of a visual distractor. Testosterone (0.5 mg/kg) decreased accuracy on non-signal trials and, at 0.1 mg/kg, decreased latencies to retrieve a reward. Dihydrotestosterone (0.5 mg/kg) decreased accuracy on non-signal trials during visual distractor sessions. The present data do not support the hypothesis that alterations in attention critically mediate androgen-induced changes in mnemonic processing. Supra-physiological androgen levels appear to be capable of impairing attentional processing.     

Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia

To test the idea that scopolamine provides a suitable pharmacological model of the memory defects associated with cortical or subcortical dementias, we assessed memory on a battery of tasks in healthy young normal subjects who received 0.5 mg scopolamine, 0.1-0.2 mg glycopyrrolate or physiological saline, once each on three separate occasions, and compared the pattern of memory failure induced by scopolamine to that observed on the same tasks in patients with Alzheimer's disease (AD) or Huntington's disease (HD). In agreement with previous reports, scopolamine impaired acquisition and delayed recall of a 14-word list and disrupted retention on the Brown-Peterson distractor task, whereas the peripherally active anticholinergic glycopyrrolate was without effect. However, under scopolamine the pattern of errors made on these memory tasks was quite different from that seen in patients with AD. Scopolamine did not increase the number of false positive errors on delayed recognition of the word list and also failed to increase the number of prior-item intrusions on the Brown-Peterson task. Also, scopolamine did not impair learning of a symbol-digit paired-associate task, and did not reduce the number of words retrieved or increase the number of words repeated on a standardized verbal fluency test. When the effects of scopolamine on memory were compared to the pattern of impairments observed in demented patients with HD, several differences were found. Although scopolamine clearly produces deficits on some measures of anterograde memory, the present findings question whether anticholinergic drugs adequately mimic the full range of memory impairments observed in cortical or subcortical dementias.     

Fetal Alcohol-Exposed Rats Exhibit Differential Response to Cholinergic Drugs on a Delay-Dependent Memory Task

Fetal alcohol exposure in human and rodents produces a number of cognitive deficits including impairments in learning and memory. Recent evidence in our laboratory has shown that fetal alcohol-exposed (FAE) rats respond differently to systemic administration of cholinergic drugs when tested for vigilance and locomotor activity. The present study examined the effects of muscarinic and nicotinic agonists and antagonists on memory performance in a delayed alternation task. Subjects were male offspring of Sprague-Dawley rats fed a 35% ethanol-derived caloric diet, pair-fed with sucrose, or chow-fed with lab chow during the last 2 weeks of gestation. Rats (3 months old) were food-deprived prior to training in the T-maze. Rats were first trained in the alternation task at no delay for five sessions. Rats were then trained at longer delays (20, 60, 180 s) until all groups showed similar performance for two consecutive sessions. Each animal was then tested following systemic injections of the cholinergic antagonists scopolamine and mecamylamine (60-s delay) and the cholinergic agonists pilocarpine and nicotine (180-s delay). Rats received saline injections on alternate days of testing. The results revealed that FAE rats exhibited no impairments in alternation performance at the no delay and 20-s delay, but showed impairments on both the 60- and 180-s delays during the initial sessions. However, with additional training, FAE rats showed performance similar to that of control groups at these delays. Following both pilocarpine and nicotine injections, control groups, but not the FAE group, showed significant memory enhancement in the alternation task. Following scopolamine injections, the FAE rats showed a significant impairment, while control groups showed a nonsignificant decrease in performance. All three groups showed impairments in the alternation task following administration of mecamylamine compared to saline treatment. These findings suggest that alterations in the cholinergic system in FAE rats may underlie some of the cognitive deficits observed with prenatal alcohol exposure.     

Effects of methylphenidate on working memory in pigeons

To assess the effects of methylphenidate on working memory, pigeons were trained in a delayed matching-to-sample task. Delay interval duration (0.2, 1, 3, 6, or 12 sec) was varied within sessions in order to separate delay-dependent from delay-independent effects of the drug on performance. A reduction in the sample response requirement from five responses to one response effectively reduced attention to the stimulus and impaired overall accuracy. Methylphenidate was administered in doses of 0.0 (saline control), 0.25, 2.5, and 10 mg/kg. Relative to performance with saline, accuracy was significantly reduced with 10 mg/kg methylphenidate to the same extent in both fixed ratio (FR) 1 and FR 5 conditions. The smaller doses had no effect, and there was no evidence that accuracy improved with drug administration. Intercepts and slopes of exponential functions fitted to measures of discriminability plotted as a function of delay showed that methylphenidate affected delay-independent aspects of performance (initial discriminability), but not delay-dependent aspects (rate of forgetting).     

Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.     

The role of attention in binding visual features in working memory: Evidence from cognitive ageing

Two experiments were conducted to assess the costs of attentional load during a feature (colour–shape) binding task in younger and older adults. Experiment 1 showed that a demanding backwards counting task, which draws upon central executive/general attentional resources, reduced binding to a greater extent than individual feature memory, but the effect was no greater in older than in younger adults. Experiment 2 showed that presenting memory items sequentially rather than simultaneously, such that items are required to be maintained while new representations are created, selectively affects binding performance in both age groups. Although this experiment exhibited an age-related binding deficit overall, both age groups were affected by the attention manipulation to an equal extent. While a role for attentional processes in colour–shape binding was apparent across both experiments, manipulations of attention exerted equal effects in both age groups. We therefore conclude that age-related binding deficits neither emerge nor are exacerbated under conditions of high attentional load. Implications for theories of visual working memory and cognitive ageing are discussed.     

Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex

The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (α7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive.     

Perirhinal cortex muscarinic receptor blockade impairs taste recognition memory formation

The relevance of perirhinal cortical cholinergic and glutamatergic neurotransmission for taste recognition memory and learned taste aversion was assessed by microinfusions of muscarinic (scopolamine), NMDA (AP-5), and AMPA (NBQX) receptor antagonists. Infusions of scopolamine, but not AP5 or NBQX, prevented the consolidation of taste recognition memory using attenuation of neophobia as an index. In addition, learned taste aversion in both short- and long-term memory tests was exclusively impaired by scopolamine. These data provide neurochemical support for the theory that cholinergic activity of the perirhinal cortex participates in the formation of the taste memory trace and that it is independent of the NMDA and AMPA receptor activity. These results support the idea that cholinergic neurotransmission in the perirhinal cortex is also essential for acquisition and consolidation of taste recognition memory.     

The memory-impairing effects of septal GABA receptor activation involve GABAergic septo-hippocampal projection neurons

Septal infusions of the gamma-aminobutyric acid (GABA)(A) agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA(A) receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are involved in the memory-impairing effects of septal GABA(A) receptor activation. Experiment 1 tested whether combining septal co-infusions of subeffective doses of muscimol with scopolamine, a drug that selectively influences GABA SH projections, would produce memory deficits. Experiment 2 tested whether hippocampal infusions of a GABA(A) receptor antagonist would block the effects of septal muscimol infusions. Fifteen minutes prior to assessing spontaneous alternation (SA) or training in a multiple trial inhibitory avoidance (CMIA) task, male Sprague-Dawley rats were given septal infusions of vehicle, muscimol, scopolamine, or co-infusions of muscimol with scopolamine, or septal infusions of vehicle or muscimol combined with hippocampal infusions of vehicle or bicuculline. Septal co-infusions of muscimol with scopolamine significantly impaired SA and CMIA. Hippocampal bicuculline infusions blocked deficits produced by septal muscimol infusions in SA and attenuated deficits produced in CMIA. Combined, these findings suggest that GABAergic SH projections are involved in the memory-impairing effects of septal GABA receptor activation.     

Visual short-term memory load strengthens selective attention

Perceptual load theory accounts for many attentional phenomena; however, its mechanism remains elusive because it invokes underspecified attentional resources. Recent dual-task evidence has revealed that a concurrent visual short-term memory (VSTM) load slows visual search and reduces contrast sensitivity, but it is unknown whether a VSTM load also constricts attention in a canonical perceptual load task. If attentional selection draws upon VSTM resources, then distraction effects—which measure attentional “spill-over”—will be reduced as competition for resources increases. Observers performed a low perceptual load flanker task during the delay period of a VSTM change detection task. We observed a reduction of the flanker effect in the perceptual load task as a function of increasing concurrent VSTM load. These findings were not due to perceptual-level interactions between the physical displays of the two tasks. Our findings suggest that perceptual representations of distractor stimuli compete with the maintenance of visual representations held in memory. We conclude that access to VSTM determines the degree of attentional selectivity; when VSTM is not completely taxed, it is more likely for task-irrelevant items to be consolidated and, consequently, affect responses. The “resources” hypothesized by load theory are at least partly mnemonic in nature, due to the strong correspondence they share with VSTM capacity.     

Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory?

The hypothesis that cortical cholinergic inputs mediate attentional functions and capacities has been extensively substantiated by experiments assessing the attentional effects of specific cholinotoxic lesions of cortical cholinergic inputs, attentional performance-associated cortical acetylcholine release, and the effects of pharmacological manipulations of the excitability of basal forebrain corticopetal cholinergic projections on attentional performance. At the same time, numerous animal experiments have suggested that the integrity of cortical cholinergic inputs is not necessary for learning and memory, and a dissociation between the role of the cortical cholinergic input system in attentional functions and in learning and memory has been proposed. We speculate that this dissociation is due, at least in part, to the use of standard animal behavioral tests for the assessment of learning and memory which do not sufficiently tax defined attentional functions. Attentional processes and the allocation of attentional capacities would be expected to influence the efficacy of the acquisition and recall of declarative information and therefore, persistent abnormalities in the regulation of the cortical cholinergic input system may yield escalating impairments in learning and memory. Furthermore, the cognitive effects of loss of cortical cholinergic inputs are augmented by the disruption of the top-down regulation of attentional functions that normally acts to optimize information processing in posterior cortical areas. Because cortical cholinergic inputs play an integral role in the mediation of attentional processing, the activity of cortical cholinergic inputs is hypothesized to also determine the efficacy of learning and memory.     

Simple and conditional discriminations in rats: The effects of delays and scopolamine

In simple delayed discriminations (DD), the reinforcer depends on information available from the sample stimulus, whereas in delayed conditional discriminations (DCD), the reinforcer depends on information jointly available from the sample and the test stimuli. The present experiments compared performance in rats trained in DD and DCD (a) during acquisition over training sessions, and as a function of increasing (b) delay in the memory interval and (c) dosage with the anticholinergic scopolamine. In this work, clicks and tones served as sample stimuli, and bright and dim overhead lights served as test stimuli for lever pressing for food during the test stimulus. The DD task was acquired more rapidly and was more resistant to the effects of delay between the sample and test stimuli. These results replicate previous work with pigeons. In addition, the dose-performance function of scopolamine differed between DD and DCD. Performance declined as a linear function of drug dose in the DCD group. In contrast, performance declined abruptly as a stepwise function of drug dose in the DD group. These latter results suggest that the cholinergic system may be utilized differently during DD and DCD.     

无关长时记忆表征能否引导视觉注意选择?

与任务相关的长时记忆表征在引导视觉注意选择的过程中扮演着重要的角色,它可以使人们在熟悉的视觉情境中快速搜索目标刺激,并偏离干扰刺激。但当长时记忆表征与任务无关时,还能否引导视觉注意选择?目前还不清楚。实验1采用眼动追踪技术直接比较无关工作记忆表征与无关长时记忆表征在视觉搜索阶段对视觉注意的捕获效应,行为反应时与首次注视点百分率的结果都发现,当无关工作记忆表征在视觉搜索中再次出现时能引导视觉注意偏向到与之匹配的干扰刺激,但无关长时记忆表征并没有表现出类似的注意引导效应;实验2探讨记忆表征由工作记忆系统转移到长时记忆系统的过程中对视觉注意的引导效应,结果发现,随着记忆表征的转移,注意引导效应消失了,实验3排除工作记忆表征的干扰后,依然没有发现无关长时记忆表征对注意的引导效应。以上结果表明,无关长时记忆表征并不能像工作记忆表征一样引导视觉注意选择,工作记忆表征和长时记忆表征对视觉注意的引导属于两个不同的认知过程。     

东莨菪碱对大鼠空间参考记忆和工作记忆的不同影响

观察东莨菪碱对空间参考记忆和空间工作记忆的编码、保持和提取过程的作用。应用Morris水迷宫实验测定大鼠的空间参考记忆和空间工作记忆,分别在训练的不同阶段腹腔注射东莨菪碱（1mg/kg）和相同容量的生理盐水,比较各东莨菪碱组和生理盐水组之间游泳潜伏期、路径长度、轨迹和游泳速度的差异。结果发现：与注射生理盐水相比,在训练前和探测实验前注射东莨菪碱的大鼠在探测实验中对目标象限不表现出空间偏爱,说明东莨菪碱干扰参考记忆的信息编码和提取过程;而在训练结束后注射东莨菪碱的大鼠探测实验的结果与生理盐水组相比没有显著差异,说明东莨菪碱对参考记忆的保持过程没有影响。在工作记忆实验中,无论第一次测试前、第一次测试后和第2次测试前注射东莨菪碱,均造成大鼠游泳潜伏期延长,说明东莨菪碱干扰工作记忆的编码、保持和提取过程。研究提示M受体在空间工作记忆和参考记忆中发挥不同作用     

Evidence for Age-related Changes to Temporal Attention and Memory from the Choice Time Production Task

ABSTRACT

The effect of aging on interval timing was examined using a choice time production task, which required participants to choose a key response based on the location of the stimulus, but to delay responding until after a learned time interval. Experiment 1 varied attentional demands of the response choice portion of the task by varying difficulty of stimulus–response mapping. Choice difficulty affected temporal accuracy equally in both age groups, but older participants' response latencies were more variable under more difficult response choice conditions. Experiment 2 tested the contribution of long-term memory to differences in choice time production between age groups over 3 days of testing. Direction of errors in time production between the two age groups diverged over the 3 sessions, but variability did not differ. Results from each experiment separately show age-related changes to attention and memory in temporal processing using different measures and manipulations in the same task.     

Differential effects of muscarinic receptor blockade in prelimbic cortex on acquisition and memory formation of an odor-reward task

The present experiments determined the consequences of blocking muscarinic cholinergic receptors of the prelimbic (PL) cortex in the acquisition and retention of an odor-reward associative task. Rats underwent a training test (five trials) and a 24-h retention test (two retention trials and two relearning trials). In the first experiment, rats were bilaterally infused with scopolamine (20 or 5 microg/site) prior to training. Although scopolamine rats showed acquisition equivalent to PBS-injected controls, they exhibited weakened performance in the 24-h retention test measured by number of errors. In the second experiment, rats were injected with scopolamine (20 microg/site) immediately or 1 h after training and tested 24 h later. Scopolamine rats injected immediately showed severe amnesia detected in two performance measures (errors and latencies), demonstrating deficits in retention and relearning, whereas those injected 1 h later showed good 24-h test performance, similar to controls. These results suggest that muscarinic transmission in the PL cortex is essential for early memory formation, but not for acquisition, of a rapidly learned odor discrimination task. Findings corroborate the role of acetylcholine in consolidation processes and the participation of muscarinic receptors in olfactory associative tasks.     

Delay-dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze

Serotonin (5-HT) plays a modulatory role in mnemonic functions, especially by interacting with the cholinergic system. The 5-HT1B receptor is a key target of this interaction. The 5-HT1B receptor knockout mice were found previously to exhibit a facilitation in hippocampal-dependent spatial reference memory learning. In the present study, we submitted mice to a delayed spatial working memory task, allowing the introduction of various delays between an exposure trial and a test trial. The 5-HT1BKO and wild-type mice learned the task in a radial-arm water maze (returning to the most recent presented arm containing the escape platform), and exhibited a high level of performance at delays of 0 and 5 min. However, at the delay of 60 min, only 5-HT1BKO mice exhibited an impairment. At a delay of 90 min, all mice were impaired. Treatment by scopolamine (0.8 mg/kg) induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. The 22-month-old wild-type and knockout mice exhibited an impairment at short delays (5 and 15 min). The effect of the mutation affected both young-adult and aged mice at delays of 15, 30, and 60 min. Neurobiological data show that stimulation of the 5-HT1B receptor inhibits the release of acetylcholine in the hippocampus, but stimulates this in the frontal cortex. This dual function might, at least in part, explain the opposite effect of the mutation on reference memory (facilitation) and delay-dependent working memory (impairment). These results support the idea that cholinergic-serotonergic interactions play an important role in memory processes.     

The role of attention and study time in explicit and implicit memory for unfamiliar visual stimuli

The effects of limited attentional resources and study time on explicit and implicit memory were studied using Schacter and Cooper’s possible and impossible objects in their recognition and object decision paradigm. In one experiment, when attention at study was limited by a flanking digits procedure, object recognition was diminished but object decision priming for possible objects was unaffected; in another experiment, limiting attention plus reducing stimulus study time impaired object recognition and eliminated object priming. Recognition memory and perceptual priming for previously unfamiliar visual stimuli were both influenced by attention, although to different degrees. The intervening variable of study time determined the degree to which priming was affected by attentional resources. These results support a limited capacity attentional model for both recognition and perceptual priming of unfamiliar visual stimuli, and they highlight the need for assessing the interaction of attentional resources and study time in explicit and implicit memory tasks.