Nucleus basalis magnocellularis and memory: differential effects of two neurotoxins

Although the cholinergic system is involved in memory, noncholinergic systems may also contribute to memory. Lesions of the nucleus basalis magnocellularis (NBM) produce behavioral impairments and reduction of cholinergic markers in the frontal cortex (FC). The present study compared the behavioral effects of lesions made with two different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid. IBO or QUIS was injected into the NBM, and rats were tested in three different tasks: cued delayed nonmatch-to-sample (CDNMS), spatial delayed nonmatch-to-sample (SDNMS), and spatial two-choice simultaneous discrimination (STCSD). IBO producted a greater behavioral impairment than QUIS in the CDNMS and the SDNMS, although QUIS produced a greater drop in choline acetyltransferase (ChAT) activity in the cortex than IBO. At the end of behavioral testing, IBO rats, but not QUIS rats, were impaired in the retention of both tasks. The fact that QUIS lesions produced a greater loss of NBM cholinergic neurons, as determined by decreased ChAT activity, but less of a behavioral impairment in both a spatial and nonspatial task, suggests that the loss of noncholinergic NBM neurons must contribute to the memory impairments following NBM cell loss.     

The Effects of Selective Cholinergic Basal Forebrain Lesions and Aging upon Expectancy in the Rat

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na⁺/K⁺-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.     

The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

The effects of guanfacine, alpha-2 agonist, on the performance of young and aged rats in spatial navigation task.

The aim of the present experiment was to study the effects of a low dose (0.001 mg/kg) of guanfacine, alpha-2 agonist, on the acquisition and retention of a water maze task measuring spatial reference memory in young and aged rats. Aged rats were impaired in the acquisition of this task. Both young and aged rats treated with guanfacine had shorter escape latencies than their saline treated counterparts. However, guanfacine treatment increased the speed of swimming in aged rats. According to the results of the probe trial, guanfacine may slightly improve the acquisition/retention of water maze task in young rats, whereas it may slightly impair the acquisition/retention of aged rats. The results suggest that a low dose of guanfacine administered peripherally may have different effects on young and aged rats in water maze performance, and a low dose of guanfacine does not improve spatial reference memory in aged rats.     

Different types of working memory binding in epilepsy patients with unilateral anterior temporal lobectomy

The medial temporal lobe is an important structure for long-term memory formation, but its role in working memory is less clear. Recent studies have shown hippocampal involvement during working memory tasks requiring binding of information. It is yet unclear whether this is limited to tasks containing spatial features. The present study contrasted three binding conditions and one single-item condition in patients with unilateral anterior temporal lobectomy.A group of 43 patients with temporal lobectomy (23 left; 20 right) and 20 matched controls were examined with a working memory task assessing spatial relational binding (object–location), non-spatial relational binding (object–object), conjunctive binding (object–colour) and working memory for single items. We varied the delay period (3 or 6 s), as there is evidence showing that delay length may modulate working memory performance.The results indicate that performance was worse for patients than for controls in both relational binding conditions, whereas patients were unimpaired in conjunctive binding. Single-item memory was found to be marginally impaired, due to a deficit on long-delay trials only.In conclusion, working memory binding deficits are found in patients with unilateral anterior temporal lobectomy. The role of the medial temporal lobe in working memory is not limited to tasks containing spatial features. Rather, it seems to be involved in relational binding, but not in conjunctive binding. The medial temporal lobe gets involved when working memory capacity does not suffice, for example when relations have to be maintained or when the delay period is long.     

Age,executive function,and social decision making: a dorsolateral prefrontal theory of cognitive aging

Current neuropsychological models propose that some age-related cognitive changes are due to frontal-lobe deterioration. However, these models have not considered the possible subdivision of the frontal lobes into the dorsolateral and ventromedial regions. This study assessed the age effects on 3 tasks of executive function and working memory, tasks dependent on dorsolateral prefrontal dysfunction; and 3 tasks of emotion and social decision making, tasks dependent on ventromedial prefrontal dysfunction. Age-related differences in performance were found on all tasks dependent on dorsolateral prefrontal dysfunction. In contrast, age-related differences were not found on the majority of the tasks dependent on ventromedial prefrontal dysfunction. The results support a specific dorsolateral prefrontal theory of cognitive changes with age, rather than a global decline in frontal-lobe function.     

Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice

Although environmental enrichment improves spatial memory and alters synaptic plasticity in aged rodents, it is unclear whether all types of enrichment treatments yield similar benefits. The present study examined the effects in aged male mice of three types of enrichment on spatial memory in Morris water maze and radial arm maze tasks, and on levels of the presynaptic protein synaptophysin in several brain regions. Non-enriched young and aged males were compared with males exposed to one of the following treatments for 10 weeks: 5 min of daily handling, 3 h of daily basic enrichment, or 24 h of continuous complex enrichment. Young controls outperformed aged controls in both tasks. Neither daily handling nor daily enrichment affected spatial memory or synaptophysin levels. In contrast, continuous enrichment significantly reduced age-related spatial memory decline in both tasks, such that this group was statistically indistinguishable from young controls in most measures of performance. Continuously enriched mice were also significantly better than other aged mice in several spatial memory measures. Despite these improvements, synaptophysin levels in the continuous enrichment group were significantly lower than those of young and aged controls in the frontoparietal cortex, hippocampus, and striatum, suggesting a negative relationship between synaptophysin levels and spatial memory in aged males. These data demonstrate that different types of enrichment in aged male mice have disparate effects on spatial memory, and that the relationship between enrichment-induced changes in synaptophysin levels and spatial memory in aged males differs from that we have previously reported in aged female mice.     

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     

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.     

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.     

Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.     

脑内乙酰胆碱与认知活动的关系

脑内细胞外乙酰胆碱（ACh）的变化主要反映胆碱能神经元的活动,皮层和海马等脑区的ACh主要来源于基底前脑胆碱能神经元的纤维投射。应用微透析等技术在体检测清醒、自由活动动物认知过程中脑内乙酰胆碱的含量,可以研究ACh与特定行为反应和认知活动之间的关系。研究发现当机体需要对新刺激进行分析时,在学习与记忆、空间工作记忆、注意、自发运动和探究行为等认知活动中,基底前脑胆碱能神经元被激活,脑内ACh的释放也随之改变。结果提示脑内胆碱能递质系统活动与认知过程密切相关     

Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity

A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3-5 mo old) and aged (19-21 mo old) male and female Balb/C mice. Animals' performance was assessed on a battery of seven diverse learning tasks. Aged animals exhibited deficits in five of the seven tasks and ranked significantly lower than their young counterparts in general learning abilities (aggregate performance across the battery of tasks). Aging added variability to common core performance (i.e., general learning ability), which translated into increased variability on the individual cognitive tasks. Relatedly, general learning abilities did not differ between the two ages among the best quartile of learners (i.e., cognitive abilities were spared in a subsample of the aged animals). Additionally, working memory capacity (resistance to interference) and duration (resistance to decay) accounted for significantly more of the variability in general learning abilities in aged relative to young animals. Tests of 15 noncognitive performance variables indicated that an increase in body weight (and an associated decrease in general activity) was characteristic of those aged animals which exhibited deficient general learning abilities. These results suggest the possibility that general cognitive deficits in aged animals reflect a failure of specific components of the working memory system, and may be related to variations in body weight and an associated decrease in activity.     

客体与空间工作记忆的分离：来自皮层慢电位的证据

利用128导事件相关电位技术,采用延迟匹配任务的实验范式,测查了16名正常被试在完成客体任务和空间任务时的皮层慢电位（slow cortical potentials,简称sp成分）,实验发现：在后部脑区,客体工作记忆与空间工作记忆在慢波活动的时间上存在分离,空间任务更早的诱发出负sp成分,并且空间任务激活更多的后部脑区;左下前额叶在客体工作记忆任务与空间工作记忆任务中都有激活,并且激活强度不存在显著差异;背侧前额叶主要负责客体信息的保持与复述,但左右背侧前额叶的激活强度存在不对称性。     

Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats

The current study investigated whether, for spatial reference memory, age impacts (1) sensitivity to surgical ovarian hormone loss (Ovx), (2) response to estradiol therapy (ET), and (3) the relation between circulating estradiol levels and memory scores in ovary-intact sham and Ovx plus ET rats. Young, middle-aged and aged Fischer-344 rats received sham, Ovx or Ovx plus ET treatments, and were then tested on the Morris maze. After the last test trial, a probe trial was given whereby the platform was removed. Circulating estradiol levels were then determined and correlated with performance. In Study 1, Ovx facilitated learning on day one, but impaired performance after day one, in young rats. Ovx did not influence performance in middle-aged rats. In young and middle-aged Ovx rats, ET enhanced performance with higher exogenous estradiol levels correlating with better performance during testing and the probe trial. There was no relationship between endogenous estradiol levels and performance in sham young or middle-aged rats. Study 2 showed that, like middle-aged rats, aged rats were not impacted by Ovx. Further, for aged Ovx rats, the ET regimen that was beneficial at earlier ages was no longer effective during test trials, and had only minor benefits for platform localization as assessed by the probe trial. Collectively, the findings suggest that the effects of Ovx as well as responsivity to the currently utilized ET regimen changes with age. Further, there appears to be a distinction between sensitivity to Ovx and responsiveness to ET after Ovx for spatial reference memory performance.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

Intraseptal Flumazenil Enhances, while Diazepam Binding Inhibitor Impairs, Performance in a Working Memory Task

GABA_A/benzodiazepine receptors in the medial septum modulate the activity of cholinergic neurons that innervate the hippocampus. Injection of benzodiazepine (BDZ) agonists into the medial septum impairs working memory performance and decreases high-affinity choline transport (HAChT) in the hippocampus. In contrast, intraseptal injection of the BDZ antagonist flumazenil increases HAChT and prevents the memory deficits induced by systemic BDZs. The present studies attempted to further characterize the behavioral effects of medial septal injections of flumazenil to an endogenous negative modulator of the GABA_A/BDZ receptor complex, diazepam binding inhibitor (DBI). Male Sprague–Dawley rats were cannulated to study the effects of intraseptal injections of these BDZ ligands on spatial working memory, anxiety-related behaviors in the elevated plus maze, and on general locomotor activity. Intraseptal flumazenil (10 nmol/0.5 μl) produced a delay-dependent enhancement of DNMTS performance after an 8-h, but not a 4-h, delay interval. This promnestic dose of flumazenil had no effect on locomotor activity and did not produce changes in measures of anxiety on the plus maze. Intraseptal injection of DBI had no effect (8 nmol/0.5 μl) or slightly impaired (4 nmol/0.5 μl) DNMTS radial maze performance following an 8-h delay, without producing changes in locomotion or plus maze behavior. These data demonstrate that flumazenil has a unique profile of activity in enhancing working memory following intraseptal injection.     

Preserved spatial memory in old rats survives 10 months without training

Aged rats with extensive prior training on the radial maze retain the capacity for accurate spatial working memory (WM) for at least 3 months without practice. To investigate the temporal limits of this influence of prior experience we compared the reacquisition of spatial WM by a group of experienced 21.5-month-old rats to the original acquisition by naive 3-month-old rats. The aged rats had received 225 radial maze tests between 3 and 11 months of age. Despite 10 months without practice the old rats rapidly reacquired critical performance. Their reacquisition was markedly superior to original learning by the young rats, even when delays as long as 5 h were imposed between the rats' fourth and fifth choices during the daily tests in the eight-arm maze. Additional tests showed that neither young nor old rats employed a response strategy to maintain accurate spatial WM performance. Experience clearly confers long-lived protection against the otherwise deleterious effects of aging on spatial WM, but the mechanism by which this influence arises is unknown.     

Implicit Learning of Affective Responses in Dementia Patients: A Face-Emotion-Association Paradigm

ABSTRACT

Young and older adults performed verbal and spatial storage-only and storage-plus-processing working memory tasks while performing a secondary finger tapping task, and the effects on both the maximum capacity (measured as the longest series correct) and the reliability (measured as the proportion of items correct) of working memory were assessed. Tapping tended to produce greater disruption of working memory tasks that place greater demands on executive processes (i.e., storage-plus-processing tasks compared to storage-only span tasks). Moreover, tapping produced domain-general interference, disrupting both verbal and spatial working memory, providing further support for the idea that tapping interferes with the executive component of the working memory system, rather than domain-specific maintenance processes. Nevertheless, tapping generally produced equivalent interference effects in young and older adults. Taken together, these findings are inconsistent with the hypothesis that age-related declines in working memory are primarily attributable to a deficit in the executive component.     

Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats

Normal aging is associated with disruption of neural systems that subserve different aspects of cognitive function, particularly in the hippocampus and frontal cortex. Abnormalities in hippocampal function have been well investigated in rodent models of aging, but studies of frontal cortex function in aged rodents are few. We tested young (4–5 mo old) and aged (27–28 mo old) male Long-Evans rats on an attentional set-shifting task modified slightly from previous publication. After training on two problems in which the reward was consistently associated with the same stimulus dimension, and a reversal of one problem, a new problem was presented in which the reward was consistently associated with the previously irrelevant stimulus dimension (extradimensional shift [EDS]). Aged rats as a group were significantly impaired on the EDS, although some individual aged rats performed as well as young rats on this phase. In addition, some aged rats were impaired on the reversal, although a group effect did not reach significance in this phase. Impairment in neither reversal nor EDS was associated with impairments in spatial learning in the Morris water maze. Young rats with neurotoxic lesions of medial frontal cortex are also selectively impaired on the EDS. These results indicate that normal aging in rats is associated with impaired medial frontal cortex function. Furthermore, age-related declines in frontal cortex function are independent of those in hippocampal function. These results provide a possible basis for correlating age-related changes in neurobiological markers in frontal cortex with cognitive decline.