Muscarinic cholinergic influences in memory consolidation

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.     

情景变换诱发已消退恐惧记忆重现的神经环路

暴露疗法是治疗创伤后应激障碍的主要行为疗法。当被试反复暴露于可引起恐惧反应的条件刺激(如白噪音), 但却不伴有非条件刺激(如足底电击)时, 恐惧记忆将被消退, 形成消退记忆。但恐惧记忆并未从根本上被擦除, 当被试在消退训练以外的情景暴露于条件刺激时, 已消退的恐惧记忆将会重现。海马、内侧前额叶皮层、杏仁核等脑区及其相互连接的神经环路是情景诱发恐惧记忆重现的生理基础。情景变化诱发恐惧记忆重现过程中, 海马可能是通过直接投射至杏仁核基底核、杏仁核外侧核或通过边缘前皮质间接调控杏仁核基底核、杏仁核外侧核的功能, 产生恐惧反应。     

Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning

Convergent evidence highlights the differential contributions of various regions of the prefrontal cortex in the service of cognitive control, but little is understood about how the brain determines and communicates the need to recruit cognitive control, and how such signals instigate the implementation of appropriate performance adjustments. Here we review recent progress from cognitive neuroscience in examining some of the main constituent processes of cognitive control as involved in dynamic decision making: goal-directed action selection, response activation and inhibition, performance monitoring, and reward-based learning. Medial frontal cortex is found to be involved in performance monitoring: evaluating outcome vis-a-vis expectancy, and detecting performance errors or conflicting response tendencies. Lateral and orbitofrontal divisions of prefrontal cortex are involved in subsequently implementing appropriate adjustments.     

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.     

A neural model of normal and abnormal learning and memory consolidation: adaptively timed conditioning,hippocampus, amnesia,neurotrophins, and consciousness

How do the hippocampus and amygdala interact with thalamocortical systems to regulate cognitive and cognitive-emotional learning? Why do lesions of thalamus, amygdala, hippocampus, and cortex have differential effects depending on the phase of learning when they occur? In particular, why is the hippocampus typically needed for trace conditioning, but not delay conditioning, and what do the exceptions reveal? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later do not? Why do thalamic or sensory cortical lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions during trace conditioning experiments degrade recent but not temporally remote learning? Why do orbitofrontal cortical lesions degrade temporally remote but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of prefrontal cortex after memory consolidation? How are attention and consciousness linked during conditioning? How do neurotrophins, notably brain-derived neurotrophic factor (BDNF), influence memory formation and consolidation? Is there a common output path for learned performance? A neural model proposes a unified answer to these questions that overcome problems of alternative memory models.     

提取学习有利于学习与记忆的认知神经基础

研究表明提取学习相比简单重复学习更加益于记忆的保持。近期的脑成像研究发现, 与简单重复学习相比, 提取学习时前额叶、顶下叶、颞叶及一些皮层下结构的脑激活更大, 这些脑区的激活也能预测随后的记忆成绩。这些研究表明, 在更多认知资源的投入和工作记忆系统的参与下, 提取学习是一个获得、加工、整合和巩固语义关系的过程。提取学习充分调用认知和情感、皮层与皮层下机能, 同时还发挥语义和情景记忆优势来促进学习与记忆。     

经颅直流电刺激技术在增强健康个体认知功能中的应用及其影响因素

经颅直流电刺激作为一种无创脑刺激技术,已在临床治疗及康复领域有广泛应用。随着研究的深入和人类对于自身认知需求的提高,近年来也有研究者开始尝试使用该技术增强健康个体的认知功能。本文从感知觉、注意、记忆、学习和复杂任务五个方面对目前经颅直流电刺激技术在健康个体认知增强领域的研究现状进行梳理和总结,讨论了机制和影响因素,以及未来面临的问题和挑战。     

Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus

Several lines of evidence indicate that Ca2+/calmodulin-stimulated isoforms of adenylyl cyclase (AC) are involved in long-term potentiation and in certain forms of learning. Recently, we found that training in different types of learning task differentially activates Ca2+-sensitive versus Ca2+-insensitive AC activities in certain brain regions, indicating that AC species other than those stimulated by Ca2+/calmodulin may play an important role in learning processes (Guillou, Rose, & Cooper, 1999). Here, we report the effects of spatial reference memory training in a radial arm maze on the levels of AC1 and AC2 mRNA in the dorsal hippocampus of C57BL/6 mice. Acquisition of the task was associated with a learning-specific and time-dependent increase of AC1 mRNA expression selectively in subfields CA1-CA2. In contrast, AC2 mRNA levels were either reduced or not reliably affected depending on the stage of acquisition. Moreover, no significant changes in AC expression were observed either in the dorsal hippocampus of mice trained in a non-spatial (procedural) version of the task or in cortical regions of mice learning the spatial or procedural task. The regional specificity of these effects indicates that the formation of spatial and non-spatial memory requires distinct contributions from Ca2+-sensitive and Ca2+-insensitive AC in the hippocampus. It is suggested that downregulation of AC2 throughout all hippocampal subfields may play a permissive role during the acquisition of spatial learning whereas an upregulation of AC1 specifically in subfield CA1, may be critical to accurately encode, store or use spatial information.     

Neuroanatomy and Neuropathology Associated with Korsakoff’s Syndrome

Although the neuropathology of Korsakoff's syndrome (KS) was first described well over a century ago and the characteristic brain pathology does not pose a diagnostic challenge to pathologists, there is still controversy over the neuroanatomical substrate of the distinctive memory impairment in these patients. Cohort studies of KS suggest a central role for the mammillary bodies and mediodorsal thalamus, and quantitative studies suggest additional damage to the anterior thalamus is required. Rare cases of KS caused by pathologies other than those of nutritional origin provide support for the role of the anterior thalamus and mammillary bodies. Taken together the evidence to date shows that damage to the thalamus and hypothalamus is required, in particular the anterior thalamic nucleus and the medial mammillary nucleus of the hypothalamus. As these nuclei form part of wider memory circuits, damage to the inter-connecting white matter tracts can also result in a similar deficit as direct damage to the nuclei. Although these nuclei and their connections appear to be the primary site of damage, input from other brain regions within the circuits, such as the frontal cortex and hippocampus, or more distant regions, including the cerebellum and amygdala, may have a modulatory role on memory function. Further studies to confirm the precise site(s) and extend of brain damage necessary for the memory impairment of KS are required.     

Constitutive activation of the G-protein subunit Galphas within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression

Memory formation requires cAMP signaling; thus, this cascade has been of great interest in the search for cognitive enhancers. Given that medications are administered long-term, we determined the effects of chronically increasing cAMP synthesis in the brain by expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas*) in postnatal forebrain neurons of mice. Previously, we showed that Galphas* mice exhibit increased adenylyl cyclase activity but decreased cAMP levels in cortex and hippocampus due to a PKA-dependent increase in total cAMP phosphodiesterase (PDE) activity. Here, we extend previous findings by determining if Galphas* mice show increased activity of specific PDE families that are regulated by PKA, if Galphas* mice show PKA-dependent deficits in fear memory, and if these memory deficits are associated with PKA-dependent alterations in neuronal activity as mapped by Arc mRNA expression. Consistent with previous findings, we show here that Galphas* mice exhibit a significant compensatory increase in cAMP PDE1 activity and a trend toward increased cAMP PDE4 activity. Further, inhibiting the presumably elevated PKA activity in Galphas* mice fully rescues short- and long-term memory deficits in a fear-conditioning task, while extending the training session from one to four CS-US pairings partially rescues these deficits. Mapping of Arc mRNA levels suggests these PKA-dependent memory deficits may be related to decreased neuronal activity specifically within the cortex. Galphas* mice show decreased Arc mRNA expression in CA1, orbital cortex, and cortical regions surrounding the hippocampus; however, only the deficits in cortical regions surrounding the hippocampus are PKA dependent. Our results imply that chronically stimulating targets upstream of cAMP may detrimentally affect cognition.     

Changes in frontal and posterior cortical activity underlie the early emergence of executive function

Executive function (EF) is a key cognitive process that emerges in early childhood and facilitates children's ability to control their own behavior. Individual differences in EF skills early in life are predictive of quality‐of‐life outcomes 30 years later (Moffitt et al., 2011). What changes in the brain give rise to this critical cognitive ability? Traditionally, frontal cortex growth is thought to underlie changes in cognitive control (Bunge & Zelazo, 2006; Moriguchi & Hiraki, 2009). However, more recent data highlight the importance of long‐range cortical interactions between frontal and posterior brain regions. Here, we test the hypothesis that developmental changes in EF skills reflect changes in how posterior and frontal brain regions work together. Results show that children who fail a “hard” version of an EF task and who are thought to have an immature frontal cortex, show robust frontal activity in an “easy” version of the task. We show how this effect can arise via posterior brain regions that provide on‐the‐job training for the frontal cortex, effectively teaching the frontal cortex adaptive patterns of brain activity on “easy” EF tasks. In this case, frontal cortex activation can be seen as both the cause and the consequence of rule switching. Results also show that older children have differential posterior cortical activation on “easy” and “hard” tasks that reflects continued refinement of brain networks even in skilled children. These data set the stage for new training programs to foster the development of EF skills in at‐risk children.     

Hippocampus, cortex, and basal ganglia: insights from computational models of complementary learning systems

We present a framework for understanding how the hippocampus, neocortex, and basal ganglia work together to support cognitive and behavioral function in the mammalian brain. This framework is based on computational tradeoffs that arise in neural network models, where achieving one type of learning function requires very different parameters from those necessary to achieve another form of learning. For example, we dissociate the hippocampus from cortex with respect to general levels of activity, learning rate, and level of overlap between activation patterns. Similarly, the frontal cortex and associated basal ganglia system have important neural specializations not required of the posterior cortex system. Taken together, this overall cognitive architecture, which has been implemented in functioning computational models, provides a rich and often subtle means of explaining a wide range of behavioral and cognitive neuroscience data. Here, we summarize recent results in the domains of recognition memory, contextual fear conditioning, effects of basal ganglia lesions on stimulus-response and place learning, and flexible responding.     

Understanding anterograde amnesia: Disconnections and hidden lesions

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesia associated with damage to the diencephalon. First, new anatomical studies have refined our understanding of the links between diencephalic and temporal brain regions associated with amnesia. These studies direct attention to the limited numbers of routes linking the two regions. Second, neuropsychological studies of patients with colloid cysts confirm the importance of at least one of these routes, the fornix, for episodic memory. By combining these anatomical and neuropsychological data strong evidence emerges for the view that damage to hippocampal—mammillary body—anterior thalamic interactions is sufficient to induce amnesia. A third development is the possibility that the retrosplenial cortex provides an integrating link in this functional system. Furthermore, recent evidence indicates that the retrosplenial cortex may suffer “covert” pathology (i.e., it is functionally lesioned) following damage to the anterior thalamic nuclei or hippocampus. This shared indirect “lesion” effect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia but may also help to explain the many similarities between temporal lobe and diencephalic amnesia.     

丰富环境对脑缺血大鼠突触界面结构修饰和PSD-95基因表达的影响

探讨丰富环境干预对局部脑缺血大鼠突触界面结构修饰和突触后致密物-95 (postsynaptic density-95,PSD-95 ) mRNA表达的影响。栓塞健康雄性Sprague-Dawley大鼠的右侧大脑中动脉,建立脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型后,分为丰富环境缺血组(IE)、标准环境缺血组(IS),同时分别设丰富环境假手术组(SE)、标准环境假手术组(SS)。以Morris水迷宫检测大鼠的空间学习记忆能力,应用透射电镜、图像分析和细胞形态计量学技术,观察海马CA1区和额叶皮层突触界面结构变化,采用RT-PCR检测突触后脚手架蛋白PSD-95 mRNA的表达。结果表明：丰富环境干预能有效改善脑缺血导致的空间学习记忆能力下降,并对正常大鼠的空间学习记忆能力也有改善作用。同时,丰富环境干预能抑制局部脑缺血导致的突触数密度减少,该作用对额叶皮层特别明显;丰富环境干预不同程度地逆转脑缺血造成的突触界面参数变化,特别使突触间隙宽度显著减小、PSD厚度明显增加;并有效抑制因脑缺血诱导的PSD-95 mRNA表达下调。以上结果提示,丰富环境改善脑缺血大鼠的空间学习记忆能力可能与其促进缺血区边缘组织突触界面结构修饰,提高PSD-95 mRNA表达有关     

Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts

The cholinergic hypothesis of geriatric memory dysfunction suggests (a) that basal forebrain lesions in animals should mimic cognitive and mnemonic impairments of human dementia and (b) that cholinergic grafts in the cortex and hippocampus may alleviate such impairments, whether induced by basal forebrain lesions or due to the intrinsic processes of ageing. Our own studies addressing these issues are reviewed. Although aged rats manifest impairments in short-term memory that are reversed by cholinergic grafts in the cortex and hippocampus, basal forebrain lesions have produced ambiguous results, which in part are attributable to nonspecific effects of the lesions. Acetylcholinesterase histochemistry and the topography of NBM-cortical connections indicate that basal forebrain lesions that include the NBM in general spare the cholinergic innervation of the prefrontal cortex, but can damage prefrontal cortical outflows via the globus pallidus. Two experiments are presented to indicate that the medial prefrontal cortex and its ventral striatal outputs provide a critical substrate for normal short-term memory performance in delayed matching and nonmatching tasks. These observations can resolve many of the discrepancies in previous lesion and graft studies.     

EPS Mid-Career Award 2006. Understanding anterograde amnesia: disconnections and hidden lesions

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesia associated with damage to the diencephalon. First, new anatomical studies have refined our understanding of the links between diencephalic and temporal brain regions associated with amnesia. These studies direct attention to the limited numbers of routes linking the two regions. Second, neuropsychological studies of patients with colloid cysts confirm the importance of at least one of these routes, the fornix, for episodic memory. By combining these anatomical and neuropsychological data strong evidence emerges for the view that damage to hippocampal-mammillary body-anterior thalamic interactions is sufficient to induce amnesia. A third development is the possibility that the retrosplenial cortex provides an integrating link in this functional system. Furthermore, recent evidence indicates that the retrosplenial cortex may suffer "covert" pathology (i.e., it is functionally lesioned) following damage to the anterior thalamic nuclei or hippocampus. This shared indirect "lesion" effect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia but may also help to explain the many similarities between temporal lobe and diencephalic amnesia.     

睡眠对恐惧学习的影响及其认知神经机制

睡眠问题可能会诱发恐惧相关情绪障碍(焦虑、创伤性应激障碍、恐怖症等),研究睡眠影响恐惧学习的认知神经机制,有助于增强对恐惧相关情绪障碍的预测、诊断和治疗。以往研究表明睡眠剥夺影响恐惧习得和消退主要是通过抑制vmPFC活动,阻碍其与杏仁核的功能连接,从而导致恐惧习得增强或是消退学习受损。进一步研究发现睡眠不同阶段对恐惧学习相关脑区有独特的影响:剥夺(缺乏)快速眼动睡眠会抑制vmPFC活动、增强杏仁核、海马激活,导致恐惧习得增强,消退学习受损,此外边缘皮层的功能连接减少破坏了记忆巩固(恐惧记忆和消退记忆);而慢波睡眠主要与海马变化有关,慢波睡眠期间进行目标记忆重激活可促进恐惧消退学习。未来研究需要增加睡眠影响恐惧泛化的神经机制研究、及昼夜节律中断对恐惧消退的影响,以及关注动物睡眠研究向人类睡眠研究转化中存在的问题。     

The retrosplenial contribution to human navigation: a review of lesion and neuroimaging findings

The clinical and neuroimaging literatures are surveyed in order to collate for the first time the available data on retrosplenial involvement in human navigation. Several notable features emerge from consideration of the case reports of relatively pure topographical disorientation in the presence of a retrosplenial lesion. The majority of cases follow damage to the right retrosplenial cortex, with Brodmann's area 30 apparently compromised in most cases. All patients displayed impaired learning of new routes, and defective navigation in familiar environments complaining they could not use preserved landmark recognition to aid orientation. The deficit generally resolved within eight weeks of onset. The majority of functional neuroimaging studies involving navigation or orientation in large-scale space also activate the retrosplenial cortex, usually bilaterally, with good concordance in the locations of the voxel of peak activation across studies, again with Brodmann's area 30 featuring prominently. While there is strong evidence for right medial temporal lobe involvement in navigation, it now seems that the inputs the hippocampus and related structures receive from and convey to right retrosplenial cortex have a similar spatial preference, while the left medial temporal and left retrosplenial cortices seem primarily concerned with more general aspects of episodic memory.     

The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat

Investigation of the anatomical substructure of the medial temporal lobe has revealed a number of highly interconnected areas, which has led some to propose that the region operates as a unitary memory system. However, here we outline the results of a number of studies from our laboratories, which investigate the contributions of the rat's perirhinal cortex and postrhinal cortex to memory, concentrating particularly on their respective roles in memory for objects. By contrasting patterns of impairment and spared abilities on a number of related tasks, we suggest that perirhinal cortex and postrhinal cortex make distinctive contributions to learning and memory: for example, that postrhinal cortex is important in learning about within-scene position and context. We also provide evidence that despite the strong connectivity between these cortical regions and the hippocampus, the hippocampus, as evidenced by lesions of the fornix, has a distinct function of its own—combining information about objects, positions, and contexts.     

The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat.

Investigation of the anatomical substructure of the medial temporal lobe has revealed a number of highly interconnected areas, which has led some to propose that the region operates as a unitary memory system. However, here we outline the results of a number of studies from our laboratories, which investigate the contributions of the rat's perirhinal cortex and postrhinal cortex to memory, concentrating particularly on their respective roles in memory for objects. By contrasting patterns of impairment and spared abilities on a number of related tasks, we suggest that perirhinal cortex and postrhinal cortex make distinctive contributions to learning and memory: for example, that postrhinal cortex is important in learning about within-scene position and context. We also provide evidence that despite the strong connectivity between these cortical regions and the hippocampus, the hippocampus, as evidenced by lesions of the fornix, has a distinct function of its own--combining information about objects, positions, and contexts.