Robust habit learning in the absence of awareness and independent of the medial temporal lobe

Habit memory is thought to involve slowly acquired associations between stimuli and responses and to depend on the basal ganglia. Habit memory has been well studied in experimental animals but is poorly understood in humans because of their strong tendency to acquire information as conscious (declarative) knowledge. Here we show that humans have a robust capacity for gradual trial-and-error learning that operates outside awareness for what is learned and independently of the medial temporal lobe. We tested two patients with large medial temporal lobe lesions and no capacity for declarative memory. Both patients gradually acquired a standard eight-pair object discrimination task over many weeks but at the start of each session could not describe the task, the instructions or the objects. The acquired knowledge was rigidly organized, and performance collapsed when the task format was altered.     

Memory for places learned long ago is intact after hippocampal damage.

The hippocampus is part of a system of structures in the medial temporal lobe that are essential for memory. One influential view of hippocampal function emphasizes its role in the acquisition and retrieval of spatial knowledge. By this view, the hippocampus constructs and stores spatial maps and is therefore essential for learning and remembering places, including those learned about long ago. We tested a profoundly amnesic patient (E.P.), who has virtually complete bilateral damage to the hippocampus and extensive damage to adjacent structures in the medial temporal lobe. We asked him to recall the spatial layout of the region where he grew up, from which he moved away more than 50 years ago. E.P. performed as well as or better than age-matched control subjects who grew up in the same region and also moved away. In contrast, E.P. has no knowledge of his current neighbourhood, to which he moved after he became amnesic. Our results show that the medial temporal lobe is not the permanent repository of spatial maps, and support the view that the hippocampus and other structures in the medial temporal lobe are essential for the formation of long-term declarative memories, both spatial and non-spatial, but not for the retrieval of very remote memories, either spatial or non-spatial.     

内侧颞叶癫痫术后认知功能长期追踪研究

目的探讨手术治疗对内侧颞叶癫痫认知功能的长期影响。方法选择32例内侧颞叶癫痫患者,并行前颞叶及内侧结构切除手术治疗,分别于术前、术后1月、术后半年、术后1年、术后1年半及术后2年对患者认知功能进行神经生理学评价,统计分析语言智商、操作商、记忆商和总智商的变化规律。结果内侧颞叶癫痫患者术后1月与术前比较语言智商、记忆商下降(P0.05),而操作商和总智商无差异(P0.05);术后半年语言智商、操作商和总智商与术前比较有明显改善(P0.05),记忆商仍下降;术后1年、术后1年半、术后2年患者的语言智商、操作商、记忆商和总智商处于一个相对稳定的水平,与术后半年比较无差异(P0.05)。结论手术治疗能部分改善内侧颞叶癫痫患者的认知功能,手术后半年认知功能改善明显。     

Cellular networks underlying human spatial navigation

Place cells of the rodent hippocampus constitute one of the most striking examples of a correlation between neuronal activity and complex behaviour in mammals. These cells increase their firing rates when the animal traverses specific regions of its surroundings, providing a context-dependent map of the environment. Neuroimaging studies implicate the hippocampus and the parahippocampal region in human navigation. However, these regions also respond selectively to visual stimuli. It thus remains unclear whether rodent place coding has a homologue in humans or whether human navigation is driven by a different, visually based neural mechanism. We directly recorded from 317 neurons in the human medial temporal and frontal lobes while subjects explored and navigated a virtual town. Here we present evidence for a neural code of human spatial navigation based on cells that respond at specific spatial locations and cells that respond to views of landmarks. The former are present primarily in the hippocampus, and the latter in the parahippocampal region. Cells throughout the frontal and temporal lobes responded to the subjects' navigational goals and to conjunctions of place, goal and view.     

Neural encoding of individual words and faces by the human hippocampus and amygdala

Patients with lesions in the medial temporal lobe (MTL) of the brain, which includes the hippocampus, amygdala and parahippocampal gyrus, are severely impaired in their ability to remember and recognize words or faces which they saw only a short time ago. These lesions also prevent the effect of word repetition on cortical event-related potentials that are associated with these tasks. We have been able to study the response of individual neurons in the human medial temporal lobe to such delayed recognition tasks in epileptic patients undergoing neurosurgery. We found that some MTL neurons preferentially fired on sight of one particular word from a set of ten words used in a memory task, and others fired in response to one particular face. This stimulus-specific firing was maximal during the time that the neocortical event potentials are most sensitive to stimulus repetition, suggesting that the MTL contributes specific information to the cortex during the retrieval of recent memories.     

Neural organization for the long-term memory of paired associates

Most of our long-term memories of episodes or objects are organized so that we can retrieve them by association. Clinical neuropsychologists assess human memory by the paired-associate learning test, in which a series of paired words or figures is presented and the subject is then asked to retrieve the other pair member associated with each cue. Patients with lesions of the temporal lobe show marked impairment in this test. In our study, we trained monkeys in a pair-association task using a set of computer-generated paired patterns. We found two types of task-related neurons in the anterior temporal cortex. One type selectively responded to both pictures of the paired associates. The other type, which had the strongest response to one picture during the cue presentation, exhibited increasing activity during the delay period when the associate of that picture was used as a cue. These results provide new evidence that single neurons acquire selectivity for visual patterns through associative learning. They also indicate neural mechanisms for storage and retrieval in the long-term memory of paired associates.     

Different time courses of learning-related activity in the prefrontal cortex and striatum

To navigate our complex world, our brains have evolved a sophisticated ability to quickly learn arbitrary rules such as 'stop at red'. Studies in monkeys using a laboratory test of this capacity--conditional association learning--have revealed that frontal lobe structures (including the prefrontal cortex) as well as subcortical nuclei of the basal ganglia are involved in such learning. Neural correlates of associative learning have been observed in both brain regions, but whether or not these regions have unique functions is unclear, as they have typically been studied separately using different tasks. Here we show that during associative learning in monkeys, neural activity in these areas changes at different rates: the striatum (an input structure of the basal ganglia) showed rapid, almost bistable, changes compared with a slower trend in the prefrontal cortex that was more in accordance with slow improvements in behavioural performance. Also, pre-saccadic activity began progressively earlier in the striatum but not in the prefrontal cortex as learning took place. These results support the hypothesis that rewarded associations are first identified by the basal ganglia, the output of which 'trains' slower learning mechanisms in the frontal cortex.     

Neuronal correlate of visual associative long-term memory in the primate temporal cortex

In human long-term memory, ideas and concepts become associated in the learning process. No neuronal correlate for this cognitive function has so far been described, except that memory traces are thought to be localized in the cerebral cortex; the temporal lobe has been assigned as the site for visual experience because electric stimulation of this area results in imagery recall and lesions produce deficits in visual recognition of objects. We previously reported that in the anterior ventral temporal cortex of monkeys, individual neurons have a sustained activity that is highly selective for a few of the 100 coloured fractal patterns used in a visual working-memory task. Here I report the development of this selectivity through repeated trials involving the working memory. The few patterns for which a neuron was conjointly selective were frequently related to each other through stimulus-stimulus association imposed during training. The results indicate that the selectivity acquired by these cells represents a neuronal correlate of the associative long-term memory of pictures.     

Neuronal correlate of pictorial short-term memory in the primate temporal cortex

It has been proposed that visual-memory traces are located in the temporal lobes of the cerebral cortex, as electric stimulation of this area in humans results in recall of imagery. Lesions in this area also affect recognition of an object after a delay in both humans and monkeys, indicating a role in short-term memory of images. Single-unit recordings from the temporal cortex have shown that some neurons continue to fire when one of two or four colours are to be remembered temporarily. But neuronal responses selective to specific complex objects, including hands and faces, cease soon after the offset of stimulus presentation. These results led to the question of whether any of these neurons could serve the memory of complex objects. We report here a group of shape-selective neurons in an anterior ventral part of the temporal cortex of monkeys that exhibited sustained activity during the delay period of a visual short-term memory task. The activity was highly selective for the pictorial information to be memorized and was independent of the physical attributes such as size, orientation, colour or position of the object. These observations show that the delay activity represents the short-term memory of the categorized percept of a picture.     

基于双反相二维色谱串联质谱技术的大鼠海马膜蛋白分析

色谱与质谱联用技术在蛋白质组学研究中应用广泛,特别是二维色谱分离技术的发展,为复杂生物样品的分离分析提供了更为精准的技术手段.海马是大脑颞叶内侧的一个重要脑区,主要负责哺乳动物的学习和记忆,实现这些功能的生理过程与海马膜蛋白密切相关,但由于海马膜蛋白具有强疏水性和低丰度的特点,因此在分离和鉴定上难度较高.运用差速离心的方法分离纯化得到成年大鼠的海马膜蛋白,采用双反相二维色谱串联质谱技术进行分离分析.最终鉴定2 502个蛋白,结合生物信息学分析发现,所鉴定到的2 502个蛋白在包含蛋白定位、突触可塑性、蛋白运输以及囊泡转运等在内的与学习记忆功能密切相关的生理过程中均有涉及.这一分析结果为更加全面的揭示海马膜蛋白与脑海马区的特定功能间的具体关系提供了重要的参考.     

On-line, voluntary control of human temporal lobe neurons

Daily life continually confronts us with an exuberance of external, sensory stimuli competing with a rich stream of internal deliberations, plans and ruminations. The brain must select one or more of these for further processing. How this competition is resolved across multiple sensory and cognitive regions is not known; nor is it clear how internal thoughts and attention regulate this competition. Recording from single neurons in patients implanted with intracranial electrodes for clinical reasons, here we demonstrate that humans can regulate the activity of their neurons in the medial temporal lobe (MTL) to alter the outcome of the contest between external images and their internal representation. Subjects looked at a hybrid superposition of two images representing familiar individuals, landmarks, objects or animals and had to enhance one image at the expense of the other, competing one. Simultaneously, the spiking activity of their MTL neurons in different subregions and hemispheres was decoded in real time to control the content of the hybrid. Subjects reliably regulated, often on the first trial, the firing rate of their neurons, increasing the rate of some while simultaneously decreasing the rate of others. They did so by focusing onto one image, which gradually became clearer on the computer screen in front of their eyes, and thereby overriding sensory input. On the basis of the firing of these MTL neurons, the dynamics of the competition between visual images in the subject's mind was visualized on an external display.     

Parietal cortex contributions to information granules following memory consolidation

Previous studies have focused on changes in cerebral cortex activity accompanying memory formation and consolidation. Although the role of the parietal cortex in memory retrieval is well established, it is not well understood how parietal cortex memory con-solidation for mathematical rules is related to granularity of stored information (i.e., degree of detail or precision). Changes in parietal cortex activity associated with memory consolidation were analyzed using the Ebbinghaus paradigm and functional magnetic resonance imaging (fMRI). Over the course of 1 week, participants learned Boolean arithmetic tasks involving stimulus-response mapping rules containing either low- or high-granularity information. FMRI images were collected on day 1 (i.e., low-granularity condition) and day 7 (i.e., high-granularity condition). The present data suggested that with practice, stored information was converted from a low-granularity to a high-granularity form. By following rule learning, it was hypothesized that the process of consolidation would involve an increased degree of rule representation granularity. Evidence for this process was reflected in parietal cortex activity. This finding was consistent with the hypothesis that mnemonic reconstruction in the parietal cortex is required for memory consolidation, and results suggested that information granules are formed during memory consolidation. The present results could increase the understanding of the relationship between memory consolidation and information granularity.     

自传体记忆研究的若干新进展

总结了自传体记忆研究中新近出现的功能研究取向以及自传体记忆脑机制的神经心理学研究和脑成像研究结果。功能取向的研究表明,自传体记忆具有自我、社会和指导这3类主要功能。神经心理学和脑成像研究发现自传体记忆主要定位于颞叶与海马,但这2方面研究的结果之间却存在着很大的不一致：以脑损伤病人进行的神经心理学研究发现自传体记忆主要表现为右侧颞叶与海马的功能,而对正常人的脑成像研究却表明提取自传体记忆事件时主要的激活部位是左侧颞叶与海马。目前尚无关于这种不一致现象的评论与解释,由于自传体记忆的脑成像研究数量较少且结论并不一致,在进行更多的脑成像研究之后再来比较神经心理学与脑成像的研究结果可能更为合适。     

Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory

Surgical, pharmacological and genetic lesion studies have revealed distinct anatomical sites involved with different forms of learning. Studies of patients with localized brain damage and work in rodent model systems, for example, have shown that the hippocampal formation participates in acquisition of declarative tasks but is not the site of their long-term storage. Such lesions are usually irreversible, however, which has limited their use for dissecting the temporal processes of acquisition, storage and retrieval of memories. Studies in bees and flies have similarly revealed a distinct anatomical region of the insect brain, the mushroom body, that is involved specifically in olfactory associative learning. We have used a temperature-sensitive dynamin transgene, which disrupts synaptic transmission reversibly and on the time-scale of minutes, to investigate the temporal requirements for ongoing neural activity during memory formation. Here we show that synaptic transmission from mushroom body neurons is required during memory retrieval but not during acquisition or storage. We propose that the hebbian processes underlying olfactory associative learning reside in mushroom body dendrites or upstream of the mushroom body and that the resulting alterations in synaptic strength modulate mushroom body output during memory retrieval.     

Odour-plume dynamics influence the brain's olfactory code

The neural computations used to represent olfactory information in the brain have long been investigated. Recent studies in the insect antennal lobe suggest that precise temporal and/or spatial patterns of activity underlie the recognition and discrimination of different odours, and that these patterns may be strengthened by associative learning. It remains unknown, however, whether these activity patterns persist when odour intensity varies rapidly and unpredictably, as often occurs in nature. Here we show that with naturally intermittent odour stimulation, spike patterns recorded from moth antennal-lobe output neurons varied predictably with the fine-scale temporal dynamics and intensity of the odour. These data support the hypothesis that olfactory circuits compensate for contextual variations in the stimulus pattern with high temporal precision. The timing of output neuron activity is constantly modulated to reflect ongoing changes in stimulus intensity and dynamics that occur on a millisecond timescale.     

视听工作记忆的相位同步与跨频耦合研究

为了深入了解视听工作记忆中的神经机制和节律耦合规律,采集了视听工作记忆任务脑电数据,通过时频分析确定关键节律及核心电极,并使用多变量模式分析确定关键时间段。theta相位同步在记忆呈现期至关重要,其中额颞叶同步参与听觉记忆,额顶叶同步参与视觉记忆,而theta和alpha的跨频耦合只在特定记忆模态的相关脑区有显著增强。工作记忆任务相关脑区通过远端theta同步协调中央执行功能,alpha同步协调记忆存储缓冲功能,theta-alpha耦合整合不同模态功能间的信息,揭示了视听模态工作记忆的部分神经机制。     

Short-term memory in olfactory network dynamics

Neural assemblies in a number of animal species display self-organized, synchronized oscillations in response to sensory stimuli in a variety of brain areas. In the olfactory system of insects, odour-evoked oscillatory synchronization of antennal lobe projection neurons (PNs) is superimposed on slower and stimulus-specific temporal activity patterns. Hence, each odour activates a specific and dynamic projection neuron assembly whose evolution during a stimulus is locked to the oscillation clock. Here we examine, using locusts, the changes in population dynamics of projection-neuron assemblies over repeated odour stimulations, as would occur when an animal first encounters and then repeatedly samples an odour for identification or localization. We find that the responses of these assemblies rapidly decrease in intensity, while they show a marked increase in spike time precision and inter-neuronal oscillatory coherence. Once established, this enhanced precision in the representation endures for several minutes. This change is stimulus-specific, and depends on events within the antennal lobe circuits, independent of olfactory receptor adaptation: it may thus constitute a form of sensory memory. Our results suggest that this progressive change in olfactory network dynamics serves to converge, over repeated odour samplings, on a more precise and readily classifiable odour representation, using relational information contained across neural assemblies.     

Cortical activity reductions during repetition priming can result from rapid response learning

Recent observation of objects speeds up their subsequent identification and classification. This common form of learning, known as repetition priming, can operate in the absence of explicit memory for earlier experiences, and functional neuroimaging has shown that object classification improved in this way is accompanied by 'neural priming' (reduced neural activity) in prefrontal, fusiform and other cortical regions. These observations have led to suggestions that cortical representations of items undergo 'tuning', whereby neurons encoding irrelevant information respond less as a given object is observed repeatedly, thereby facilitating future availability of pertinent object knowledge. Here we provide experimental support for an alternative hypothesis, in which reduced cortical activity occurs because subjects rapidly learn their previous responses. After a primed object classification (such as 'bigger than a shoebox'), cue reversal ('smaller than a shoebox') greatly slowed performance and completely eliminated neural priming in fusiform cortex, which suggests that these cortical item representations were no more available for primed objects than they were for new objects. In contrast, prefrontal cortex activity tracked behavioural priming and predicted the degree to which cue reversal would slow down object classification--highlighting the role of the prefrontal cortex in executive control.     

Altered brain response to verbal learning following sleep deprivation

The effects of sleep deprivation on the neural substrates of cognition are poorly understood. Here we used functional magnetic resonance imaging to measure the effects of 35 hours of sleep deprivation on cerebral activation during verbal learning in normal young volunteers. On the basis of a previous hypothesis, we predicted that the prefrontal cortex (PFC) would be less responsive to cognitive demands following sleep deprivation. Contrary to our expectations, however, the PFC was more responsive after one night of sleep deprivation than after normal sleep. Increased subjective sleepiness in sleep-deprived subjects correlated significantly with activation of the PFC. The temporal lobe was activated after normal sleep but not after sleep deprivation; in contrast, the parietal lobes were not activated after normal sleep but were activated after sleep deprivation. Although sleep deprivation significantly impaired free recall compared with the rested state, better free recall in sleep-deprived subjects was associated with greater parietal lobe activation. These findings show that there are dynamic, compensatory changes in cerebral activation during verbal learning after sleep deprivation and implicate the PFC and parietal lobes in this compensation.