Neuronal basis of age-related working memory decline

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.     

前额叶Gamma频段tACS对工作记忆影响的研究

基于行为学与脑电(Electroencephalogram EEG) 特征评估40Hz经颅交流电刺激（transcranial alternating current stimulation, tACS）对工作记忆的影响,进一步探究40Hz经颅交流电刺激对脑电与认知功能的调节作用。选取34名被试,并在伪刺激或真刺激后参与工作记忆任务,同时采集被试的行为学数据与脑电数据,最终通过MATLAB与SPSS-26.0进行数据分析,得出40Hz经颅交流电刺激对脑电、行为学数据指标的影响。通过数据分析发现事件相关电位中P3a成分与P3b成分的幅值在不同刺激、不同任务量下表现出显著性,且被试在真刺激后顶叶区的theta-gamma相位幅值耦合显著提升。因此可以得出40Hz经颅交流电刺激使得事件相关电位(Event-related potential, ERP)相关成分幅值有显著变化,且能显著提升被试脑内的相位幅值耦合程度,从而提升了专注度,进而显著提升工作记忆的能力,使得相关行为学数据显著提高。     

Top-down signal from prefrontal cortex in executive control of memory retrieval.

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.     

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.     

Neurons in medial prefrontal cortex signal memory for fear extinction

Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.     

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.     

The role of the anterior prefrontal cortex in human cognition.

Complex problem-solving and planning involve the most anterior part of the frontal lobes including the fronto-polar prefrontal cortex (FPPC), which is especially well developed in humans compared with other primates. The specific role of this region in human cognition, however, is poorly understood. Here we show, using functional magnetic resonance imaging, that bilateral regions in the FPPC alone are selectively activated when subjects have to keep in mind a main goal while performing concurrent (sub)goals. Neither keeping in mind a goal over time (working memory) nor successively allocating attentional resources between alternative goals (dual-task performance) could by themselves activate these regions. Our results indicate that the FPPC selectively mediates the human ability to hold in mind goals while exploring and processing secondary goals, a process generally required in planning and reasoning.     

Single neurons in prefrontal cortex encode abstract rules.

The ability to abstract principles or rules from direct experience allows behaviour to extend beyond specific circumstances to general situations. For example, we learn the 'rules' for restaurant dining from specific experiences and can then apply them in new restaurants. The use of such rules is thought to depend on the prefrontal cortex (PFC) because its damage often results in difficulty in following rules. Here we explore its neural basis by recording from single neurons in the PFC of monkeys trained to use two abstract rules. They were required to indicate whether two successively presented pictures were the same or different depending on which rule was currently in effect. The monkeys performed this task with new pictures, thus showing that they had learned two general principles that could be applied to stimuli that they had not yet experienced. The most prevalent neuronal activity observed in the PFC reflected the coding of these abstract rules.     

Categorization of behavioural sequences in the prefrontal cortex

Although it has long been thought that the prefrontal cortex of primates is involved in the integrative regulation of behaviours, the neural architecture underlying specific aspects of cognitive behavioural planning has yet to be clarified. If subjects are required to remember a large number of complex motor sequences and plan to execute each of them individually, categorization of the sequences according to the specific temporal structure inherent in each subset of sequences serves to facilitate higher-order planning based on memory. Here we show, using these requirements, that cells in the lateral prefrontal cortex selectively exhibit activity for a specific category of behavioural sequences, and that categories of behaviours, embodied by different types of movement sequences, are represented in prefrontal cells during the process of planning. This cellular activity implies the generation of neural representations capable of storing structured event complexes at an abstract level, exemplifying the development of macro-structured action knowledge in the lateral prefrontal cortex.     

Neuronal correlates of a perceptual decision

The relationship between neuronal activity and psychophysical judgement has long been of interest to students of sensory processing. Previous analyses of this problem have compared the performance of human or animal observers in detection or discrimination tasks with the signals carried by individual neurons, but have been hampered because neuronal and perceptual data were not obtained at the same time and under the same conditions. We have now measured the performance of monkeys and of visual cortical neurons while the animals performed a psychophysical task well matched to the properties of the neurons under study. Here we report that the reliability and sensitivity of most neurons on this task equalled or exceeded that of the monkeys. We therefore suggest that under our conditions, psychophysical judgements could be based on the activity of a relatively small number of neurons.     

Neural correlates of decision variables in parietal cortex.

Decision theory proposes that humans and animals decide what to do in a given situation by assessing the relative value of each possible response. This assessment can be computed, in part, from the probability that each action will result in a gain and the magnitude of the gain expected. Here we show that the gain (or reward) a monkey can expect to realize from an eye-movement response modulates the activity of neurons in the lateral intraparietal area, an area of primate cortex that is thought to transform visual signals into eye-movement commands. We also show that the activity of these neurons is sensitive to the probability that a particular response will result in a gain. When animals can choose freely between two alternative responses, the choices subjects make and neuronal activation in this area are both correlated with the relative amount of gain that the animal can expect from each response. Our data indicate that a decision-theoretic model may provide a powerful new framework for studying the neural processes that intervene between sensation and action.     

Watching cartoons activates the medial prefrontal cortex in children

The medial prefrontal cortex (MPFC) of human adults is involved in attributing mental states to real human agents but not to virtual artificial characters. This study examined whether such differential MPFC activity can be observed in children who are more fascinated by cartoons than adults. We measured brain activity using functional magnetic resonance imaging (fMRI) while 10-year-old children watched movie and cartoon clips, simulating real and virtual visual worlds, respectively. We showed neuroimaging evidence that, in contrast to adults, the MPFC of children was activated when perceiving both human agents and artificial characters in coherent visual events. Our findings suggest that, around the age of 10 years, the MPFC activity in children is different from that in adults in that it can be spontaneously activated by non-human agents in a virtual visual world.     

NR1基因敲除对小鼠前额叶脑区LTP的影响

用前脑特异性NR1基因敲除小鼠,采用离体脑片场电位技术,研究了NR1亚基在前额叶脑区突触可塑性中的作用.刺激强度—反应(input-output curve)和双脉冲抑制反应(paired pulse depression, PPD)的结果表明,与同窝对照组小鼠相比,NR1基因敲除小鼠前额叶脑区的基本突触传递无明显变化.采用高频刺激(100 Hz, 1 000 ms ×2, 间隔30 s)在小鼠的前额叶脑区诱导长时程增强(long-term potentiation, LTP),与对照组小鼠相比,NR1基因敲除小鼠前额叶脑区的LTP明显受损.以上数据提示,NR1亚基在前额叶脑区LTP的诱导中起着重要的作用.     

Damage to the prefrontal cortex increases utilitarian moral judgements

The psychological and neurobiological processes underlying moral judgement have been the focus of many recent empirical studies. Of central interest is whether emotions play a causal role in moral judgement, and, in parallel, how emotion-related areas of the brain contribute to moral judgement. Here we show that six patients with focal bilateral damage to the ventromedial prefrontal cortex (VMPC), a brain region necessary for the normal generation of emotions and, in particular, social emotions, produce an abnormally 'utilitarian' pattern of judgements on moral dilemmas that pit compelling considerations of aggregate welfare against highly emotionally aversive behaviours (for example, having to sacrifice one person's life to save a number of other lives). In contrast, the VMPC patients' judgements were normal in other classes of moral dilemmas. These findings indicate that, for a selective set of moral dilemmas, the VMPC is critical for normal judgements of right and wrong. The findings support a necessary role for emotion in the generation of those judgements.     

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.     

Long-term potentiation of prefrontal cortex in NR1 knockout mice

利用前脑特异性NR1基因敲除小鼠,采用离体脑片场电位技术,研究了NR1亚基在前额叶脑区突触可塑性中的作用.刺激强度—反应( input-output curve)和双脉冲抑制反应(paired pulse depression,PPD)的结果表明,与同窝对照组小鼠相比,NR1基因敲除小鼠前额叶脑区的基本突触传递无明显变化.采用高频刺激(100 Hz,1 000 ms×2,间隔30 s)在小鼠的前额叶脑区诱导长时程增强( long-term potentiation,LTP),与对照组小鼠相比,NR1基因敲除小鼠前额叶脑区的LTP明显受损.以上数据提示,NR1亚基在前额叶脑区LTP的诱导中起着重要的作用.     

Discrete fixed-resolution representations in visual working memory

Limits on the storage capacity of working memory significantly affect cognitive abilities in a wide range of domains, but the nature of these capacity limits has been elusive. Some researchers have proposed that working memory stores a limited set of discrete, fixed-resolution representations, whereas others have proposed that working memory consists of a pool of resources that can be allocated flexibly to provide either a small number of high-resolution representations or a large number of low-resolution representations. Here we resolve this controversy by providing independent measures of capacity and resolution. We show that, when presented with more than a few simple objects, human observers store a high-resolution representation of a subset of the objects and retain no information about the others. Memory resolution varied over a narrow range that cannot be explained in terms of a general resource pool but can be well explained by a small set of discrete, fixed-resolution representations.     

Imaging cortical correlates of illusion in early visual cortex

Exploring visual illusions reveals fundamental principles of cortical processing. Illusory motion perception of non-moving stimuli was described almost a century ago by Gestalt psychologists. However, the underlying neuronal mechanisms remain unknown. To explore cortical mechanisms underlying the 'line-motion' illusion, we used real-time optical imaging, which is highly sensitive to subthreshold activity. We examined, in the visual cortex of the anaesthetized cat, responses to five stimuli: a stationary small square and a long bar; a moving square; a drawn-out bar; and the well-known line-motion illusion, a stationary square briefly preceding a long stationary bar presentation. Whereas flashing the bar alone evoked the expected localized, short latency and high amplitude activity patterns, presenting a square 60-100 ms before a bar induced the dynamic activity patterns resembling that of fast movement. The preceding square, even though physically non-moving, created gradually propagating subthreshold cortical activity that must contribute to illusory motion, because it was indistinguishable from cortical representations of real motion in this area. These findings demonstrate the effect of spatio-temporal patterns of subthreshold synaptic potentials on cortical processing and the shaping of perception.