A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory

The prefrontal cortex is involved in the integration and interpretation of information for directing thoughts and planning action. Working memory is defined as the active maintenance of information in mind and is thought to lie at the core of many prefrontal functions. Although dopamine and other neurotransmitters have been implicated, the intracellular events activated by their receptors that influence working memory are poorly understood. We demonstrate that working memory involves transient changes in prefrontal G(q/11)-signaling and in calcium-dependent intracellular protein phosphatase and kinase activity. Interestingly, inhibition of the calcium activated phosphatase calcineurin impaired, while calcium/calmodulin dependent kinase II (CaMKII) and calcium-dependent protein kinase C (PKC) enhanced, working memory. Our findings suggest that the active maintenance of information required for working memory involves transient changes in the balance of these enzymes' activities.     

Distinct prefrontal molecular mechanisms for information storage lasting seconds versus minutes

The prefrontal cortex (PFC) is known to actively hold information "online" for a period of seconds in working memory for guiding goal-directed behavior. It has been proposed that relevant information is stored in other brain regions, which is retrieved and held in working memory for subsequent assimilation by the PFC in order to guide behavior. It is uncertain whether PFC stores information outside the temporal limits of working memory. Here, we demonstrate that although enhanced cAMP-dependent protein kinase A (PKA) activity in the PFC is detrimental to working memory, it is required for performance in tasks involving conflicting representations when memory storage is needed for minutes. This study indicates that distinct molecular mechanisms within the PFC underlie information storage for seconds (working memory) and for minutes (short-term memory). In addition, our results demonstrate that short-term memory storage within the prefrontal cortex is required for guiding behavior in tasks with conflicts and provides a plausible mechanism by which the prefrontal cortex executes cognitive control.     

Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness

The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.     

Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.     

Remembering the time: a continuous clock

The neural mechanisms for time measurement are currently a subject of much debate. This article argues that our brains can measure time using the same dorsolateral prefrontal cells that are known to be involved in working memory. Evidence for this is: (1) the dorsolateral prefrontal cortex is integral to both cognitive timing and working memory; (2) both behavioural processes are modulated by dopamine and disrupted by manipulation of dopaminergic projections to the dorsolateral prefrontal cortex; (3) the neurons in question ramp their activity in a temporally predictable way during both types of processing; and (4) this ramping activity is modulated by dopamine. The dual involvement of these prefrontal neurons in working memory and cognitive timing supports a view of the prefrontal cortex as a multipurpose processor recruited by a wide variety of tasks.     

前额皮层肾上腺素能受体在工作记忆中的作用

前额皮层去甲肾上腺素能神经支配主要来自脑干蓝斑核。前额皮层存在不同类型的肾上腺素能受体。其中突触后α2及β2肾上腺素能受体的激活提高工作记忆;α1及β1肾上腺素能受体的激活损害工作记忆。不同受体是通过激活不同的信号通路发挥对工作记忆的调节作用。来自人类被试的研究结果与对动物的研究结果之间尚存在不一致。了解前额皮层不同肾上腺素受体的作用为开发治疗与前额皮层功能失调相关疾病的药物提供了新的方向。     

Neuroanatomical correlates of processing in visual and visuospatial working memory

Working memory is traditionally seen as being organised in a modular way with a central executive orchestrating at least two slave systems (phonological loop and visuospatial sketch pad). Neuroanatomical correlates of the visual and visuospatial subsystems and the central executive are discussed in this article. A series of experiments are presented yielding evidence for a differentiation into active and passive processing in working memory as well as their neuroanatomical correlates in the prefrontal cortex. Data, yielding evidence for an interaction and separation of visual and visuospatial working memory are presented and discussed. Further results are presented which suggest a convergence of these two systems with increasing working memory demands. The discussed findings will give new insight in the organisation of visual and visuospatial working memory on the anatomical level.     

The primate working memory networks

Working memory has long been associated with the prefrontal cortex, since damage to this brain area can critically impair the ability to maintain and update mnemonic information. Anatomical and physiological evidence suggests, however, that the prefrontal cortex is part of a broader network of interconnected brain areas involved in working memory. These include the parietal and temporal association areas of the cerebral cortex, cingulate and limbic areas, and subcortical structures such as the mediodorsal thalamus and the basal ganglia. Neurophysiological studies in primates confirm the involvement of areas beyond the frontal lobe and illustrate that working memory involves parallel, distributed neuronal networks. In this article, we review the current understanding of the anatomical organization of networks mediating working memory and the neural correlates of memory manifested in each of their nodes. The neural mechanisms of memory maintenance and the integrative role of the prefrontal cortex are also discussed.     

振动触觉频率信息的工作记忆容量及存储机制

工作记忆可以同时保存多个信息并且容量有限, 这一内在机制是工作记忆研究的重点问题。视觉和言语等研究领域都发现工作记忆能够存储多个信息单元, 但对振动触觉工作记忆是否能存储多个频率信息目前尚无相关研究。由于振动触觉频率刺激和视觉刺激具有不同的神经编码机制, 以及振动频率信息是通过躯体感觉产生的模拟的、单维的、参数化信息, 振动触觉工作记忆容量及其加工存储机制的研究也必不可少。首先, 本项目将采用新的实验范式, 探究不同的刺激呈现方式以及不同反应报告方式下, 振动触觉工作记忆的容量及其认知机制。其次, 本项目也将同时运用功能磁共振成像(fMRI)技术, 来阐述振动触觉工作记忆加工存储的神经机制。探究基于触觉频率信息的参数工作记忆容量及其神经机制是完善工作记忆模型的重要补充, 将有助于提高我们对工作记忆系统的理解, 并为视觉、听觉、触觉多模态感知觉信息的跨通道研究奠定基础。     

人类工作记忆的某些神经影像研究

采用神经影像技术研究人类工作记忆的脑机理是目前一个十分活跃的研究领域。研究表明存在负责不同信息加工的工作记忆系统 ,如词语工作记忆、空间工作记忆等 ,其中词语工作记忆主要由大脑左半球参与 ,空间工作记忆主要由大脑右半球参与。前额叶在工作记忆中的作用相当复杂 ,包括对记忆信息的注意和抑制、管理、整合等功能。合理巧妙的实验设计、多种研究手段的综合应用必将使人类工作记忆的脑机理得到充分阐明。     

Updating working memory in aircraft noise and speech noise causes different fMRI activations

The present study used fMRI/BOLD neuroimaging to investigate how visual‐verbal working memory is updated when exposed to three different background‐noise conditions: speech noise, aircraft noise and silence. The number‐updating task that was used can distinguish between “substitution processes,” which involve adding new items to the working memory representation and suppressing old items, and “exclusion processes,” which involve rejecting new items and maintaining an intact memory set. The current findings supported the findings of a previous study by showing that substitution activated the dorsolateral prefrontal cortex, the posterior medial frontal cortex and the parietal lobes, whereas exclusion activated the anterior medial frontal cortex. Moreover, the prefrontal cortex was activated more by substitution processes when exposed to background speech than when exposed to aircraft noise. These results indicate that (a) the prefrontal cortex plays a special role when task‐irrelevant materials should be denied access to working memory and (b) that, when compensating for different types of noise, either different cognitive mechanisms are involved or those cognitive mechanisms that are involved are involved to different degrees.     

Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism?

This study tested the hypothesis that dorsolateral prefrontal cortex deficits contribute to both working memory and long-term memory disturbances in schizophrenia. It also examined whether such deficits were more severe for verbal than nonverbal stimuli. Functional magnetic resonance imaging was used to assess cortical activation during performance of verbal and nonverbal versions of a working memory task and both encoding and recognition tasks in 38 individuals with schizophrenia and 48 healthy controls. Performance of both working memory and long-term memory tasks revealed disturbed dorsolateral prefrontal cortex activation in schizophrenia, although medial temporal deficits were also present. Some evidence was found for more severe cognitive and functional deficits with verbal than nonverbal stimuli, although these results were mixed.     

The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences

Concomitant deficits in working memory and behavioral inhibition in several psychiatric disorders like attention-deficit/hyperactivity disorder, addiction or mania, suggest that common brain mechanisms may underlie their etiologies. Based on the theoretical assumption that a continuum exists between health and mental disorders, we explored the relationship between working memory and inhibition in healthy individuals, through spontaneous inter individual differences in behavior, and tested the hypothesis of a functional link through the fronto-striatal dopaminergic system. Rats were classified into three groups, showing good, intermediate and poor working memory and were compared for their inhibitory abilities. These two functions were simultaneously modulated by a dose-effect of d-amphetamine and in situ hybridization was used to quantify dopaminergic receptor (RD1) mRNAs in prefrontal cortex and striatal areas. A functional relationship between working memory and inhibition abilities was revealed. Both functions were similarly modulated by d-amphetamine according to an inverted-U shaped relationship and depending on initial individual performances. D-amphetamine selectively improved working memory and inhibition of poor and intermediate performers at low doses whereas it impaired both processes in good performers at a higher dose. D1 receptors were less expressed in prelimbic, infralimbic and anterior cingulate cortices of good compared to intermediate and poor performers, whereas no difference was observed between groups in striatal areas. The synergy of working memory and inhibitory abilities, observed in both healthy and psychiatric populations, may originate from endogenous variability in dopaminergic prefrontal cortex activity. Such findings confirm the validity of a dimensional approach, based on the concept of continuity between health and mental disorders for identifying endophenotypes of mental disorders.     

Greater dependence on working memory and restricted familiarity in orangutans compared with rhesus monkeys

The prefrontal cortex is larger than would be predicted by body size or visual cortex volume in great apes compared with monkeys. Because prefrontal cortex is critical for working memory, we hypothesized that recognition memory tests would engage working memory in orangutans more robustly than in rhesus monkeys. In contrast to working memory, the familiarity response that results from repetition of an image is less cognitively taxing and has been associated with nonfrontal brain regions. Across three experiments, we observed a striking species difference in the control of behavior by these two types of memory. First, we found that recognition memory performance in orangutans was controlled by working memory under conditions in which this memory system plays little role in rhesus monkeys. Second, we found that unlike the case in monkeys, familiarity was not involved in recognition memory performance in orangutans, shown by differences with monkeys across three different measures. Memory in orangutans was not improved by use of novel images, was always impaired by a concurrent cognitive load, and orangutans did not accurately identify images seen minutes ago. These results are surprising and puzzling, but do support the view that prefrontal expansion in great apes favored working memory. At least in orangutans, increased dependence on working memory may come at a cost in terms of the availability of familiarity.

The prefrontal cortex is critical for a suite of cognitive control processes that are conspicuous in human cognition (Miller 2000; Rougier et al. 2005; Braver et al. 2009). One such process is working memory, which actively maintains representations in a state of heightened access for further processing (Baddeley and Hitch 1974; Engle 2010). Working memory and cognitive control are positively correlated with measures of general intelligence in humans, implicating the prefrontal cortex as a key neural structure in the evolution of human cognition (Gray et al. 2003; Unsworth and Engle 2007; Cole et al. 2012). Some neuroanatomical studies have found that the prefrontal cortex is larger than would be predicted based on body size and visual cortex volume in apes compared with monkeys (Rilling 2006; Passingham and Smaers 2014). These findings suggest that the prefrontal cortex expanded disproportionately in great apes during primate evolution. Disproportionate expansion of the prefrontal cortex in great apes may have resulted in greater capacity for cognitive control functions, such as working memory, compared with monkeys. Thus, studies directly comparing working memory in monkeys and apes are critical to understanding the evolution of intelligence in primates.The role of cognitive control, and thus the prefrontal cortex, varies among memory systems. For instance, working memory relies heavily on cognitive control, consuming substantial cognitive resources, and is known to depend on frontal brain areas (Goldman-Rakic 1995; Fuster 1997). In contrast, familiarity, which is a strength-based memory signal that codes for whether or not a percept has previously been experienced (Kelley and Jacoby 1998; Yonelinas 2002), relies substantially less on cognitive control, consumes fewer cognitive resources, and has been mostly associated with nonfrontal areas of the brain such as the perirhinal cortex (Bachevalier and Mishkin 1986; Brown and Aggleton 2001; Haskins et al. 2008; Tu et al. 2011; O''Neil et al. 2012). Thus, working memory and familiarity vary in the degree to which they rely on cognitive control, and the degree to which they rely on prefrontal areas of the brain.If a relatively large prefrontal cortex enhances cognitive control and working memory, then we should expect recognition memory tests to engage working memory relatively more in apes than in monkeys. We evaluated this hypothesis by comparing the contributions of working memory and familiarity with recognition memory performance in orangutans and rhesus monkeys. Because the orangutans and monkeys here compared have different experience with cognitive testing, we aimed to compare the relative contributions of working memory and familiarity in each species, rather than the absolute accuracy of the two species in a particular memory test. This follows a logic similar to that used in many comparative anatomical studies; for example, those cited here that found the prefrontal cortex is larger in apes relative to body weight or visual cortex volume, rather than simply absolute volume.The relative contributions of working memory and familiarity to behavior can be measured in visual recognition memory tests. In these tests subjects study a sample image at the beginning of each trial and after a delay they are presented with a test consisting of the recently seen sample image among distractors (Fig. 1). The images used in these tests can either be repeated, such that the subject''s job is to determine which image in a set of familiar images was seen most recently, or the images can be trial unique, such that at test subjects need to discriminate a previously seen image from novel distractors. Working memory is critical for solving tests with repeating images, but much less so for tests using trial unique images, where familiarity plays a much greater role (Brady and Hampton 2018a). Monkeys (Jitsumori et al. 1988; Basile and Hampton 2013a) and apes (Harlow 1944; Hayes and Thompson 1953) are more accurate and better tolerate long delay intervals in tests with trial-unique stimuli, when familiarity can support performance. Experimentally naïve monkeys require comparatively little training to demonstrate proficient use of familiarity as a mnemonic cue, compared with the training required to become proficient in using working memory (Mishkin and Delacour 1975). Active working memory and passive familiarity are independent mnemonic processes that can be doubly dissociated. Working memory is impaired by a concurrent cognitive load imposed during the memory interval, while familiarity is not affected (Logie 1986; Jacoby et al. 1989; Basile and Hampton 2013a; Brady and Hampton 2018a). Completing the double dissociation, equating the familiarity of the sample and distractor images during study impairs choice based on familiarity, but not working memory (Brady and Hampton 2018a). Thus, recognition memory tests may allow us to compare the relative contributions of these two memory processes with recognition performance across species.Open in a separate windowFigure 1.Recognition memory tests with repeating and trial-unique images. (A) In tests with trial-unique images, each image was only used once as a sample or a distractor within a session. (B) When tested with repeating images, the images were the same on each trial. The sample image was pseudorandomly selected each trial such that each image appeared equally often as the sample or as a distractor.One might expect orangutans to show greater dependence on working memory compared with rhesus monkeys for at least two reasons. First, working memory is highly refined in humans and orangutans are more closely related to humans phylogenetically, sharing a common ancestor 13 million to 14 million years ago (Stewart and Disotell 1998), whereas rhesus monkeys and humans shared a common ancestor ∼32 million years ago (Roos and Zinner 2015). Second, orangutans have a relatively larger prefrontal cortex compared with monkeys (Rilling 2006; Passingham and Smaers 2014). We compared the ability of rhesus monkeys and orangutans to maintain images from different sets in working memory. We also determined the extent to which familiarity contributed to recognition memory performance. Across three experiments, we observed striking species differences. We found that in orangutans, recognition memory performance for both repeating and trial-unique images was controlled by working memory. In contrast, monkeys relied on working memory for repeating images, and on familiarity for trial-unique images. Furthermore, monkeys dramatically outperformed orangutans in tests that exceeded the capacity and duration of working memory, and thus depended on familiarity.     

Laminar cortical dynamics of cognitive and motor working memory, sequence learning and performance: toward a unified theory of how the cerebral cortex works

How does the brain carry out working memory storage, categorization, and voluntary performance of event sequences? The LIST PARSE neural model proposes an answer that unifies the explanation of cognitive, neurophysiological, and anatomical data. It quantitatively simulates human cognitive data about immediate serial recall and free recall, and monkey neurophysiological data from the prefrontal cortex obtained during sequential sensory-motor imitation and planned performance. The model clarifies why spatial and non-spatial working memories share the same type of circuit design. It proposes how laminar circuits of lateral prefrontal cortex carry out working memory storage of event sequences within layers 6 and 4, how these event sequences are unitized through learning into list chunks within layer 2/3, and how these stored sequences can be recalled at variable rates that are under volitional control by the basal ganglia. These laminar prefrontal circuits are variations of visual cortical circuits that explained data about how the brain sees. These examples from visual and prefrontal cortex illustrate how laminar neocortex can represent both spatial and temporal information, and open the way towards understanding how other behaviors derive from shared laminar neocortical designs.     

Executive Function in Pediatric Bipolar Disorder and Attention-Deficit Hyperactivity Disorder: In Search of Distinct Phenotypic Profiles

Often, there is diagnostic confusion between bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) in youth due to similar behavioral presentations. Both disorders have been implicated as having abnormal functioning in the prefrontal cortex; however, there may be subtle differences in the manner in which the prefrontal cortex functions in each disorder that could assist in their differentiation. Executive function is a construct thought to be a behavioral analogy to prefrontal cortex functioning. We provide a qualitative review of the literature on performance on executive function tasks for BD and ADHD in order to determine differences in task performance and neurocognitive profile. Our review found primary differences in executive function in the areas of interference control, working memory, planning, cognitive flexibility, and fluency. These differences may begin to establish a pediatric BD profile that provides a more objective means of differential diagnosis between BD and ADHD when they are not reliably distinguished by clinical diagnostic methods.     

Neural Bases of Human Working Memory

Working memory is the memory system that allows us to briefly keep information active, often so we can operate on it. Studies with rhesus monkeys first established that this system is partly mediated by neural mechanisms in the prefrontal cortex. Recently, there has been a substantial effort to study the neural bases of working memory in humans, using neuroimaging techniques such as positron emission tomography and functional magnetic resonance imaging. Some of the initial neuroimaging studies with humans focused on the neural mechanisms that mediate our ability to keep spatial information active. These results indicated that human spatial working memory is partly mediated by regions in parietal and prefrontal cortex. Subsequent research has shown that a different neural system is involved when people store object (rather than spatial) information, a difference similar to that found in monkeys.     

视觉工作记忆的过滤效能

过滤效能反映了视觉工作记忆的干扰抑制功能, 研究者可基于储存容量或表征精度对其进行测量, 其神经加工过程主要分为觉察分心项目、过滤启动、实现过滤或储存, 涉及前额叶皮层和基底核、后顶叶皮层的协同作用。过滤效能的变化方向受到年龄、特殊障碍、情绪、认知特点等因素的影响。未来研究仍需解决的问题包括厘清过滤效能与工作记忆容量的关系, 辨明过滤效能的心理实现过程, 探索不同年龄、特殊障碍和职业等群体过滤效能的脑机制以及提升基础研究范式的生态学效度。     

Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation

Dopamine receptors are abundant in the prefrontal cortex (PFC), a critical region involved in working memory. This pharmacological fMRI study tested the relationships between dopamine, PFC function, and individual differences in working memory capacity. Subjects performed a verbal delayed-recognition task after taking either the dopamine receptor agonist bromocriptine or a placebo. Behavioral effects of bromocriptine treatment depended on subjects’ working memory spans, with the greatest behavioral benefit for lower span subjects. After bromocriptine, PFC activity was positively correlated with a measure of cognitive efficiency (RT slope) during the probe period of the task. Less efficient subjects with slower memory retrieval rates had greater PFC activity, whereas more efficient subjects had less activity. After placebo, these measures were uncorrelated. These results support the role of dopamine in verbal working memory and suggest that dopamine may modulate the efficiency of retrieval of items from the contents of working memory. Individual differences in PFC dopamine receptor concentration may thus underlie the behavioral effects of dopamine stimulation on working memory function.     

Developmental differences in prefrontal activation during working memory maintenance and manipulation for different memory loads

The ability to keep information active in working memory is one of the cornerstones of cognitive development. Prior studies have demonstrated that regions which are important for working memory performance in adults, such as dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and superior parietal cortex, become increasingly engaged across school-aged development. The primary goal of the present functional MRI study was to investigate the involvement of these regions in the development of working memory manipulation relative to maintenance functions under different loads. We measured activation in DLPFC, VLPFC, and superior parietal cortex during the delay period of a verbal working memory task in 11-13-year-old children and young adults. We found evidence for age-related behavioral improvements in working memory and functional changes within DLPFC and VLPFC activation patterns. Although activation profiles of DLPFC and VLPFC were similar, group differences were most pronounced for right DLPFC. Consistent with prior studies, right DLPFC showed an interaction between age and condition (i.e. manipulation versus maintenance), specifically at the lower loads. This interaction was characterized by increased activation for manipulation relative to maintenance trials in adults compared to children. In contrast, we did not observe a significant age-dependent load sensitivity. These results suggest that age-related differences in the right DLPFC are specific to working memory manipulation and are not related to task difficulty and/or differences in short-term memory capacity.