Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.     

Using TD learning to simulate working memory performance in a model of the prefrontal cortex and basal ganglia

Delayed-response tasks (DRTs) have been used to assess working memory (WM) processes in human and nonhuman animals. Experiments have shown that the basal ganglia (BG) and dorsolateral prefrontal cortex (DLPFC) subserve DRT performance. Here, we report the results of simulation studies of a systems-level model of DRT performance. The model was trained using the temporal difference (TD) algorithm and uses an actor-critic architecture. The matrisomes of the BG represent the actor and the striosomes represent the critic. Unlike existing models, we hypothesize that the BG subserve the selection of both motor- and cognitive-related information in these tasks. We also assume that the learning of both processes is based on reward presentation. A novel feature of the model is the incorporation of delay-active neurons in the matrisomes, in addition to DLPFC. Another novel feature of the model is the subdivision of the matrisomal neurons into segregated winner-take-all (WTA) networks consisting of delay- versus transiently-active units.Our simulation model proposes a new neural mechanism to account for the occurrence of perseverative responses in WM tasks in striatal-, as well as in prefrontal damaged subjects. Simulation results also show that the model both accounts for the phenomenon of time shifting of dopamine phasic signals and the effects of partial reinforcement and reward magnitude on WM performance at both behavioral and neural levels. Our simulation results also found that the TD algorithm can subserve learning in delayed-reversal tasks.     

The neural basis of cognitive control: Response selection and inhibition

The functional neuroanatomy of tasks that recruit different forms of response selection and inhibition has to our knowledge, never been directly addressed in a single fMRI study using similar stimulus–response paradigms where differences between scanning time and sequence, stimuli, and experimenter instructions were minimized. Twelve right-handed participants were scanned on two standard cognitive control tasks, a stimulus–response incompatibility task, and a response inhibition task. A compound trial design allowed comparison of preparing to inhibit an upcoming automatic response to wholly inhibiting an automatic response. Furthermore, inhibiting an automatic response to perform an alternative task-relevant response was compared to wholly inhibiting an automatic response. No differences were found in prefrontal activity when preparing to inhibit an automatic response was compared to wholly inhibiting an automatic response, suggesting a mostly common network. The left inferior frontal gyrus was found to be commonly recruited during both tasks when controlled responses were required, likely due to its role in response selection. In contrast, the right inferior frontal gyrus was found to be more involved when task demands were stronger for response inhibition. Our results are largely consistent with models of cognitive control that postulate that separate psychological constructs, such as response selection and inhibition, are related processes largely served by a common prefrontal network. This prefrontal network is recruited to a greater or lesser extent depending on specific task demands.     

A developmental study of the influence of task characteristics on motor overflow

Motor overflow refers to involuntary movement or muscle activity that may coincide with voluntary movement. This study examined factors influencing motor overflow in 17 children (8-11 years), and 17 adults (18-35 years). Participants performed a finger pressing task by exerting either 33% or 66% of their maximal force output using their dominant or non-dominant hand. Attention was manipulated by tactile stimulation to one or both hands. Overflow relative to the target force was greater in children compared to adults, and at the lower target force for both groups, but was not influenced by attentional stimulation. Childhood overflow was greater when the left-hand performed the task. Although an immature motor system may underlie an inability to suppress involuntary movement, childhood overflow may provide motor stabilization.     

工作记忆的保持与操控：腹侧和背侧额叶皮层的特异性功能磁共振成像活动

为了进行大样本的老化与记忆的功能磁共振成像(fMRI)研究, 研究者设计了言语工作记忆的方案, 并且对一组健康青年人进行了施测。字母的呈现方式主要为两种条件: (i) 保持, 要求被试记住呈现的字母并且能够在4秒的间隔后保持; (ii) 操控, 被试需要将呈现的字母按字母表的顺序进行转换, 并且记住新的顺序。不管是用全脑分析, 还是用预先定义的感兴趣区域的分析方法, 对fMRI数据的分析表明本方案诱发了可靠的额叶皮层的激活, 且操控条件则引发了更为广泛的激活。背外侧和腹内侧前额叶的激活也表现出了不同特点, 操控引发了更多的背外侧前额叶激活。一些皮下区域也得到了激活, 特别是以前发现与工作记忆任务相关的一些区域。这说明该工作记忆研究方案适合探索额叶功能的与年龄相关的改变。     

联觉的认知神经机制

联觉是指由一种感官刺激引起其他感官体验的心理过程。近年来的研究将行为实验和脑成像技术结合,发现了联觉的认知神经基础。本文总结了最受关注的字形-颜色联觉的研究成果,认为联觉发生在视知觉加工的早期阶段,与知觉在本质上有许多共同特征,其脑区涉及梭状回（V4）和顶叶。未来联觉的研究将通过综合运用各种方法,进一步拓宽研究范围。     

空间-数字反应编码联合效应下冲突适应过程的ERP研究

为了考察被试在不能意识到任务中包含冲突的情况下的认知控制过程,将产生SNARC效应的奇偶判断任务看作是一种潜在的冲突任务。大小与反应手一致的视为一致的试次,大小与反应手不一致的视为不一致的试次。根据不一致试次之前一个试次的类型将其划分为iI(不一致—不一致,incongruent-incongruent)试次和cI(一致—不一致,congruent-incongruent)试次两种类型。对冲突适应过程的分析表明iI试次的反应时显著快于cI试次,iI试次和cI试次相比,两者的脑电在大约260~300ms的时间段内在FCz位置上差异最大。偶极子分析表明差异波的产生源定位于背侧前扣带回(dorsal anterior cingulate cortex),这些结果与前扣带回的意识监测理论并不一致。最后结合冲突监测理论和其他解释前扣带回功能的理论对研究结果做了相应的解释,认为冲突适应可以是一个无意识的过程     

The neural evidence for simulation is weaker than I think you think it is

Simulation theory accounts of mind-reading propose that the observer generates a mental state that matches the state of the target and then uses this state as the basis for an attribution of a similar state to the target. The key proposal is thus that mechanisms that are primarily used online, when a person experiences a kind of mental state, are then co-opted to run Simulations of similar states in another person. Here I consider the neuroscientific evidence for this view. I argue that there is substantial evidence for co-opted mechanisms, leading from one individual’s mental state to a matching state in an observer, but there is no evidence that the output of these co-opted mechanisms serve as the basis for mental state attributions. There is also substantial evidence for attribution mechanisms that serve as the basis for mental state attributions, but there is no evidence that these mechanisms receive their input from co-opted mechanisms.     

The expression of c-Fos and colocalisation of c-Fos and glucocorticoid receptors in brain structures of low and high anxiety rats subjected to extinction trials and re-learning of a conditioned fear response

We designed an animal model to examine the mechanisms of differences in individual responses to aversive stimuli. We used the rat freezing response in the context fear test as a discriminating variable: low responders (LR) were defined as rats with a duration of freezing response one standard error or more below the mean value, and high responders (HR) were defined as rats with a duration of freezing response one standard error or more above the mean value. We sought to determine the colocalisation of c-Fos and glucocorticoid receptors-immunoreactivity (GR-ir) in HR and LR rats subjected to conditioned fear training, two extinction sessions and re-learning of a conditioned fear. We found that HR animals showed a marked decrease in conditioned fear in the course of two extinction sessions (16 days) in comparison with the control and LR groups. The LR group exhibited higher activity in the cortical M2 and prelimbic areas (c-Fos) and had an increased number of cells co-expressing c-Fos and GR-ir in the M2 and medial orbital cortex after re-learning a contextual fear. HR rats showed increased expression of c-Fos, GR-ir and c-Fos/GR-ir colocalised neurons in the basolateral amygdala and enhanced c-Fos and GR-ir in the dentate gyrus (DG) in comparison with LR animals. Our data indicate that recovery of a context-related behaviour upon re-learning of contextual fear is accompanied in HR animals by a selective increase in c-Fos expression and GRs-ir in the DG area of the hippocampus.     

Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. Several studies have investigated functional and anatomical EE effects. However, as EE effects are different according to cerebral region, cortical layer, dendritic field and morphological index considered, a univocal characterization of neuronal morphological changes following rearing in enriched environments is lacking.Aim of the present study was to characterize in the rat the effects of EE on the neuronal morphology of frontal and parietal cortical regions, the main target areas of the stimulation provided by the paradigm. Male Wistar rats were housed in an enriched environment for 3.5 months from the 21st postnatal day. For the morphological analysis, biotinylated dextran amine (BDA)-labeled pyramidal neurons were selected from frontal (M1–M2) and parietal (S1–S2) cortical layers III and V. Apical and basal dendritic branching and spines were analyzed using the Sholl method.Results showed that EE increased branching and spines in both layers of frontal cortex, but had a greater effect on apical arborization. In parietal cortex, EE significantly affected branching and spines in layer III but not layer V neurons, in which only a tendency to be influenced by the rearing conditions was observed in basal arborization.It is hypothesized that these multifaceted morphological EE effects are connected to the heavy involvement of a sensory-motor circuit engaged in the guidance of voluntary action and in motor learning activated by EE stimulation.