Prelimbic and infralimbic prefrontal cortex interact during fast network oscillations

Background

The medial prefrontal cortex has been implicated in a variety of cognitive and executive processes such as decision making and working memory. The medial prefrontal cortex of rodents consists of several areas including the prelimbic and infralimbic cortex that are thought to be involved in different aspects of cognitive performance. Despite the distinct roles in cognitive behavior that have been attributed to prelimbic and infralimbic cortex, little is known about neuronal network functioning of these areas, and whether these networks show any interaction during fast network oscillations.

Methodology/Principal Findings

Here we show that fast network oscillations in rat infralimbic cortex slices occur at higher frequencies and with higher power than oscillations in prelimbic cortex. The difference in oscillation frequency disappeared when prelimbic and infralimbic cortex were disconnected.

Conclusions/Significance

Our data indicate that neuronal networks of prelimbic and infralimbic cortex can sustain fast network oscillations independent of each other, but suggest that neuronal networks of prelimbic and infralimbic cortex are interacting during these oscillations.     

Prefrontal neurons predict choices during an auditory same-different task

The detection of stimuli is critical for an animal's survival [1]. However, it is not adaptive for an animal to respond automatically to every stimulus that is present in the environment [2-5]. Given that the prefrontal cortex (PFC) plays a key role in executive function [6-8], we hypothesized that PFC activity should be involved in context-dependent responses to uncommon stimuli. As a test of this hypothesis, monkeys participated in a same-different task, a variant of an oddball task [2]. During this task, a monkey heard multiple presentations of a "reference" stimulus that were followed by a "test" stimulus and reported whether these stimuli were the same or different. While they participated in this task, we recorded from neurons in the ventrolateral prefrontal cortex (vPFC; a cortical area involved in aspects of nonspatial auditory processing [9, 10]). We found that vPFC activity was correlated with the monkeys' choices. This finding demonstrates a direct link between single neurons and behavioral choices in the PFC on a nonspatial auditory task.     

Hippocampal-prefrontal connectivity predicts midfrontal oscillations and long-term memory performance

The hippocampus and prefrontal cortex interact to support working memory (WM) and long-term memory [1-3]. Neurophysiologically, WM is thought to be subserved by reverberatory activity of distributed networks within the prefrontal cortex (PFC) [2, 4-8], which become synchronized with reverberatory activity in the hippocampus [1, 4]. This electrophysiological synchronization is difficult to study in humans because noninvasive electroencephalography (EEG) cannot measure hippocampus activity. Here, using a novel integration of EEG and diffusion-weighted imaging, it is shown that individuals with relatively stronger anatomical connectivity linking the hippocampus to the right ventrolateral PFC (ventral Brodmann area 46) exhibited slower frequency neuronal oscillations during a WM task. Furthermore, subjects with stronger hippocampus-PFC connectivity were better able to encode the complex pictures used in the WM task into long-term memory. These findings are consistent with models suggesting that electrophysiological oscillations provide a mechanism of long-range interactions [9] and link hippocampus-PFC structural connectivity to PFC rhythmic electrical dynamics and memory performance. More generally, these results highlight the importance of incorporating individual differences when linking structure and function to cognition.     

Neuronal responses related to long-term recognition memory processes in prefrontal cortex

Much evidence indicates that prefrontal cortex plays an important role in long-term recognition memory processes. Here, we report primate prefrontal neuronal responses carrying information necessary for long-term visual recognition memory. The responses of many neurons signaled stimulus familiarity even when the period over which stimuli had to be remembered extended to 24 hr. Such responses occurred frequently in ventromedial, orbitofrontal, and anterior cingulate but not dorsolateral prefrontal cortex. Prefrontal information processing, as indicated by the response latencies, started after that in inferior temporal cortex and might be related to retrieval processes, as responses were typically larger for familiar than for novel stimuli.     

Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.     

Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory

Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus. However, LTP in the prefrontal cortex is less well characterized than in the hippocampus. Here we report that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol. Furthermore, pharmacological or genetic blockade of the NR2B subunit in the cingulate cortex impaired the formation of early contextual fear memory. Our results demonstrate that the NR2B subunit of the NMDA receptor in the prefrontal cortex is critically involved in both LTP and contextual memory.     

Specific contributions of ventromedial, anterior cingulate, and lateral prefrontal cortex for attentional selection and stimulus valuation

Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early-onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network.     

Cognitive Control in Auditory Working Memory Is Enhanced in Musicians

Musical competence may confer cognitive advantages that extend beyond processing of familiar musical sounds. Behavioural evidence indicates a general enhancement of both working memory and attention in musicians. It is possible that musicians, due to their training, are better able to maintain focus on task-relevant stimuli, a skill which is crucial to working memory. We measured the blood oxygenation-level dependent (BOLD) activation signal in musicians and non-musicians during working memory of musical sounds to determine the relation among performance, musical competence and generally enhanced cognition. All participants easily distinguished the stimuli. We tested the hypothesis that musicians nonetheless would perform better, and that differential brain activity would mainly be present in cortical areas involved in cognitive control such as the lateral prefrontal cortex. The musicians performed better as reflected in reaction times and error rates. Musicians also had larger BOLD responses than non-musicians in neuronal networks that sustain attention and cognitive control, including regions of the lateral prefrontal cortex, lateral parietal cortex, insula, and putamen in the right hemisphere, and bilaterally in the posterior dorsal prefrontal cortex and anterior cingulate gyrus. The relationship between the task performance and the magnitude of the BOLD response was more positive in musicians than in non-musicians, particularly during the most difficult working memory task. The results confirm previous findings that neural activity increases during enhanced working memory performance. The results also suggest that superior working memory task performance in musicians rely on an enhanced ability to exert sustained cognitive control. This cognitive benefit in musicians may be a consequence of focused musical training.     

Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

A 4 Hz oscillation adaptively synchronizes prefrontal, VTA, and hippocampal activities

Network oscillations support transient communication across brain structures. We show here, in rats, that task-related neuronal activity in the medial prefrontal cortex (PFC), the hippocampus, and the ventral tegmental area (VTA), regions critical for working memory, is coordinated by a 4 Hz oscillation. A prominent increase of power and coherence of the 4 Hz oscillation in the PFC and the VTA and its phase modulation of gamma power in both structures was present in the working memory part of the task. Subsets of both PFC and hippocampal neurons predicted the turn choices of the rat. The goal-predicting PFC pyramidal neurons were more strongly phase locked to both 4 Hz and hippocampal theta oscillations than nonpredicting cells. The 4 Hz and theta oscillations were phase coupled and jointly modulated both gamma waves and neuronal spikes in the PFC, the VTA, and the hippocampus. Thus, multiplexed timing mechanisms in the PFC-VTA-hippocampus axis may support processing of information, including working memory.     

Short-term memory trace in rapidly adapting synapses of inferior temporal cortex

Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory.     

Differential Patterns of Prefrontal MEG Activation during Verbal & Visual Encoding and Retrieval

The spatiotemporal profile of activation of the prefrontal cortex in verbal and non-verbal recognition memory was examined using magnetoencephalography (MEG). Sixteen neurologically healthy right-handed participants were scanned whilst carrying out a modified version of the Doors and People Test of recognition memory. A pattern of significant prefrontal activity was found for non-verbal and verbal encoding and recognition. During the encoding, verbal stimuli activated an area in the left ventromedial prefrontal cortex, and non-verbal stimuli activated an area in the right. A region in the left dorsolateral prefrontal cortex also showed significant activation during the encoding of non-verbal stimuli. Both verbal and non-verbal stimuli significantly activated an area in the right dorsomedial prefrontal cortex and the right anterior prefrontal cortex during successful recognition, however these areas showed temporally distinct activation dependent on material, with non-verbal showing activation earlier than verbal stimuli. Additionally, non-verbal material activated an area in the left anterior prefrontal cortex during recognition. These findings suggest a material-specific laterality in the ventromedial prefrontal cortex during encoding for verbal and non-verbal but also support the HERA model for verbal material. The discovery of two process dependent areas during recognition that showed patterns of temporal activation dependent on material demonstrates the need for the application of more temporally sensitive techniques to the involvement of the prefrontal cortex in recognition memory.     

A Predictive Reinforcement Model of Dopamine Neurons for Learning Approach Behavior

A neural network model of how dopamine and prefrontal cortex activity guides short- and long-term information processing within the cortico-striatal circuits during reward-related learning of approach behavior is proposed. The model predicts two types of reward-related neuronal responses generated during learning: (1) cell activity signaling errors in the prediction of the expected time of reward delivery and (2) neural activations coding for errors in the prediction of the amount and type of reward or stimulus expectancies. The former type of signal is consistent with the responses of dopaminergic neurons, while the latter signal is consistent with reward expectancy responses reported in the prefrontal cortex. It is shown that a neural network architecture that satisfies the design principles of the adaptive resonance theory of Carpenter and Grossberg (1987) can account for the dopamine responses to novelty, generalization, and discrimination of appetitive and aversive stimuli. These hypotheses are scrutinized via simulations of the model in relation to the delivery of free food outside a task, the timed contingent delivery of appetitive and aversive stimuli, and an asymmetric, instructed delay response task.     

Vasopressin Inhibits LTP in the CA2 Mouse Hippocampal Area

Growing evidence points to vasopressin (AVP) as a social behavior regulator modulating various memory processes and involved in pathologies such as mood disorders, anxiety and depression. Accordingly, AVP antagonists are actually envisaged as putative treatments. However, the underlying mechanisms are poorly characterized, in particular the influence of AVP on cellular or synaptic activities in limbic brain areas involved in social behavior. In the present study, we investigated AVP action on the synapse between the entorhinal cortex and CA2 hippocampal pyramidal neurons, by using both field potential and whole-cell recordings in mice brain acute slices. Short application (1 min) of AVP transiently reduced the synaptic response, only following induction of long-term potentiation (LTP) by high frequency stimulation (HFS) of afferent fibers. The basal synaptic response, measured in the absence of HFS, was not affected. The Schaffer collateral-CA1 synapse was not affected by AVP, even after LTP, while the Schaffer collateral-CA2 synapse was inhibited. Although investigated only recently, this CA2 hippocampal area appears to have a distinctive circuitry and a peculiar role in controlling episodic memory. Accordingly, AVP action on LTP-increased synaptic responses in this limbic structure may contribute to the role of this neuropeptide in controlling memory and social behavior.     

与作业无关的新异刺激对猕猴额叶神经元延缓期反应的作用

在猕猴执行延缓辨别作业和单纯辨别作业时,观察了与作业无关的新异刺激对额叶神经元延缓期放电的影响。在这两种作业中,延缓期在1—4s之间随机变化。此时,动物必须高度注意信号的变化,稍不注意即导致操作错误。此外,在延缓辨别作业中,动物在延缓期还要暂时记住暗示期的信号,单纯辨别作业则无此要求。在203个与作业相关的神经元中,有70个神经元在延缓期出现放电频率变化,其中见于延缓辨别作业者41个,见于单纯辨别作业者29个。实验结果表明,在这两种作业的延缓期所出现的神经元放电增多的反应,有着许多相同的特点。与课题无关的声、光、触、痛等刺激引起分心时,神经元的延缓期反应出现明显的变化,随之出现操作错误。多数神经元的反应受到抑制,但也有出现反应增强者,而且同一神经元对不同感觉模式的无关刺激可出现不同的效应,表现出不同程度的感觉模式特异性。此外,无关刺激在延缓期和在测试间歇期可产生不同甚至相反的效应。上述在延缓期出现反应的神经元主要位于额叶弓状沟上支内侧部的一定范围内。本文对实验结果进行了讨论,认为额叶神经元的延缓期反应,可能在很大程度上与注意有关。额叶神经元感觉模式各种程度的特异性可能是注意的通道选择性的神经基础。额叶的背内侧部,包括前额叶后部和运动前区前部     

Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.     

猕猴执行痛、热延缓辨别作业时额叶神经元及肌电活动的观察

为研究额叶神经元对躯体痛、热刺激出现反应的机能意义,设计了痛、热延缓辨别作业对猕猴进行实验。痛和热仅在暗示期给予,要求动物对此不立即作出行为反应。而是暂时记住这个信号,等到行动期再作出反应。待作业正确率连续三天达90%以上,记录额叶神经元和两侧上肢肌肉的电活动.以观察神经元活动与信号刺激以及肌肉活动之间的关系。在记录的142个作业相关神经元中,与痛、热刺激相关者87个(66.4%)。其中22个仅对痛刺激、18个仅对热刺激起反应,47个对痛、热刺激都起反应(其中4个反应方向相反)。此外,有21个对痛、热、视都出现反应。其余仅对视觉刺激起反应。这些神经元主要位于额叶弓状沟上支内侧,包括前额叶和运动前区皮层。在两侧上肢12块肌肉中,除操作侧指总伸肌、尺侧腕屈肌和桡侧腕屈肌在压放杠杆时,可记录到短暂的肌电活动外,在作业的其它时期和其它肌肉均未记录到规律的肌电活动。这表明痛热刺激在暗示期引起的神经元反应与行为动作的发动没有直接关系,从而支持关于额叶皮层这一区域的神经元在对刺激物信号意义的辨别机制中,可能起着重要作用的假说。     

Individual variations in maternal care early in life correlate with later life decision-making and c-fos expression in prefrontal subregions of rats

Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology--e.g. depression, anxiety and schizophrenia--later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-fos expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-fos expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-fos expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures.     

Visual attention mediated by biased competition in extrastriate visual cortex.

According to conventional neurobiological accounts of visual attention, attention serves to enhance extrastriate neuronal responses to a stimulus at one spatial location in the visual field. However, recent results from recordings in extrastriate cortex of monkeys suggest that any enhancing effect of attention is best understood in the context of competitive interactions among neurons representing all of the stimuli present in the visual field. These interactions can be biased in favour of behaviourally relevant stimuli as a result of many different processes, both spatial and non-spatial, and both bottom-up and top-down. The resolution of this competition results in the suppression of the neuronal representations of behaviourally irrelevant stimuli in extrastriate cortex. A main source of top-down influence may derive from neuronal systems underlying working memory.     

Long-term potentiation in mice lacking the neural cell adhesion molecule L1

Genetic evidence indicates that cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) are critical for activity-dependent synapse formation at the neuromuscular junction in Drosophila and have also been implicated in synaptic remodelling during learning in Aplysia (see [1] for review). In mammals, a widely adopted model for the process of learning at the cellular level is long-term potentiation (LTP) in the hippocampal formation. Studies in vitro have shown that antibodies to the IgCAMs L1 and NCAM reduce LTP in CA1 neurons of rat hippocampus, suggesting a role for these molecules in the modulation of synaptic efficacy, perhaps by regulating synaptic remodelling [2]. A role for NCAM in LTP has been confirmed in mice lacking NCAM [3] (but see [4]), but similar studies have not been reported for L1. Here we examine LTP in the hippocampus of mice lacking L1 [5,6], using different experimental protocols in three different laboratories. In tests of LTP in vitro and in vivo we found no significant differences between mutant animals and controls. Thus, contrary to expectation, our data suggest that L1 function is not necessary for the establishment or maintenance of LTP in the hippocampus. Impaired performance in spatial learning exhibited by L1 mutants may therefore not be due to hippocampal dysfunction [6].