Diminished medial prefrontal activity behind autistic social judgments of incongruent information

Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information.     

大脑前额叶是怎样处理空间信息的

我们的大脑可能使用多个参考系来处理空间信息,比如使用"自我为中心的参考系"和"以大环境为参考系"来处理空间信息。灵长类大脑前额叶位于大脑皮层额叶的前端,尽管对前额叶在脑高级功能中的作用谁都不会怀疑,但很多具体的细节还是不甚清楚,比如背侧大脑前额叶在处理工作记忆信息时,是否处理所有的空间工作记忆信息?该文首先回顾对前额叶的研究情况,然后讨论背侧前额叶在处理自我为中心的空间信息中的作用,最后指出背侧前额叶仅对自我为中心的空间信息处理负责,而与大环境为中心的空间信息处理无关。     

Dynamic construction of stimulus values in the ventromedial prefrontal cortex

Signals representing the value assigned to stimuli at the time of choice have been repeatedly observed in ventromedial prefrontal cortex (vmPFC). Yet it remains unknown how these value representations are computed from sensory and memory representations in more posterior brain regions. We used electroencephalography (EEG) while subjects evaluated appetitive and aversive food items to study how event-related responses modulated by stimulus value evolve over time. We found that value-related activity shifted from posterior to anterior, and from parietal to central to frontal sensors, across three major time windows after stimulus onset: 150-250 ms, 400-550 ms, and 700-800 ms. Exploratory localization of the EEG signal revealed a shifting network of activity moving from sensory and memory structures to areas associated with value coding, with stimulus value activity localized to vmPFC only from 400 ms onwards. Consistent with these results, functional connectivity analyses also showed a causal flow of information from temporal cortex to vmPFC. Thus, although value signals are present as early as 150 ms after stimulus onset, the value signals in vmPFC appear relatively late in the choice process, and seem to reflect the integration of incoming information from sensory and memory related regions.     

Electrical activity of prefrontal cortex and ventral tegmental area during rat maternal behavior

Maternal behavior is a motivated behavior that includes pup-directed sequential motor acts. The dopaminergic (DAergic) brain systems have been proposed to play an important role in voluntary maternal acts, however, not much is known about the way these systems function during the performance of this behavior. The electroencephalogram (EEG) is a sensitive tool that allows determination of the simultaneous functioning of different structures in relation to specific cognitive processes or motor acts. The present study recorded the function of the two structures that constitute the mesoprefrontal DAergic system, ventral tegmental area (VTA) and prefrontal cortex (PFC) by EEG during the performance of various maternal behaviors. Bilateral EEG from the VTA and medial PFC (mPFC) was simultaneously recorded during typical maternal acts and was compared to that recorded during non-maternal behaviors in freely moving female rats. Three different frequency bands (6-7, 8-11, and 12-21 Hz) were obtained from principal component analysis applied to the EEG for both structures. In the left and right mPFC and VTA, absolute power (AP) of the 8-11 Hz band showed a significant increase during pup retrieval compared to the EEG during walking. In the left and right mPFC and VTA, AP of the three bands showed a significant increase during pup licking with respect to forepaw licking. No differences in the EEG were found during inactive nursing behaviors compared to the awake quiet condition. The mPFC and VTA presented characteristic EEG patterns during active maternal behaviors but not during inactive maternal behaviors. This provides electrical evidence of the involvement of these structures in the performance of maternal behavior.     

Spontaneous processing of abstract categorical information in the ventrolateral prefrontal cortex

In various aspects of linguistic analysis and human cognition, some forms of observed variation are ignored in the service of handling more abstract categories. In the absence of training, rhesus discriminate between different types of vocalizations based on the information conveyed as opposed to their acoustic morphologies. We hypothesized that neurons in the ventrolateral prefrontal cortex (vPFC), an area involved in auditory-object processing, might be involved in this spontaneous categorization. To test this hypothesis, we recorded vPFC activity while rhesus listened to vocalizations conveying information about food and non-food events. Results showed between, but not within category discrimination. That is, vPFC neurons discriminated between vocalizations associated with food versus non-food events but not within the class of food calls associated with differences in quality. These results indicate that the vPFC plays a significant role in spontaneously processing abstract categorical information.     

Anxiety- and depression-like behavior are correlated with leptin and leptin receptor expression in prefrontal cortex of streptozotocin-induced diabetic rats

Anxiety and depression are common in diabetics. Diabetes also may cause reduced leptin levels in the blood. We investigated the relation between diabetes induced anxiety- and depression-like behavior, and leptin and leptin receptor expression levels in diabetic rats. The anxiety- and depression-like behaviors of rats were assessed 4 weeks after intraperitoneal injection of streptozotocin. Diabetic rats exhibited greater anxiety-like behavior; they spent more time in closed branches of the elevated plus maze test and less time in the center cells of the open field arena. Increased depression-like behavior was observed in diabetic rats using the Porsolt swim test. Prefrontal cortex (PFC), blood leptin levels and PFC neuron numbers were decreased, and leptin receptor expression and apoptosis were increased in diabetic rats. Blood corticosterone levels also were increased in diabetic rats. These results indicate that reduction of leptin up-regulates leptin receptor expression and may affect PFC neurons, which eventually triggers anxiety- and depression-like behaviors in diabetic rats.     

Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity

The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing of single units from the mPFC of mice exploring standard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distinguished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task-related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC.     

内侧前额叶皮质DNA甲基化调控大鼠酒精相关行为

酒精滥用不仅导致组织器官损伤,还易诱发神经精神疾病。研究表明,DNA甲基化在酒精诱导基因表达和行为改变中发挥重要作用,但具体的神经生物学机制尚未被阐明。为了探索DNA甲基化在酒精滥用中的作用机制,本研究选取健康成年雄性SD大鼠(Rattus norvegicus)32只,随机分为饮水对照组(n=16)和慢性酒精暴露组(n=16),运用双瓶选择实验(two bottle choice test,TBCT)评估大鼠酒精偏爱率(alcohol preference),通过旷场行为(open field test,OFT)评估活动状态并检测血酒精浓度。分离两组大鼠内侧前额叶皮质(medial prefrontal cortex,mPFC),提取总DNA,利用简化代表性重亚硫酸盐测序技术(reduced representation bisulfite sequencing,RRBS)构建mPFC甲基化谱,对差异基因进行功能富集和通路分析,筛选与酒精滥用密切相关的甲基化差异基因,运用qRT-PCR技术检测差异基因的表达,验证DNA甲基化对基因的表达调控;利用qRT-PCR和Western blot检测甲基转移酶(DNA methyltransferases,DNMTs)和甲基化CpG位点结合蛋白2(methyl CpG binding protein 2,MeCP2)的表达;同时,还检测了短期酒精暴露(7 d)对大鼠mPFC内DNMTs和MeCP2的影响(n=8/组)。结果表明,慢性酒精暴露大鼠mPFC内基因启动子区甲基化水平显著升高。与酒精滥用密切相关的差异基因中,慢性酒精暴露组Ntf3和Ppm1G启动子区甲基化水平升高,mRNA表达降低;Hap1和DUSP1启动子区甲基化水平降低,mRNA表达升高。慢性酒精暴露使DNMT3B和MeCP2 mRNA和蛋白表达升高,而短期内酒精暴露不影响它们的表达。本研究初步证实DNA甲基化与酒精滥用的发展相关,可能受DNMT3B和MeCP2分子的调控,并发现了与酒精滥用相关的靶基因Ntf3、Ppm1G、Hap1和DUSP1,为研究酒精滥用的神经生物学机制提供了新见解,同时为酒精滥用治疗提供了可能的药理学靶点。     

Sulfation patterns of glycosaminoglycans encode molecular recognition and activity

Although glycosaminoglycans contribute to diverse physiological processes, an understanding of their molecular mechanisms has been hampered by the inability to access homogeneous glycosaminoglycan structures. Here, we assembled well-defined chondroitin sulfate oligosaccharides using a convergent, synthetic approach that permits installation of sulfate groups at precise positions along the carbohydrate backbone. Using these defined structures, we demonstrate that specific sulfation motifs function as molecular recognition elements for growth factors and modulate neuronal growth. These results provide both fundamental insights into the role of sulfation and direct evidence for a 'sulfation code' whereby glycosaminoglycans encode functional information in a sequence-specific manner analogous to that of DNA, RNA and proteins.     

Behavioral planning in the prefrontal cortex

Recent studies have presented evidence that the prefrontal cortex plays a crucial role in every aspect of the cognitive processes necessary for behavioral planning: processing and integration of perceived or memorized information, associative learning, reward-based behavioral control, behavioral selection/decision-making and behavioral guidance. We propose that the creation of novel information is the means by which the prefrontal cortex operates to achieve executive control over behavioral planning. The prefrontal cortex is the site of operation of nodal points, where neural circuits integrate currently available or memorized information to generate the information that is necessary to perform an action. The prefrontal cortex also regulates the flow of information through multiple nodes to meet behavioral demands.     

Coding of cognitive magnitude: compressed scaling of numerical information in the primate prefrontal cortex

Whether cognitive representations are better conceived as language-based, symbolic representations or perceptually related, analog representations is a subject of debate. If cognitive processes parallel perceptual processes, then fundamental psychophysical laws should hold for each. To test this, we analyzed both behavioral and neuronal representations of numerosity in the prefrontal cortex of rhesus monkeys. The data were best described by a nonlinearly compressed scaling of numerical information, as postulated by the Weber-Fechner law or Stevens' law for psychophysical/sensory magnitudes. This nonlinear compression was observed on the neural level during the acquisition phase of the task and maintained through the memory phase with no further compression. These results suggest that certain cognitive and perceptual/sensory representations share the same fundamental mechanisms and neural coding schemes.     

Unit activity of the prefrontal cortex during delayed alternation performance in monkey.

Unit activity in the dorsolateral regions of the prefrontal cortex (s. principalis) of the monkey was analysed by multineuronal recording technique. The sequence during delayed-response alternation included anticipatory stimulus, non-specific expectancy, conditioned cue, delay, trigger stimulus and alternation performance. Food reward completed the sequence. Unit activity in s. principalis was found to be involved in such learning processes as integration of behavioural acts into an accomplished programme and storage of traces in short-term memory. The latter can be observed in successive involvement of neuronal populations during a 10 sec delay as well as in rearrangements of unit activity, the maximum of which shifts to the latest part of the delay period. Unit activity in s. principalis reflects the level of correct response, corresponding correlates of which depend on the level of attention. The dorsolateral prefrontal cortex has structural and functional characteristics for short-term storage of external signals in its neuronal nets according to the level of attention.     

Early social environment interferes with the development of NADPH-diaphorase-reactive neurons in the rodent orbital prefrontal cortex

The influence of early parental deprivation on the development of NADPH-diaphorase-(NO-synthase) reactive neuron numbers in subregions of the orbital prefrontal cortex (ventrolateral orbital, lateral orbital, and agranular insular cortex) was quantitatively investigated in the precocious lagomorph Octodon degus. Forty-five-day-old degus from three groups were compared: (1) repeated parental separation: degus that were repeatedly separated from their parents during the first three postnatal weeks and thereafter raised in undisturbed social conditions; (2) chronic isolation: degus that were raised under undisturbed social conditions until postnatal day 21, and then were reared in chronic social isolation; and (3) control: degus that were reared undisturbed in their families. Compared to the control animals the ventrolateral orbital prefrontal cortex and agranular insular cortex of the two deprived groups displayed significantly decreased density of NADPH-diaphorase-reactive neurons (down to 62% in the ventrolateral orbital prefrontal cortex of males, 70% in the agranular insular cortex, and in the lateral orbital prefrontal cortex 80% in both genders). These results confirm that early changes of social environment interferes with the development of limbic circuits, which might determine normal or pathological behaviors in later life.     

Hippocampal neurons encode information about different types of memory episodes occurring in the same location

Firing patterns of hippocampal complex-spike neurons were examined for the capacity to encode information important to the memory demands of a task even when the overt behavior and location of the animal are held constant. Neuronal activity was recorded as rats continuously alternated left and right turns from the central stem of a modified T maze. Two-thirds of the cells fired differentially as the rat traversed the common stem on left-turn and right-turn trials, even when potentially confounding variations in running speed, heading, and position on the stem were taken into account. Other cells fired differentially on the two trial types in combination with behavioral and spatial factors or appeared to fire similarly on both trial types. This pattern of results suggests that hippocampal representations encode some of the information necessary for representing specific memory episodes.     

The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity

Atypical antipsychotics show preferential 5-HT 2A versus dopamine (DA) D2 receptor affinity. At clinical doses, they fully occupy cortical 5-HT2 receptors, which suggests a strong relationship with their therapeutic action. Half of the pyramidal neurones in the medial prefrontal cortex (mPFC) express 5-HT 2A receptors. Also, neurones excited through 5-HT 2A receptors project to the ventral tegmental area (VTA). We therefore hypothesized that prefrontal 5-HT 2A receptors can modulate DA transmission through excitatory mPFC-VTA inputs. In this study we used single unit recordings to examine the responses of DA neurones to local (in the mPFC) and systemic administration of the 5-HT 2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl-2-aminopropane] (DOI). Likewise, using microdialysis, we examined DA release in the mPFC and VTA (single/dual probe) in response to prefrontal and systemic drug administration. The local (in the mPFC) and systemic administration of DOI increased the firing rate and burst firing of DA neurones and DA release in the VTA and mPFC. The increase in VTA DA release was mimicked by the electrical stimulation of the mPFC. The effects of DOI were reversed by M100907 and ritanserin. These results indicate that the activity of VTA DA neurones is under the excitatory control of 5-HT 2A receptors in the mPFC. These observations may help in the understanding of the therapeutic action of atypical antipsychotics.     

Dynamic social adaptation of motion-related neurons in primate parietal cortex

Social brain function, which allows us to adapt our behavior to social context, is poorly understood at the single-cell level due largely to technical limitations. But the questions involved are vital: How do neurons recognize and modulate their activity in response to social context? To probe the mechanisms involved, we developed a novel recording technique, called multi-dimensional recording, and applied it simultaneously in the left parietal cortices of two monkeys while they shared a common social space. When the monkeys sat near each other but did not interact, each monkey's parietal activity showed robust response preference to action by his own right arm and almost no response to action by the other's arm. But the preference was broken if social conflict emerged between the monkeys-specifically, if both were able to reach for the same food item placed on the table between them. Under these circumstances, parietal neurons started to show complex combinatorial responses to motion of self and other. Parietal cortex adapted its response properties in the social context by discarding and recruiting different neural populations. Our results suggest that parietal neurons can recognize social events in the environment linked with current social context and form part of a larger social brain network.