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.     

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.     

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.     

Specificity in the functional architecture of primate prefrontal cortex

Multiple lines of evidence indicate that the performance of complex cognitive processes, such as those involving working memory, depend upon the functional properties of the circuitry of the prefrontal cortex (PFC). In primates, working memory has been proposed to be dependent upon the sustained activity of specific populations of PFC pyramidal cells, with this activity regulated by certain types of GABAergic interneurons. Thus, knowledge of the connectivity between PFC pyramidal cells and interneurons is crucial to the understanding the neural mechanisms that subserve working memory. This paper reviews recent findings that reveal specificity in the spatial organization, synaptic targets and postnatal development of pyramidal cells and interneurons in the primate prefrontal cortex, and considers the relevance of these findings for the neural circuitry that subserves working memory.     

The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats

Although prefrontal and hippocampal neurons are critical for spatial working memory, the function of glial cells in spatial working memory remains uncertain. In this study we investigated the function of glial cells in rats’ working memory. The glial cells of rat brain were inhibited by intracerebroventricular (icv) injection of fluorocitrate (FC). The effects of FC on the glial cells were examined by using elec-troencephalogram (EEG) recordings and delayed spatial alternation tasks. After icv injection of 10 μL of 0.5 nmol/L or 5 nmol/L FC, the EEG power spectrum recorded from the hippocampus increased, but the power spectrum for the prefrontal cortex did not change, and working memory was unaffected. Fol-lowing an icv injection of 10 μL of 20 nmol/L FC, the EEG power spectra in both the prefrontal cortex and the hippocampus increased, and working memory improved. The icv injection of 10 μL of 50 nmol/L FC, the EEG power spectra in both the prefrontal cortex and in the hippocampus decreased, and working memory was impaired. These results suggest that spatial working memory is affected by cen-trally administered FC, but only if there are changes in the EEG power spectrum in the prefrontal cortex. Presumably, the prefrontal glial cells relate to the working memory.     

Prefrontal cortex function, quasi-physiological stimuli, and synaptic plasticity

The prelimbic area of rat medial frontal cortex may be functionally analogous to human/primate dorsolateral prefrontal cortex. This area may be involved in selective attention to the external stimuli and the coupling of the attention to a repertory of actions. It was suggested that this function may rely on a form of long-term memory [Biol. Rev. 77 (2002) 563]. Indeed, during learning of this type of behavior, a portion of prelimbic neurons persistently change their firing characteristics [Prog. Brain Res. 126 (2000) 287]. It is therefore important to study long-term potentiation (LTP) and depression (LTD) in rat prelimbic neurons. In this article, the author first briefly reviews recent findings on the prefrontal cortex function and discusses that the prefrontal cortex may be involved in long-term memory. Second, the author will show some new results which indicate that quasi-physiological patterns of stimuli mimicking prelimbic neuronal activity during behavior can induce LTP in prelimbic pyramidal neuron synapses. These results suggest that prelimbic neuronal activity during behavior may lastingly modify prelimbic synaptic efficacy.     

Probing the Frontostriatal Loops Involved in Executive and Limbic Processing via Interleaved TMS and Functional MRI at Two Prefrontal Locations: A Pilot Study

Background

The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment.

Methods

Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability.

Results

Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals.

Conclusion

These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.     

Traveling waves in the prefrontal cortex during working memory

Neural oscillations are evident across cortex but their spatial structure is not well- explored. Are oscillations stationary or do they form “traveling waves”, i.e., spatially organized patterns whose peaks and troughs move sequentially across cortex? Here, we show that oscillations in the prefrontal cortex (PFC) organized as traveling waves in the theta (4-8Hz), alpha (8-12Hz) and beta (12-30Hz) bands. Some traveling waves were planar but most rotated. The waves were modulated during performance of a working memory task. During baseline conditions, waves flowed bidirectionally along a specific axis of orientation. Waves in different frequency bands could travel in different directions. During task performance, there was an increase in waves in one direction over the other, especially in the beta band.     

Decreased Fronto-Temporal Interaction during Fixation after Memory Retrieval

Previous studies have revealed top-down control during memory retrieval from the prefrontal cortex to the temporal cortex. In the present functional MRI study, we investigated whether the fronto-temporal functional interaction occurs even during fixation periods after memory retrieval trials. During recency judgments, subjects judged the temporal order of two items in a study list. The task used in the present study consisted of memory trials of recency judgments and non-memory trials of counting dots, and post-trial fixation periods. By comparing the brain activity during the fixation periods after the memory trials with that during the fixation periods after the non-memory trials, we detected heightened brain activity in the lateral prefrontal cortex, the lateral temporal cortex and the hippocampus. Functional interactions during the fixation periods after the memory vs. non-memory trials as examined using a psychophysiological interaction revealed a decreased interaction from the lateral prefrontal cortex to the lateral temporal cortex, but not to the hippocampus. The functional interaction between the same frontal and temporal regions was also present during the memory trials. A trial-based functional connectivity analysis further revealed that the fronto-temporal interaction was positive and decreased during the fixation periods after the memory trials, relative to the fixation periods after the non-memory trials. These results suggest that the fronto-temporal interaction existed during the post-trial fixation periods, which had been present during the memory trials and temporally extended into the fixation periods.     

Spatial learning and action planning in a prefrontal cortical network model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.     

低剂量氯胺酮对工作记忆的影响

氯胺酮是一种N-甲基-D-天冬氨酸受体（NMDAR）阻滞剂，低剂量氯胺酮具有良好的镇痛、抗炎和抗抑郁作用，近年来受到了广泛的关注。但是低剂量氯胺酮对于高级认知功能的影响尚未全面阐明。工作记忆是涉及众多复杂认知活动的关键功能，有研究显示低剂量氯胺酮急性或慢性使用均会损伤工作记忆，其神经机制也开始受到关注。深入分析低剂量氯胺酮对于工作记忆的影响及其机制对于指导氯胺酮的临床使用具有重要意义。本文首先介绍了低剂量氯胺酮作用于神经系统的药理作用途径，以及工作记忆本身的神经环路机制，进而回顾了近年来关于低剂量氯胺酮对工作记忆的急性和慢性作用的相关研究，并重点分析了低剂量氯胺酮损伤工作记忆的可能的神经机制，希望对低剂量氯胺酮在临床中的合理使用提供科学依据。     

The Importance of Encoding-Related Neural Dynamics in the Prediction of Inter-Individual Differences in Verbal Working Memory Performance

Studies of brain-behaviour interactions in the field of working memory (WM) have associated WM success with activation of a fronto-parietal network during the maintenance stage, and this mainly for visuo-spatial WM. Using an inter-individual differences approach, we demonstrate here the equal importance of neural dynamics during the encoding stage, and this in the context of verbal WM tasks which are characterized by encoding phases of long duration and sustained attentional demands. Participants encoded and maintained 5-word lists, half of them containing an unexpected word intended to disturb WM encoding and associated task-related attention processes. We observed that inter-individual differences in WM performance for lists containing disturbing stimuli were related to activation levels in a region previously associated with task-related attentional processing, the left intraparietal sulcus (IPS), and this during stimulus encoding but not maintenance; functional connectivity strength between the left IPS and lateral prefrontal cortex (PFC) further predicted WM performance. This study highlights the critical role, during WM encoding, of neural substrates involved in task-related attentional processes for predicting inter-individual differences in verbal WM performance, and, more generally, provides support for attention-based models of WM.     

Simultaneous EEG-fMRI during a Working Memory Task: Modulations in Low and High Frequency Bands

Background

EEG studies of working memory (WM) have demonstrated load dependent frequency band modulations. FMRI studies have localized load modulated activity to the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and posterior parietal cortex (PPC). Recently, an EEG-fMRI study found that low frequency band (theta and alpha) activity negatively correlated with the BOLD signal during the retention phase of a WM task. However, the coupling of higher (beta and gamma) frequencies with the BOLD signal during WM is unknown.

Methodology

In 16 healthy adult subjects, we first investigated EEG-BOLD signal correlations for theta (5–7 Hz), alpha1 (8–10), alpha2 (10–12 Hz), beta1 (13–20), beta2 (20–30 Hz), and gamma (30–40 Hz) during the retention period of a WM task with set size 2 and 5. Secondly, we investigated whether load sensitive brain regions are characterised by effects that relate frequency bands to BOLD signals effects.

Principal Findings

We found negative theta-BOLD signal correlations in the MPFC, PPC, and cingulate cortex (ACC and PCC). For alpha1 positive correlations with the BOLD signal were found in ACC, MPFC, and PCC; negative correlations were observed in DLPFC, PPC, and inferior frontal gyrus (IFG). Negative alpha2-BOLD signal correlations were observed in parieto-occipital regions. Beta1-BOLD signal correlations were positive in ACC and negative in precentral and superior temporal gyrus. Beta2 and gamma showed only positive correlations with BOLD, e.g., in DLPFC, MPFC (gamma) and IFG (beta2/gamma). The load analysis revealed that theta and—with one exception—beta and gamma demonstrated exclusively positive load effects, while alpha1 showed only negative effects.

Conclusions

We conclude that the directions of EEG-BOLD signal correlations vary across brain regions and EEG frequency bands. In addition, some brain regions show both load sensitive BOLD and frequency band effects. Our data indicate that lower as well as higher frequency brain oscillations are linked to neurovascular processes during WM.     

Excitation,inhibition, local oscillations,or large-scale loops: what causes the symptoms of schizophrenia?

What causes the positive, negative, and cognitive symptoms of schizophrenia? The importance of circuits is underscored by the finding that no single gene contributes strongly to the disease. Thus, some circuit abnormality to which many proteins can contribute is the likely cause. There are several major hypotheses regarding the circuitry involved: first, a change in the balance of excitation/inhibition in the prefrontal cortex (PFC); second, abnormal EEG oscillations in the gamma range; third, an increase in theta/delta EEG power related to changes in the thalamus (particularly midline nuclei); fourth, hyperactivity in the hippocampus and consequent dopamine hyperfunction; and fifth, deficits in corollary discharge. Evidence for these hypotheses will be reviewed.     

Oscillations in the prefrontal cortex: a gateway to memory and attention

We consider the potential role of oscillations in the prefrontal cortex (PFC) in mediating attention, working memory and memory consolidation. Activity in the theta, beta, and gamma bands is related to communication between PFC and different brain areas. While gamma/beta oscillations mediate bottom-up and top-down interactions between PFC and visual cortices, related to attention, theta rhythms are engaged by hippocampal/PFC interplay. These interactions are dynamic, depending on the nature and relevance of the information currently being processed. The profound modifications of the PFC neuronal network associated with changes in oscillatory coherence are controlled by neuromodulators such as dopamine, which thereby allow or prevent the formation of cell assemblies for information encoding and storage.     

Differential Contributions of Dorso-Ventral and Rostro-Caudal Prefrontal White Matter Tracts to Cognitive Control in Healthy Older Adults

Prefrontal cortex mediates cognitive control by means of circuitry organized along dorso-ventral and rostro-caudal axes. Along the dorso-ventral axis, ventrolateral PFC controls semantic information, whereas dorsolateral PFC encodes task rules. Along the rostro-caudal axis, anterior prefrontal cortex encodes complex rules and relationships between stimuli, whereas posterior prefrontal cortex encodes simple relationships between stimuli and behavior. Evidence of these gradients of prefrontal cortex organization has been well documented in fMRI studies, but their functional correlates have not been examined with regard to integrity of underlying white matter tracts. We hypothesized that (a) the integrity of specific white matter tracts is related to cognitive functioning in a manner consistent with the dorso-ventral and rostro-caudal organization of the prefrontal cortex, and (b) this would be particularly evident in healthy older adults. We assessed three cognitive processes that recruit the prefrontal cortex and can distinguish white matter tracts along the dorso-ventral and rostro-caudal dimensions –episodic memory, working memory, and reasoning. Correlations between cognition and fractional anisotropy as well as fiber tractography revealed: (a) Episodic memory was related to ventral prefrontal cortex-thalamo-hippocampal fiber integrity; (b) Working memory was related to integrity of corpus callosum body fibers subserving dorsolateral prefrontal cortex; and (c) Reasoning was related to integrity of corpus callosum body fibers subserving rostral and caudal dorsolateral prefrontal cortex. These findings confirm the ventrolateral prefrontal cortex''s role in semantic control and the dorsolateral prefrontal cortex''s role in rule-based processing, in accordance with the dorso-ventral prefrontal cortex gradient. Reasoning-related rostral and caudal superior frontal white matter may facilitate different levels of task rule complexity. This study is the first to demonstrate dorso-ventral and rostro-caudal prefrontal cortex processing gradients in white matter integrity.     

Effects of carbon dioxide exposure on early brain development in rats

The developing brain is vulnerable to environmental factors. We investigated the effects of air that contained 0.05, 0.1 and 0.3% CO₂ on the hippocampus, prefrontal cortex (PFC) and amygdala. We focused on the circuitry involved in the neurobiology of anxiety, spatial learning, memory, and on insulin-like growth factor-1 (IGF-1), which is known to play a role in early brain development in rats. Spatial learning and memory were impaired by exposure to 0.3% CO₂ air, while exposure to 0.1 and 0.3% CO₂ air elevated blood corticosterone levels, intensified anxiety behavior, increased superoxide dismutase (SOD) enzyme activity and MDA levels in hippocampus and PFC; glutathione peroxidase (GPx) enzyme activity decreased in the PFC with no associated change in the hippocampus. IGF-1 levels were decreased in the blood, PFC and hippocampus by exposure to both 0.1 and 0.3% CO₂. In addition, apoptosis was increased, while cell numbers were decreased in the CA1 regions of hippocampus and PFC after 0.3% CO₂ air exposure in adolescent rats. A positive correlation was found between the blood IGF-1 level and apoptosis in the PFC. We found that chronic exposure to 0.3% CO₂ air decreased IGF-1 levels in the serum, hippocampus and PFC, and increased oxidative stress. These findings were associated with increased anxiety behavior, and impaired memory and learning.     

Differential prefrontal white matter development in chimpanzees and humans

A comparison of developmental patterns of white matter (WM) within the prefrontal region between humans and nonhuman primates is key to understanding human brain evolution. WM mediates complex cognitive processes and has reciprocal connections with posterior processing regions [1, 2]. Although the developmental pattern of prefrontal WM in macaques differs markedly from that in humans [3], this has not been explored in our closest evolutionary relative, the chimpanzee. The present longitudinal study of magnetic resonance imaging scans demonstrated that the prefrontal WM volume in chimpanzees was immature and had not reached the adult value during prepuberty, as observed in humans but not in macaques. However, the rate of prefrontal WM volume increase during infancy was slower in chimpanzees than in humans. These results suggest that a less mature and more protracted elaboration of neuronal connections in the prefrontal portion of the developing brain existed in the last common ancestor of chimpanzees and humans, and that this served to enhance the impact of postnatal experiences on neuronal connectivity. Furthermore, the rapid development of the human prefrontal WM during infancy may help the development of complex social interactions, as well as the acquisition of experience-dependent knowledge and skills to shape neuronal connectivity.     

The treatment of Goji berry (Lycium barbarum) improves the neuroplasticity of the prefrontal cortex and hippocampus in aged rats

The main characteristic of brain aging is an exacerbated inflammatory and oxidative response that affects dendritic morphology and the function of the neurons of the prefrontal cortex (PFC) and the hippocampus. This consequently causes memory loss. Recently, the use of the Goji berry (Lycium barbarum) as an antioxidant extract has provided neuroprotection and neuroplasticity, however, its therapeutic potential has not been demonstrated in aging conditions. The objective of this study was to evaluate the effect of Goji administration on memory recognition, as well as the changes in the dendritic morphology of the PFC and Hippocampus pyramidal neurons in old rats. Goji (3 g/kg) was administrated for 60 days in 18-month-old rats. After the treatment, recognition memory was evaluated using the new object recognition task (NORt). The changes in the neuron morphology of the PFC and hippocampus pyramidal neurons in old rats were evaluated by Golgi-cox stain and immunoreactivity for synaptophysin, glial fibrillary acidic protein (GFAP), caspase-3, 3-nitrotyrosine (3-NT) and nuclear factor erythroid 2-related factor 2 (Nrf2). The rats treated with Goji showed a significant increase in dendritic morphology in the PFC and hippocampus neurons, a greater immunoreactivity to synaptophysin and a decrease in reactive astrogliosis and also in caspase-3, in 3-NT and in Nrf2 in these brain regions was also observed. Goji administration promotes the plasticity processes in the PFC and in the hippocampus of old rats, critical structures in the brain aging process.     

Time Course of Functional Connectivity in Primate Dorsolateral Prefrontal and Posterior Parietal Cortex during Working Memory

The dorsolateral prefrontal and posterior parietal cortex play critical roles in mediating attention, working memory, and executive function. Despite proposed dynamic modulation of connectivity strength within each area according to task demands, scant empirical data exist about the time course of the strength of effective connectivity, particularly in tasks requiring information to be sustained in working memory. We investigated this question by performing time-resolved cross-correlation analysis for pairs of neurons recorded simultaneously at distances of 0.2–1.5 mm apart of each other while monkeys were engaged in working memory tasks. The strength of effective connectivity determined in this manner was higher throughout the trial in the posterior parietal cortex than the dorsolateral prefrontal cortex. Significantly higher levels of parietal effective connectivity were observed specifically during the delay period of the task. These differences could not be accounted for by differences in firing rate, or electrode distance in the samples recorded in the posterior parietal and prefrontal cortex. Differences were present when we restricted our analysis to only neurons with significant delay period activity and overlapping receptive fields. Our results indicate that dynamic changes in connectivity strength are present but area-specific intrinsic organization is the predominant factor that determines the strength of connections between neurons in each of the two areas.