Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex

In both primates and rodents, the prefrontal cortex (PFC) is highly innervated by dopaminergic fibers originating from the ventral tegmental area, and activation of this mesocortical dopaminergic system decreases spontaneous and evoked activity in the PFC in vivo. We have examined the effects of dopamine (DA), over a range of concentrations, on the passive and active membrane properties of layer V pyramidal cells from the rat medial PFC (mPFC). Whole-cell and perforated-patch recordings were made from neurons in rat mPFC. As a measure of cell excitability, trains of action potentials were evoked with 1-sec-long depolarizing current steps. Bath application of DA (0.05-30 microM) produced a reversible decrease in the number of action potentials evoked by a given current step. In addition, DA reversibly decreased the input resistance (RN) of these cells. In a subset of experiments, a transient increase in excitability was observed after the washout of DA. Control experiments suggest that these results are not attributable to changes in spontaneous synaptic activity, age-dependent processes, or strain-specific differences in dopaminergic innervation and physiology. Pharmacological analyses, using D1 agonists (SKF 38393 and SKF 81297), a D1 antagonist (SCH 23390), a D2 receptor agonist (quinpirole), and a D2 antagonist (sulpiride) suggest that decreases in spiking and RN are mediated by D2 receptor activation. Together, these results demonstrate that DA, over a range of concentrations, has an inhibitory effect on layer V pyramidal neurons in the rat mPFC, possibly through D2 receptor activation.     

Development of the dendritic fields of layer 3 pyramidal cells in the kitten's visual cortex

The cat's visual cortex is immature at birth and undergoes extensive postnatal development. For example, cells of layers 2 and 3 do not complete migration until about 3 weeks after birth. Despite the importance of dendritic growth for synaptic and functional development, there have been few studies of dendritic development in the cat's visual cortex to correlate with numerous studies of functional and synaptic development. Accordingly, we used the Golgi method to study the development of the dendrites of layer 3 pyramidal cells in the visual cortex of a series of cats ranging in age from 2 days to 3 years. Blocks of visual cortex were impregnated by the Golgi-Kopsch method and sectioned in the tangential plane. Layer 3 pyramidal cells were drawn with a camera lucida and analyzed by Sholl diagrams and vector addition. In kittens < 1 week old, these cells were very immature, with only an apical dendrite and no basal dendrites. Basal dendrites appeared during the second week. By 2 weeks, all of the basal dendrites had emerged from the soma, but they had few branches and were tipped with growth cones. By 4 weeks, they had finished branching but continued to grow in length until, by 5 weeks, they reached their adult size. Examination of the basal dendritic fields in the tangential plane revealed that their dendritic fields were more elongated at 2 weeks than at later ages, perhaps because of their smaller size. The distribution of dendritic field orientations was uniform at all ages except 3 and 4 weeks, when there was a preponderance of fields oriented in the rostrocaudal direction. Because dendritic growth and branching occurred very rapidly over a period that precedes and overlaps with the peak periods of synaptogenesis and of sensitivity to the effects of early visual experience, they may depend on afferent visual activity. The early emergence of primary dendrites, however, suggests that this process is independent of afferent activity. The coincident timing of dendritic branching with the presence of dendritic growth cones suggests that branching may occur at growth cones.     

Postnatal maturation of the layer III pyramidal neurons in the human prefrontal cortex: a quantitative Golgi analysis

In this study we examined the morphological maturation of the basal dendritic field of layer III pyramidal neurons located in the human dorsolateral prefrontal cortex in subjects ranging from 7.5 months after birth up to 27 years. The sections were stained with the Golgi-Cox method and the three-dimensional branching pattern was measured with a semi-automatic dendrite measuring system. Results show a rapid growth phase of the dendritic field from 7.5 months after birth up to one year. A marked increase in total dendritic length is observed, for which elongation of the terminal segments, longer intermediate segments and an increase in number of segments is an explanation. The dendritic length appears to have stabilized after one year, leading us to conclude that the postnatal morphological maturation of the layer III pyramidals does not continue well into childhood, but is completed at a much younger age. Additionally we analyzed the effect of varying section thickness on dendritic parameters and found no tendency for higher dendritic values with increasing section thickness for the range of thickness values of the histological sections used.     

Functional synergism between putative gamma-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex

The responses of putative gamma-aminobutyratergic interneurons (fast-spiking) and pyramidal (regular-spiking) cell pairs were compared in monkeys performing visual and memory-guided oculomotor tasks. Both fast- and regular-spiking neurons had similar receptive fields, indicating that gamma-aminobutyratergic interneurons carry a specific informational signal, as opposed to providing nonspecific modulation. However, the responses of the pairs were inverted and the timing of excitatory and inhibitory responses appeared to be phased, a property consistent with gamma-aminobutyrate-mediated shaping of receptive fields. These observations (i) provide evidence that interneurons and pyramidal cells can be differentiated in vivo and (ii) begin to elucidate the role of gamma-aminobutyratergic mechanisms in cognition.     

Parcellation of the human prefrontal cortex using MRI

NMR spectroscopy and NMR imaging with magnetic field gradients make strange bedfellows, the requirements for one seemingly ruling out the other for human applications. Nevertheless, their stories are intertwined; the advent of high field imaging systems arose because of the desire for human spectroscopy. Localized spectroscopy is possible because of NMR imaging. Both have links to physics at Nottingham, at least in the personalized account that follows. Today, virtually all NMR spectroscopy experiments can be conceived with a localized in vivo spectroscopy counterpart.     

Postnatal development of pyramidal dendritic and axonal bundles in the visual cortex of the rat

We studied the development and spatial organization of vertically arranged pyramidal dendritic and axonal bundles in the visual cortex of the rat by using extracellular biocytin injections into frontal brain slice preparations. Vertical bundles of intracortical axons could be clearly observed at time of birth with a initial center-to-center distance of 18 microns +/- 3.1 microns. At the same time a clustering of pyramidal cell apical dendrites was completely absent. Dendritic bundles were demonstrated for the first time at postnatal day 5 when the supragranular layer 2/3 begins to differentiate. In the following weeks both axonal as well as dendritic bundles grew continuously and completely in parallel with regard to their center-to-center distances, diameters and number of elements up to their adult values at around postnatal day 90. At adulthood both types of bundles showed a center-to-center distance of 50.1 microns +/- 20.1 microns (axons) and 52.6 microns +/- 18.1 microns (dendrites), respectively. Our results demonstrate that axonal and dendritic bundles originating from the same neurons in the visual cortex of the rat correspond very well with regard to their size and distances. Developing neurons migrating along radial glia fibers group their axons together in fascicles before the lamination of the cortex is completely matured. After all layers have been developed, the apical dendrites of pyramidal cells with aggregated axons also group in clusters. The following development of axonal and dendritic bundles is presumably concerned with the volume increase of the maturating neocortex. Evidence for activity dependent plasticity after eye opening could not be found.     

A quantitative analysis of the dendritic organization of pyramidal cells in the rat hippocampus

The three dimensional organization of the dendritic trees of pyramidal cells in the rat hippocampus was investigated using intracellular injection of horseradish peroxidase in the in vitro hippocampal slice preparation and computer-aided reconstruction. The total dendritic length, dendritic length in each of the hippocampal laminae, and the number of dendritic branches were measured in 20 CA1 pyramidal cells, 7 neurons in CA2 and 20 CA3 pyramidal cells. The total dendritic length of CA3 pyramidal cells varied in a consistent fashion depending on their position within the field. Cells located close to the dentate gyrus had the smallest dendritic trees which averaged 9,300 microns in total length. Cells in the distal part of CA3 (near CA2) had the largest dendritic trees, averaging 15,800 microns. The CA2 field contained cells which resembled CA3 pyramidal cells in most respects except for the absence of thorny excrescences on their proximal dendrites. There were also smaller pyramidal cells that resembled CA1 neurons. CA1 pyramidal cells tended to be more homogeneous. Pyramidal neurons throughout the transverse extent of CA1 had a total dendritic length on the order of 13,500 microns. The quantitative analysis of the laminar distribution of dendrites demonstrated that the stratum oriens and stratum radiatum contained significant portions of the pyramidal cell dendritic trees. In Ca3, for example, 42-51% of the total dendritic length was located in stratum oriens; about 34% of the dendritic tree was located in stratum radiatium. The amount of dendritic length in stratum lacunosum-moleculare of CA3 varied depending on the location of the cell. Many CA3 cells located within the limbs of the dentate gyrus, for example, had no dendrites extending into stratum lacunosum-moleculare whereas those located distally in CA3 had about the same percentage of their dendritic tree in stratum lacunosum-moleculare as in stratum radiatum. In CA1, nearly half of the dendritic length was located in stratum radiatum, 34% was in stratum oriens and 18% was in stratum lacunosum-moleculare. These studies identified distinctive dendritic branching patterns, in the stratum radiatum and stratum lacunosum-moleculare, which clearly distinguished CA3 from CA1 neurons.     

Quantitative study of primitive pyramidal cells in rat anterior cingular cortex

In the present paper the primitive pyramidal cells of the Vthlayer of the anterior cingulate cortex in adult male white rats were analyzed quantitatively and compared statisticaly with large pyramidal cells of the same region. The number of dendrites, the total lengths of dendrites, the number of spines and the density of spines -- according to the order of dendrites -- show similarity between the primitive pyramidal cells and the large pyramidal cells the latter one exhibit the higher values. The curves of distribution of the various density of spines along the apical main dendrite of both cell types are similar in shape, too. The lengths of the dendritic fields and their basal spines-values are without significant distinction for both cell types, however there are more dendritic fields in large pyramidal cells. Refered to a complete pyramidal neuron they can say: there are significantly higher values in large pyramidal cells for the number of dendrites and their total lengths, the total number of spines, the number of branching sites sites and free endings. However the density of spines of the complete neuron has no significant differences between primitive and large pyramidal cells.     

Dissociating working memory from task difficulty in human prefrontal cortex

A functional magnetic resonance imaging (fMRI) study was conducted to determine whether prefrontal cortex (PFC) increases activity in working memory (WM) tasks as a specific result of the demands placed on WM, or to other processes affected by the greater difficulty of such tasks. Increased activity in dorsolateral PFC (DLPFC) was observed during task conditions that placed demands on active maintenance (long retention interval) relative to control conditions matched for difficulty. Furthermore, the activity was sustained over the entire retention interval and did not increase when task difficulty was manipulated independently of WM requirements. This contrasted with the transient increases in activity observed in the anterior cingulate, and other regions of frontal cortex, in response to increased task difficulty but not WM demands. Thus, this study established a double-dissociation between regions responsive to WM versus task difficulty, indicating a specific involvement of DLPFC and related structures in WM function.     

Functional modularity of the medial prefrontal cortex: Involvement in human empathy.

To investigate medial frontal lobe mediation of human empathy, the authors analyzed the activation areas in statistical parametric maps of 80 studies reporting neural correlates of empathic processing. The meta-analysis revealed 6 spatially distinct activation clusters in the medial part of the frontal lobe dorsal to the intercommissural plane. The most dorsal cluster coincided with the left supplementary motor area (SMA). Rostrally adjacent was a cluster that overlapped with the right pre-SMA. In addition, there were 3 left-hemispheric and 1 right-hemispheric clusters located at the border between the superior frontal and anterior cingulate gyrus. A broad spectrum of cognitive functions were associated with these clusters, including attention to one's own action, which was related to activations in the SMA, and valuation of other people's behavior and ethical categories, which was related to activations in the most rostroventral cluster. These data complement the consistent observation that lesions of the medial prefrontal cortex interfere with a patient's perception of own bodily state, emotional judgments, and spontaneous behavior. The results of the current meta-analysis suggest the medial prefrontal cortex mediates human empathy by virtue of a number of distinctive processing nodes. In this way, the authors' findings suggest differentiated aspects of self-control of behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Catecholamine regulation of the prefrontal cortex

In order to contribute to the understanding of the biological properties of nafazatrom, an antithrombotic agent (NAP), we studied its effects on peroxidation of low density lipoproteins (LDL), lipid liposomes, heart homopgenate, and its interaction with alpha-tocopherol radical. NAP decreased the FeSO4 and H202-induced peroxidation of phosphatidylcholine liposomes and heart homogenate, and it decreased peroxidation of LDL induced by CuSO4 or 2,2'-azobis(2-amidinopropane). The antioxidant effect of NAF was about 3 times less potent than that of alpha-tocopherol (alpha-TOC) in phosphatidylcholine liposomes, and NAF was about 2-4 times more efficient to decrease peroxidation of LDL than alpha-TOC. Possible interaction of NAF with alpha-tocopherol radical (alpha-TR) was studied by EPR spectroscopy. NAF decreased the concentration of alpha-TR, but it was about 100-times less efficient than vitamin C. This may indicate that NAF does not interfere with alpha-TR formation and/or reduction of alpha-TR in biological system. The obtained results may help the explanation of biological effects of NAF.     

The neuropsychology of the prefrontal cortex

Single photon emission computed tomography with the xenon inhalation technique is used to compare activation of regional cerebral blood flow in frontal brain regions during the performance of four widely used neuropsychological tests: the Continuous Performance Test, the Wisconsin Card Sorting Test, the Tower of London, and Porteus Mazes. Healthy normal volunteers performing these tasks show significant increases in frontal regions during the Continuous Performance Test, the Wisconsin Card Sorting Test, and the Tower of London, but not the Porteus Mazes. Activation produced by the Continuous Performance Test and the Tower of London are mesial and bilateral and may reflect stimulation of midline attentional circuits. The Wisconsin Card Sorting Test produces a left dorsolateral area of prefrontal activation. These findings indicate that regional activation of the frontal lobes occurs in response to cognitive challenges produced through performance of standard neuropsychological tests.     

Embryonic development and postnatal changes in free D-aspartate and D-serine in the human prefrontal cortex

We have analyzed free chiral amino acids (aspartate and serine) in the human frontal cortex at different ontogenic stages (from 14 weeks of gestation to 101 years of age) by HPLC with fluorometric detection after derivatization with N-tert-butyl-oxycarbonyl-L-cysteine and o-phthaldialdehyde. Exceptionally high levels of free D-aspartate and D-serine were demonstrated in the fetal cortex at gestational week 14. The ratios of D-aspartate and of D-serine to the total corresponding amino acids were also high, at 0.63 and 0.27, respectively. The concentration of D-aspartate dramatically decreased to a trace level by gestational week 41 and then remained very low during all postnatal stages. In contrast, the frontal tip contained persistently high levels of D-serine throughout embryonic and postnatal life, whereas the D-amino acid content in adolescents and aged individuals was about half of that in the fetuses. Because D-aspartate and D-serine are known to have selective actions at the NMDA-type excitatory amino acid receptor, the present data suggest that these D-amino acids might play a pivotal role in cerebral development and functions that are related to the NMDA receptor.     

Skeletal progenitor cells and ageing human populations

PURPOSE: To investigate (1) the radiosensitivity of B versus T lymphocytes with respect to micronucleus (MN) induction and (2) the possible application of the B cell MN assay for biological dosimetry of individuals after acute exposure to low doses of ionizing radiation. MATERIALS AND METHODS: MN analysis was performed in T and B lymphocytes of six healthy volunteers exposed in vitro to gamma-ray doses ranging from 0.05 Gy to 1 Gy. For the MN assay on B cells, peripheral blood mononuclear cells were cultured and stimulated with pokeweed mitogen (PWM). Afterwards the B lymphocytes (characterized by the CD20+ phenotype) were separated with the FACSort flow cytometer and the number of MN in the sorted binucleate cells was scored. For T lymphocytes the standard MN protocol was applied. RESULTS: The number of spontaneous and radiation induced MN were significantly higher in B lymphocytes compared to T lymphocytes in the low dose range up to 1 Gy. An analysis of the present data showed that when the spontaneous MN frequencies are not known, doses from 0.08 Gy could be detected with the B cell MN assay while the conventional MN assay only allowed detection of doses > 0.25 Gy. However, in contradiction to the linear-quadratic dose-response for T cells, for B cells the initial steep increase of the MN yield with the very low dose was followed by a flattening of the curve towards higher doses. CONCLUSION: This study shows that B lymphocytes express a high number of MN for doses up to 1 Gy gamma-rays reflecting the highly radiosensitive behaviour of B cells. The results also point to the possible application of the B-cell MN assay for individual dose assessment. When blood samples can be taken within 24 h after acute accidental overexposure, the B-cell MN assay can be performed but only as a supplementary test to the conventional MN assay.     

Interaction of ventral and orbital prefrontal cortex with inferotemporal cortex in conditional visuomotor learning.

Five rhesus monkeys (Macaca mulatta) were trained to learn novel conditional visuomotor associations, to perform this task with familiar stimuli, and to perform a visual matching-to-sample task with the same familiar stimuli. Removal of the orbital and ventral prefrontal cortex (PFv+o) in 1 hemisphere and inferotemporal cortex (IT) in the other, thus completing a surgical disconnection of these 2 regions, yielded an impairment on all 3 tasks. Addition of a premotor cortex lesion to the hemisphere containing the PFv+o lesion did not worsen the impairments. The results indicate that PFv+o interacts with IT in both the learning and retention of conditional visuomotor associations. In addition to those associations, which might be considered lower order rules for choosing a response, frontotemporal interaction also appears to be important for higher order rules, such as those involved in the matching task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The growth of the dendritic trees of Purkinje cells in irradiated agranular cerebellar cortex

The heads of noenatal Wistar rats were irradiated with 200 rads daily from birth to the 10th day post-partum. Ten litters each containing 5 animals were killed at 30 days post-partum and their brains treated by the Golgi-Cox technique. The dendritic trees of 24 Purkinje cells were analysed using the quantitative technique of network analysis, and comparisons made between parameters obtained from 20 normal Purkinje cells. All dendritic trees in agranular irradiated cortex were markedly reduced in size (as indicated by total dendritic length and total number of segments) although mean path lengths were normal. Segment lengths were normal over proximal branches, but uniformly increased over distal branches. Abnormal appendages, called 'giant spines' were observed on many dendrites. They were often some 10 mum in length and their presence effectively reduced segment lengths, increased the frequency of trichotomy and deviated growth from the normal random terminal pattern so that long collateral branching topologies were formed. Nevertheless, trichotomy was uniformly reduced in those trees without 'giant spines' and the distribution of branching patterns suggested that growth had proceeded by random terminal dichotomy. These results demonstrate that the development of dendritic trees is retarded in the agranular irradiated cerebellum, where synaptogenesis is very greatly reduced below normal. The quantitative changes in segment lengths, size of trees, and trichotomy accord with those predicted by the filopodial synaptogenic hypothesis of dendritic growth formulated by Vaughn et al. 99, whilst the results of the topological analysis suggest that branching is established by a degree of non-random interaction between growing dendrites and their substrate. 'Claw-like' dendritic complexes within some Purkinje cell trees may have been induced by aberrent fibre bundles of few surviving granule cells.     

Activation of human dendritic cells following infection with Mycobacterium tuberculosis

Dendritic cells (DC) play an essential role in the initiation of primary T cell responses to foreign Ag. It is likely that these potent APC are critical in the initiation of immune responses to pathogens, such as bacteria or parasites. However, little is known about the interaction of these important APC with pathogens. To address this issue, the interaction of the bacterium Mycobacterium tuberculosis with human DC was studied. DC generated from human peripheral blood by short term culture in medium containing recombinant human cytokines granulocyte-macrophage-CSF and IL-4 were capable of phagocytosing M. tuberculosis. Infection of DC with live M. tuberculosis bacilli resulted in increased APC surface expression of the costimulatory molecules CD54, CD40, and B7.1, as well as MHC class I molecules. In addition, infected DC secreted elevated levels of inflammatory cytokines, including TNF-alpha, IL-1, and IL-12. M. tuberculosis-infected human monocytes also secreted inflammatory cytokines, but exhibited no enhancement of costimulatory or MHC class I molecule expression. These data indicate that infection with M. tuberculosis results in the direct activation and maturation of these DC. In vivo, such activation may facilitate migration to the lymph nodes, and enhance presentation of Ag to T cells, thereby facilitating the induction of the immune response against this pathogen.     

Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts.

Reviews studies demonstrating that cholinergic grafts can ameliorate some deficits in aged animals and in animals with basal forebrain or fimbria-fornix lesions. Additional experiments were conducted with 35 male rats in Exp 1 and 26 female rats in Exp 2. Lesions of the motor and parietal zones of dorsolateral neocortex did not affect Ss' performance on a delayed-matching-to-performance task. Transection of the fimbria-fornix disrupted task performance in a delay-dependent manner, suggesting a specific disruption of short-term retention. Data confirm involvement of the medial prefrontal cortex and its ventral striatal outputs in performance of the task and in age-related deficits in short-term memory. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased benzodiazepine receptor density in the prefrontal cortex in patients with panic disorder

There are published studies concerning a regionally changed function of GABA-benzodiazepine-receptor-complexes in anxiety disorder. These studies implicate the limbic lobe, the brainstem and the prefrontal cortex. Using 123I-Iomazenil and single photon emission tomography (SPET) we investigated the benzodiazepine receptor density in twelve patients with panic disorder who had never been treated with benzodiazepines before. Nine age- and sex-matched volunteers who were free of mental illness served as controls. Patients with panic disorder showed a significant increase of benzodiazepine receptor binding in the right supraorbital cortex and a trend to an increased uptake in the right temporal cortex. There was no correlation between receptor density and scores on Spielberger's State Trait Anxiety Inventory in the patient group. Since the findings cannot be explained by benzodiazepine exposure we hypothesize an upregulation due to functional or neuroanatomic changes (at least) in the frontotemporal cortex.     

Topographic organization of medial pulvinar connections with the prefrontal cortex in the rhesus monkey

The medial nucleus of the pulvinar complex (PM) has widespread connections with association cortex. We investigated the connections of the PM with the prefrontal cortex (PFC) in macaque monkeys, with tracers placed into the PM and the PFC, respectively. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) placed into the PM resulted in widespread anterograde terminal labeling in layers III and IV, and retrograde cellular labeling in layer VI of the PFC. Injections of tracers centered on the central/lateral PM resulted in labeling of dorsolateral and orbital regions, whereas injections centered on caudal, medial PM resulted in labeling of dorsomedial and medial PFC. Since injections of the PM included neighboring thalamic nuclei, retrograde tracers were placed into distinct cytoarchitectonic regions of the PFC and retrogradely labeled cells in the posterior thalamus were charted. The results of this series of tracer injections confirmed the results of thalamic injections. Injections placed into areas 8a, 12 (lateral and orbital), 45, 46 and 11, retrogradely labeled neurons in the central/lateral PM, while tracer injections placed into areas 9, 12 (lateral), 10 and 24, labeled medial PM. The connections of the PM with temporal, parietal, insular, and cingulate cortices were also examined. The central/lateral PM has reciprocal connections with posterior parietal areas 7a, 7ip, and 7b, insular cortex, caudal superior temporal sulcus (STS), caudal superior temporal gyrus (STG), and posterior cingulate, whereas medial PM is connected mainly with the anterior STS and STG, as well as the cingulate cortex and the amygdala. These connectional studies suggest that the central/ lateral and medial PM have divergent connections which may be the substrate for distinct functional circuits.