Spatial working memory specific activity in dorsal prefrontal cortex? Disparate answers from fMRI beta-weight and timecourse analysis

Visual spatial processing and object processing rely on dorsal and ventral cortical pathways, respectively. Whether this functional segregation exists in the prefrontal cortex is currently a source of debate. Using functional MRI (fMRI), there has been some evidence that the superior frontal sulcus (within dorsal prefrontal cortex) is specialised for spatial working memory, while ventral prefrontal cortex is associated with object working memory. Employing beta-weight analysis, Postle, Berger, Taich, and D'Esposito (2000) challenged these results, finding no differential activity associated with spatial working memory versus two-dimensional saccades in the superior frontal sulcus. In the present reanalysis of Postle et al.'s data, both beta-weight analysis and event-related timecourse analysis were utilised. Beta-weight analysis results replicated Postle et al.; however, timecourse analysis revealed greater activity associated with spatial working memory versus two-dimensional saccades in the superior frontal sulcus. Thus, identical fMRI data analysed via distinct methods yielded results with different theoretical conclusions.     

Spatial working memory specific activity in dorsal prefrontal cortex? Disparate answers from fMRI beta-weight and timecourse analysis

Visual spatial processing and object processing rely on dorsal and ventral cortical pathways, respectively. Whether this functional segregation exists in the prefrontal cortex is currently a source of debate. Using functional MRI (fMRI), there has been some evidence that the superior frontal sulcus (within dorsal prefrontal cortex) is specialised for spatial working memory, while ventral prefrontal cortex is associated with object working memory. Employing beta-weight analysis, Postle, Berger, Taich, and D'Esposito (2000) challenged these results, finding no differential activity associated with spatial working memory versus two-dimensional saccades in the superior frontal sulcus. In the present reanalysis of Postle et al.'s data, both beta-weight analysis and event-related timecourse analysis were utilised. Beta-weight analysis results replicated Postle et al.; however, timecourse analysis revealed greater activity associated with spatial working memory versus two-dimensional saccades in the superior frontal sulcus. Thus, identical fMRI data analysed via distinct methods yielded results with different theoretical conclusions.     

The neural mechanisms of percept–memory comparison in visual working memory

Researchers have revealed that comparing the perceptual input with the representations stored in visual working memory initiates a rapid attention-shift, which is predominantly triggered by the relevant-feature change. The comprehension of the change contents further necessitates a follow-up comparison that contrasts all the object features regardless of the task relevancy. However, whether such a distinct stage exists and how the process is carried on need further verification. We explored this issue by investigating the underlying neural mechanisms of the percept–memory comparison. By recording EEG, we found that both the task-relevant and -irrelevant feature changes elicited significantly more negative anterior N2 waves (230–340 ms) rooting in the anterior cingulate cortex (ACC), and meanwhile activated the frontal theta (5–8 Hz, 250–550 ms). These results suggest that a distinct comparison stage does exist, which is supported by the anterior N2, ACC and frontal theta.     

Is the relationship of prosaccade reaction times and antisaccade errors mediated by working memory?

The mechanisms that control eye movements in the antisaccade task are not fully understood. One influential theory claims that the generation of antisaccades is dependent on the capacity of working memory. Previous research also suggests that antisaccades are influenced by the relative processing speeds of the exogenous and endogenous saccadic pathways. However, the relationship between these factors is unclear, in particular whether or not the effect of the relative speed of the pro and antisaccade pathways is mediated by working memory. The present study contrasted the performance of healthy individuals with high and low working memory in the antisaccade and prosaccade tasks. Path analyses revealed that antisaccade errors were strongly predicted by the mean reaction times of prosaccades and that this relationship was not mediated by differences in working memory. These data suggest that antisaccade errors are directly related to the speed of saccadic programming. These findings are discussed in terms of a race competition model of antisaccade control.     

What does neuroimaging tell us about the role of prefrontal cortex in memory retrieval?

The past five years have seen an outpouring of neuroimaging studies of memory — using both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These studies have convincingly demonstrated that neuroimaging can be used to study the functional anatomy of normal human memory and that neuroimaging can precisely localize memory related brain activations within small areas of cortex. As one illustration of the application of neuroimaging in the study of memory, this review shows how several laboratories have produced data that converge on the notion that specific areas in the prefrontal cortex are active during long-term memory retrieval. Moreover, the data further suggest that distinct prefrontal brain areas might make differential contributions to different kinds of long-term memory retrieval.     

Differential effects of β-adrenergic receptor blockade in the medial prefrontal cortex during aversive and incidental taste memory formation

The medial prefrontal cortex (mPFC) is a brain area crucial for memory, attention, and decision making. Specifically, the noradrenergic system in this cortex is involved in aversive learning, as well as in the retrieval of these memories. Some evidence suggests that this area has an important role during taste memory, particularly during conditioned taste aversion (CTA), a model of aversive memory. Despite some previous evidence, there is scarce information about the role of adrenergic receptors in the mPFC during formation of aversive taste memory and appetitive/incidental taste memory. The goal of this research was to evaluate the role of mPFC β-adrenergic receptors during CTA acquisition/consolidation or CTA retrieval, as well as during incidental taste memory formation using the model of latent inhibition of CTA. The results showed that infusions in the mPFC of the β-adrenergic antagonist propranolol before CTA acquisition impaired both short- and long-term aversive taste memory formation, and also that propranolol infusions before the memory test impaired CTA retrieval. However, propranolol infusions before pre-exposure to the taste during the latent inhibition procedure had no effect on incidental taste memory acquisition or consolidation. These data indicate that β-adrenergic receptors in the mPFC have different functions during taste memory formation: they have an important role during aversive taste association as well as during aversive retrieval but not during incidental taste memory formation.     

Structure–activity relationship of tocopherol derivatives suggesting a novel non-antioxidant mechanism in antiprion potency

Beneficial effects of tocopherols, or vitamin E, on degenerative brain conditions have been attributed mainly to their antioxidant effects. Non-antioxidant effects of the tocopherols have been shown to be mediated by inhibition of protein kinase C (PKC) signaling. Prion disease is a paradigmatic protein conformational disease characterized by the induced conversion of a normal host protein PrP^C to adopt a pathogenic conformation PrP^Sc. The molecular regulation of prion replication is poorly understood. Here, we show that tocopherols inhibit prion replication by a structure–activity relationship for antiprion activity independent of antioxidant activity with tocopherol succinate (TS) posessing highest EC₅₀ at 7 μM. Only TS but not an equally antiprion active PKC inhibitor could be partially antagonized by substochiometric 1 nM rapamycin suggesting that there are pathways via mammalian target of rapamycin (mTOR) that interfere with tocopherol's biological effects. Interaction with the mTOR pathway is a yet undescribed characteristic of tocopherol derivatives, potentially significant for pathophysiological processes other than prion propagation.     

Species-specific distributions of tyrosine hydroxylase–immunoreactive neurons in the prefrontal cortex of anthropoid primates

In this study, we assessed the distribution of cortical neurons immunoreactive for tyrosine hydroxylase (TH) in prefrontal cortical regions of humans and nonhuman primate species. Immunohistochemical methods were used to visualize TH-immunoreactive (TH-ir) neurons in areas 9 (dorsolateral prefrontal cortex) and 32 (anterior paracingulate cortex). The study sample included humans, great apes (chimpanzee, bonobo, gorilla, orangutan), one lesser ape (siamang), and Old World monkeys (golden guenon, patas monkey, olive baboon, moor macaque, black and white colobus, and François' langur). The percentage of neurons within the cortex expressing TH was quantified using computer-assisted stereology. TH-ir neurons were present in layers V and VI and the subjacent white matter in each of the Old World monkey species, the siamang, and in humans. TH-ir cells were also occasionally observed in layer III of human, siamang, baboon, colobus, and François' langur cortex. Cortical cells expressing TH were notably absent in each of the great ape species. Quantitative analyses did not reveal a phylogenetic trend for percentage of TH-ir neurons in these cortical areas among species. Interestingly, humans and monkey species exhibited a bilaminar pattern of TH-ir axon distributions within prefrontal regions, with layers I–II and layers V–VI having the densest contingent of axons. In contrast, the great apes had a different pattern of laminar innervation, with a remarkably denser distribution of TH-ir axons within layer III. It is possible that the catecholaminergic afferent input to layer III in chimpanzees and other great apes covaries with loss of TH-ir cells within the cortical mantle.     

Visual neglect: Is there a relationship between impaired spatial working memory and re-cancellation?

In visual search tasks, neglect patients tend to explore and repeatedly re-cancel stimuli on the ipsilesional side, as if they did not realize that they had previously examined the rightward locations favoured by their lateral bias. The aim of this study was to explore the hypothesis that a spatial working memory deficit explains these ipsilesional re-cancellation errors in neglect patients. For the first time, we evaluated spatial working memory and re-cancellation through separate and independent tasks in a group of patients with right hemisphere damage and a diagnosis of left neglect. Results showed impaired spatial working memory in neglect patients. Compared to the control group, neglect patients cancelled fewer targets and made more re-cancellations both on the left side and on the right side. The spatial working memory deficit appears to be related to re-cancellations, but only for some neglect patients. Alternative interpretations of re-exploration of space are discussed.     

Structure–function relationships and source-to-ground distance in electrospun polycaprolactone

The strength of electrospun scaffolds has direct relevance to their function within tissue engineering. We characterized the effects of source-to-ground distance on the mechanical properties of electrospun poly(ε-caprolactone) (PCL). Source-to-ground distances of 10, 15 and 20 cm, solids concentrations of 12 and 18 wt.% and mandrel rotation surface speeds of 0–12 m s^?1 were utilized. Tensile tests evaluated elastic modulus, tensile strength and elongation at failure. Scanning electron microscopy provided morphology and quantified fiber alignment. Increased source-to-ground distance yielded a microstructure allowing greater fiber rearrangement under load, tripling the observed tensile strength. Increases in rotational speed generally increased fiber alignment and strength at high but not low to moderate speeds. As fiber is quickly pulled out of a comparatively gentle falling process, collision with neighboring fibers moving at different speeds and in different directions can occur. The source-to-ground distance influences these collisions and thus has critical implications for microstructure and biocompatibility. In larger diameter (18 wt.% PCL), heavily point-bonded fibers (produced using a shorter, 10 cm source-to-ground distance), elongation at failure in the aligned direction increases dramatically due to severe localized necking. These specimens show only half of the tensile strength (from 2.6 to 4.5 MPa) and a dramatic increase (from 94% to 503%) in elongation at failure vs. a longer 20 cm source-to-ground distance. Strains of several hundred per cent are accompanied by periodic necking of large-diameter fibers in which microstructural failure appears to occur in a sequential manner involving an equilibrium between localized strain in the tensile direction and anisotropic point bonding that locally resists strain.     

Investigating principles of human brain function underlying working memory: What insights from schizophrenia?

Working memory dysfunction is a core component of schizophrenia, which likely contributes substantially to the pervasive and profound cognitive deficits observed in patients with this illness. Developments in functional imaging have facilitated the investigation of the neural basis of these cognitive deficits. A strong tradition within neuropsychology has been that circumscribed lesions provide observations which constrain theoretical models, and generate testable predictions on the basis of observed relationships between structural abnormalities and behavioral dysfunction. In this article, the extent to which the neuropsychological tradition can be applied to neuropsychiatry to advance understanding of the biological basis of working memory is addressed. Empirical studies in schizophrenia research are reviewed in relation to principles of normal brain function sub-serving working memory: the functional role of the lateral prefrontal cortex, physiological response capacity constraints, inter-regional functional integration, and compensatory adaptations. However, complex heterogeneous psychiatric disorders such as schizophrenia cannot be considered akin to a pure lesion model, and there are considerable methodological challenges in interpreting disruptions of working memory in psychiatric conditions, resulting from clinical, treatment and performance related confounds. The increasing use of psychopharmacological models of disease in healthy human subjects is therefore considered as an attempt to address, or to some extent circumvent these issues.     

Associations of age and sex with brain volumes and asymmetry in 2–5-week-old infants

Brain Structure and Function - Information on normal brain structure and development facilitates the recognition of abnormal developmental trajectories and thus needs to be studied in more detail....     

Morphological alterations in the occipital cortex of aged rats with impaired memory: A Golgi–Cox study

This study investigated a possible link between morphological alterations of pyramidal neurons in layer V of the occipital cortex and the degree of spatial memory impairment in aged rats. Measurements of cortical thickness, density of dendritic branching, and spine counts were carried out in young adult (5 months old) and aged (26 months old) Long-Evans female rats on Golgi–Cox silver-stained material. Using the water-maze task, well- and poorly performing rats were distinguished statistically on the basis of their reference-memory scores. When subsequently compared with young rats or to aged rats with good performances, the well-performing rats had a reduced cortical thickness and exhibited weaker high-order branching of basal dendrites on their pyramidal neurons. When dendritic spines were counted on a 50-m-long straight portion of a basal dendrite, no difference was observed between young and aged rats. Our results suggest that structural alterations affecting pyramidal neurons in the occipital cortex of aged rats may contribute to spatial memory impairment. Indeed, in a subpopulation of well-performing aged rats, these structural alterations were less marked than in the population of bad performers.     

The interplay between nanostructured carbon-grafted chitosan scaffolds and protein adsorption on the cellular response of osteoblasts: Structure–function property relationship

The rapid adsorption of proteins occurs during the early stages of biomedical device implantation into physiological systems. In this regard, the adsorption of proteins is a strong function of the nature of a biomedical device, which ultimately governs the biological functions. The objective of this study was to elucidate the interplay between nanostructured carbon-modified (graphene oxide and single-walled carbon nanohorn) chitosan scaffolds and consequent protein adsorption and biological function (osteoblast function). We compare and contrast the footprint of protein adsorption on unmodified chitosan and nanostructured carbon-modified chitosan. A comparative analysis of cell–substrate interactions using an osteoblast cell line (MC3T3-E1) implied that biological functions were significantly enhanced in the presence of nanostructured carbon, compared with unmodified chitosan. The difference in their respective behaviors is related to the degree and topography of protein adsorption on the scaffolds. Furthermore, there was a synergistic effect of nanostructured carbon and protein adsorption in terms of favorably modulating biological functions, including cell attachment, proliferation and viability, with the effect being greater on nanostructured carbon-modified scaffolds. The study also underscores that protein adsorption is favored in nanostructured carbon-modified scaffolds such that bioactivity and biological function are promoted.     

Navigating the structure–function–evolutionary relationship of CsaA chaperone in archaea

CsaA is a protein involved in the post-translational translocation of proteins across the cytoplasmic membrane. It is considered to be a functional homolog of SecB which participates in the Sec-dependent translocation pathway in an analogous manner. CsaA has also been reported to act as a molecular chaperone, preventing aggregation of unfolded proteins. It is essentially a prokaryotic protein which is absent in eukaryotes, but found extensively in bacteria and earlier thought to be widely present in archaea. The study of phylogenetic distribution of CsaA among prokaryotes suggests that it is present only in few archaeal organisms, mainly species of Thermoplasmatales and Halobacteriales. Interestingly, the CsaA protein from these two archaeal orders cluster separately on the phylogenetic tree with CsaA from Gram-positive and Gram-negative bacteria. It, thus, appears that this protein might have been acquired in these archaeal organisms through independent horizontal gene transfer (HGT) events from different bacteria. In this review, we summarize the earlier biochemical, structural, and functional characterization studies of CsaA. We draw new insights into the evolutionary history of this protein through phylogenetic and structural comparison of bacterial CsaA with modelled archaeal CsaA from Picrophilus torridus and Natrialba magadii.     

Excitotoxic lesions to the prefrontal cortex of Sprague–Dawley rats do not impair response matching

Perseveration refers to maladaptive persistence of behavior outside appropriate contexts and despite negative outcomes. In humans, perseveration is a symptom of a variety of psychiatric disorders. In rats, perseveration has been observed in reversal learning tasks following lesions of the prefrontal cortex (PFC). However, the exact nature of the impairment underlying this effect remains unclear. Male Sprague–Dawley rats were trained on a novel reversal task that requires switching between two rewarded options varying in effort (concurrent fixed and progressive ratios) necessary to obtain the reward. Following initial training, bilateral lesions of the dorsal PFC, medial PFC, or orbitofrontal cortex were produced by NMDA infusions. When animals were re-tested post-surgery, no significant impairments were found. These results indicate that, in trained rats, the PFC is not necessary for selecting responses on the basis of favorable effort-to-reward contingencies.     

Structure and function of Norrin in assembly and activation of a Frizzled 4–Lrp5/6 complex

Norrin is a cysteine-rich growth factor that is required for angiogenesis in the eye, ear, brain, and female reproductive organs. It functions as an atypical Wnt ligand by specifically binding to the Frizzled 4 (Fz4) receptor. Here we report the crystal structure of Norrin, which reveals a unique dimeric structure with each monomer adopting a conserved cystine knot fold. Functional studies demonstrate that the novel Norrin dimer interface is required for Fz4 activation. Furthermore, we demonstrate that Norrin contains separate binding sites for Fz4 and for the Wnt ligand coreceptor Lrp5 (low-density lipoprotein-related protein 5) or Lrp6. Instead of inducing Fz4 dimerization, Norrin induces the formation of a ternary complex with Fz4 and Lrp5/6 by binding to their respective extracellular domains. These results provide crucial insights into the assembly and activation of the Norrin–Fz4–Lrp5/6 signaling complex.     

Structure–transfection activity relationships with glucocorticoid–polyethyl-enimine conjugate nuclear gene delivery systems

Efficient nuclear gene delivery is essential for successful gene therapy. It was previously reported that the transport of DNA into nucleus may be facilitated by glucocorticoid (GC). In this study, five glucocorticoids with different structures and potencies were conjugated with low molecular weight PEI 1800, and the degree of substitution of glucocorticoids was controlled to be close to each other. The glucocorticoid–polyethylenimine (GC–PEI)/pDNA complexes were prepared and their physico-chemical properties and transfection efficiency were investigated. The results showed that the complexes had similar physico-chemical properties, but their transfection activities were different statistically. In order to explore the reason of this difference, the affinity of GC–PEI polymer with GC receptor was analyzed by the application of molecular docking, and the correlation between transfection activity and the potency of five GC was investigated. The result showed that receptor binding of five GC was different and transgene expression enhanced linearly with the increasing GC potency, but log P. In addition, confocal microscopy examination confirmed that GC–PEI/DNA complexes were more effectively translocated in the nucleus than PEI 25 K or PEI 1800 complexes and the cytotoxicities of the GC–PEI polymers were lower than that of PEI 25 K. These results demonstrated that transfection activity of GC–PEI polymer correlated with its GC potency, and this regularity might be useful for the development of more efficient GC substituted polymer as promising nuclear-targeting carrier.     

The GABA(A)ρ receptors in hippocampal spontaneous activity and their distribution in hippocampus, amygdala and visual cortex

A bicuculline-resistant and TPMPA-sensitive GABAergic component was identified in hippocampal neurons in culture and in acute isolated brain slices. In both preparations, total GABAergic activity showed two inactivation kinetics: fast and slow. RT-PCR, in situ hybridization (ISH) and immunohistochemistry detected expression of GABAρ subunits. Immunogold and electron microscopy indicated that the receptors are mostly extrasynaptic. In addition, by RT-PCR and immunofluorescence we found GABAρ present in amygdala and visual cortex.