Amplitude variability and extracellular low-pass filtering of neuronal spikes

The influence of neural morphology and passive electrical parameters on the width and amplitude of extracellular spikes is investigated by combined analytical and numerical investigations of idealized and anatomically reconstructed pyramidal and stellate neuron models. The main results are: 1), All models yield a low-pass filtering effect, that is, a spike-width increase with increasing distance from soma. 2), A neuron's extracellular spike amplitude is seen to be approximately proportional to the sum of the dendritic cross-sectional areas of all dendritic branches connected to the soma. Thus, neurons with many, thick dendrites connected to soma will produce large amplitude spikes, and therefore have the largest radius of visibility. 3), The spike shape and amplitude are found to be dependent on the membrane capacitance and axial resistivity, but not on the membrane resistivity. 4), The spike-amplitude decay with distance r is found to depend on dendritic morphology, and is decaying as 1/rⁿ with 1 ≤ n ≤ 2 close to soma and n ≥ 2 far away.     

Transgenic Melon and Squash Expressing Coat Protein Genes of Aphid-borne Viruses do not Assist the Spread of an Aphid Non- transmissible Strain of Cucumber Mosaic Virus in the Field

Transgenic melon and squash containing the coat protein (CP) gene of the aphid transmissible strain WL of cucumber mosaic cucumovirus (CMV) were grown under field conditions to determine if they would assist the spread of the aphid non-transmissible strain C of CMV, possibly through heterologous encapsidation and recombination. Transgenic melon were susceptible to CMV strain C whereas transgenic squash were resistant although the latter occasionally developed chlorotic blotches on lower leaves. Transgenic squash line ZW-20, one of the parents of commercialized cultivar Freedom II, which expresses the CP genes of the aphid transmissible strains FL of zucchini yellow mosaic (ZYMV) and watermelon mosaic virus 2 (WMV 2) potyviruses was also tested. Line ZW-20 is resistant to ZYMV and WMV 2 but is susceptible to CMV. Field experiments conducted over two consecutive years showed that aphid-vectored spread of CMV strain C did not occur from any of the CMV strain C-challenge inoculated transgenic plants to any of the uninoculated CMV-susceptible non- transgenic plants. Although CMV was detected in 3% (22/764) of the uninoculated plants, several assays including ELISA, RT- PCR-RFLP, identification of CP amino acid at position 168, and aphid transmission tests demonstrated that these CMV isolates were distinct from strain C. Instead, they were non-targeted CMV isolates that came from outside the field plots. This is the first report on field experiments designed to determine the potential of transgenic plants expressing CP genes for triggering changes in virus-vector specificity. Our results indicate that transgenic plants expressing CP genes of aphid transmissible strains of CMV, ZYMV, and WMV 2 are unlikely to mediate the spread of aphid non-transmissible strains of CMV. This finding is of practical relevance because transgenic crops expressing the three CP genes are targeted for commercial release, and because CMV is economically important, has a wide host range, and is widespread worldwide.     

Intrinsic dendritic filtering gives low-pass power spectra of local field potentials

The local field potential (LFP) is among the most important experimental measures when probing neural population activity, but a proper understanding of the link between the underlying neural activity and the LFP signal is still missing. Here we investigate this link by mathematical modeling of contributions to the LFP from a single layer-5 pyramidal neuron and a single layer-4 stellate neuron receiving synaptic input. An intrinsic dendritic low-pass filtering effect of the LFP signal, previously demonstrated for extracellular signatures of action potentials, is seen to strongly affect the LFP power spectra, even for frequencies as low as 10 Hz for the example pyramidal neuron. Further, the LFP signal is found to depend sensitively on both the recording position and the position of the synaptic input: the LFP power spectra recorded close to the active synapse are typically found to be less low-pass filtered than spectra recorded further away. Some recording positions display striking band-pass characteristics of the LFP. The frequency dependence of the properties of the current dipole moment set up by the synaptic input current is found to qualitatively account for several salient features of the observed LFP. Two approximate schemes for calculating the LFP, the dipole approximation and the two-monopole approximation, are tested and found to be potentially useful for translating results from large-scale neural network models into predictions for results from electroencephalographic (EEG) or electrocorticographic (ECoG) recordings.     

Solution structure by 1H and dynamics by natural abundance 13C NMR of a receptor recognising peptide derived from a C-terminal fragment of neuropeptide Y

Summary A peptide consisting of 20 amino acid residues, derived from a C-terminal fragment of neuropeptide Y (NPY) and showing high affinity to NPY receptors, was synthesised. Its sequence is PAADLARYRHYIN-LITRQRY-NH₂, and the solution structure was calculated from NMR-derived distance and torsion angle restraints, obtained at 15°C in a solvent mixture of water and 30% (v/v) 1,1,1,3,3,3-hexafluoro-2-propanol, by using DIANA and restrained energy minimisation. The structure was found to consist of a well-defined -helix in the centre, with a few residues at the termini having less well defined conformations. The spinlattice and spin-spin relaxation rates of -carbons have been determined on ¹³C at natural abundance. From 1D experiments the global rotational correlation time was determined and from 2D experiments the dynamics of each individual residue was obtained. The results demonstrate that the C-H vectors in the -helix essentially follow the global motion. Towards the termini, contributions from local dynamics increase. This tendency is correlated to the increasing uncertainty of the structure towards the peptide ends. An effective molecular volume was calculated from the temperature dependence of the global rotational correlation time. This is well compatible with a monomeric peptide, solvated by water and 1,1,1,3,3,3-hexafluoro-2-propanol. The presence of peptide dimers was ruled out as being inconsistent with the relaxation data.Supplementary material available from the authors: Two data tables and 10 PDB coordinate files of the calculated NMR structures of P7. One data table contains all detected and integrated NOE intensities; the other connects each proton and pseudoatom to an atom number used in the NOE table. The table contents served as input data files for CALIBA.Currently on leave from the Institute of Chemical Physics and Biophysics, Tallinn, Estonia.     

Modeling the spatial reach of the LFP

The local field potential (LFP) reflects activity of many?neurons in the vicinity of the recording electrode and is therefore useful for studying local network dynamics. Much of the nature of the LFP is, however, still unknown. There are, for instance, contradicting reports on the spatial extent of the region generating the LFP. Here, we use a detailed biophysical modeling approach to investigate the size of the contributing region by simulating the LFP from a large number of neurons around the electrode. We find that the size of the generating region depends on the neuron morphology, the synapse distribution, and the correlation in synaptic activity. For uncorrelated activity, the LFP represents cells in a small region (within a radius of a few hundred micrometers). If the LFP contributions from different cells are correlated, the size of the generating region is determined by the spatial extent of the correlated activity.     

Rat Mesentery Angiogenesis Assay

The adult rat mesentery window angiogenesis assay is biologically appropriate and is exceptionally well suited to the study of sprouting angiogenesis in vivo [see review papers], which is the dominating form of angiogenesis in human tumors and non-tumor tissues, as discussed in invited review papers^1,2. Angiogenesis induced in the membranous mesenteric parts by intraperitoneal (i.p.) injection of a pro-angiogenic factor can be modulated by subcutaneous (s.c.), intravenous (i.v.) or oral (p.o.) treatment with modifying agents of choice. Each membranous part of the mesentery is translucent and framed by fatty tissue, giving it a window-like appearance.The assay has the following advantageous features: (i) the test tissue is natively vascularized, albeit sparsely, and since it is extremely thin, the microvessel network is virtually two-dimensional, which allows the entire network to be assessed microscopically in situ; (ii) in adult rats the test tissue lacks significant physiologic angiogenesis, which characterizes most normal adult mammalian tissues; the degree of native vascularization is, however, correlated with age, as discussed in¹; (iii) the negligible level of trauma-induced angiogenesis ensures high sensitivity; (iv) the assay replicates the clinical situation, as the angiogenesis-modulating test drugs are administered systemically and the responses observed reflect the net effect of all the metabolic, cellular, and molecular alterations induced by the treatment; (v) the assay allows assessments of objective, quantitative, unbiased variables of microvascular spatial extension, density, and network pattern formation, as well as of capillary sprouting, thereby enabling robust statistical analyses of the dose-effect and molecular structure-activity relationships; and (vi) the assay reveals with high sensitivity the toxic or harmful effects of treatments in terms of decreased rate of physiologic body-weight gain, as adult rats grow robustly.Mast-cell-mediated angiogenesis was first demonstrated using this assay^3,4. The model demonstrates a high level of discrimination regarding dosage-effect relationships and the measured effects of systemically administered chemically or functionally closely related drugs and proteins, including: (i) low-dosage, metronomically administered standard chemotherapeutics that yield diverse, drug-specific effects (i.e., angiogenesis-suppressive, neutral or angiogenesis-stimulating activities⁵); (ii) natural iron-unsaturated human lactoferrin, which stimulates VEGF-A-mediated angiogenesis⁶, and natural iron-unsaturated bovine lactoferrin, which inhibits VEGF-A-mediated angiogenesis⁷; and (iii) low-molecular-weight heparin fractions produced by various means^8,9. Moreover, the assay is highly suited to studies of the combined effects on angiogenesis of agents that are administered systemically in a concurrent or sequential fashion.The idea of making this video originated from the late Dr. Judah Folkman when he visited our laboratory and witnessed the methodology being demonstrated.Review papers (invited) discussing and appraising the assayNorrby, K. In vivo models of angiogenesis. J. Cell. Mol. Med. 10, 588-612 (2006).Norrby, K. Drug testing with angiogenesis models. Expert Opin. Drug. Discov. 3, 533-549 (2008).     

Does Social Isolation and Low Societal Participation Predict Disability Pension? A Population Based Study

Purpose

The aim was to examine the potential influence of social isolation and low societal participation on the future risk of receiving disability pension among individuals in Sweden. A specific aim was to describe differences depending on disability pension diagnoses, and how the results were modified by sex and age.

Method

The study comprised representative samples of Swedish women and men, who had been interviewed in any of the annual Swedish Surveys of Living Conditions between 1990 and 2007. Information on disability pension and diagnoses was added from the Swedish Social Insurance Agency’s database (1991-2011). The mean number of years of follow-up for the 53920 women and men was twelve years (SD 5.5), and the study base was restricted to the ages 20 to 64 years of age. The predictors were related to disability pension by Cox’s proportional hazards regression.

Results

Social isolation and low societal participation were associated with future disability pension also after control for age, year of interview, socio demographic conditions and self reported longstanding illness. Lone individuals were at increased risk of disability pension, and the effect of living without children was modified by sex and age. An increase in risk was particularly noticeable among younger women who reported that they had sparse contacts with others, and no close friend. Both women and men who reported that they did not participate in political discussions and who could not appeal on a decision by a public authority were also at increased risk. The effects of social isolation were mainly attributed to disability pension with mental diagnoses, and to younger individuals.

Conclusions

The study suggests that social isolation and low societal participation are predictors of future disability pension. Social isolation and low societal participation increased particularly the risk of future disability pension in mental diagnoses among younger individuals.     

Therapeutic Benefits of Delayed Lithium Administration in the Neonatal Rat after Cerebral Hypoxia-Ischemia

Aim

We have previously shown that lithium treatment immediately after hypoxia-ischemia (HI) in neonatal rats affords both short- and long-term neuroprotection. The aim of this study was to evaluate possible therapeutic benefits when lithium treatment was delayed 5 days, a time point when most cell death is over.

Methods

Eight-day-old male rats were subjected to unilateral HI and 2 mmol/kg lithium chloride was injected intraperitoneally 5 days after the insult. Additional lithium injections of 1 mmol/kg were administered at 24 h intervals for the next 14 days. Brain injury was evaluated 12 weeks after HI. Serum cytokine measurements and behavioral analysis were performed before sacrificing the animals.

Results

Brain injury, as indicated by tissue loss, was reduced by 38.7%, from 276.5±27.4 mm³ in the vehicle-treated group to 169.3±25.9 mm³ in the lithium-treated group 12 weeks after HI (p<0.01). Motor hyperactivity and anxiety-like behavior after HI were normalized by lithium treatment. Lithium treatment increased neurogenesis in the dentate gyrus as indicated by doublecortin labeling. Serum cytokine levels, including IL-1α, IL-1β, and IL-6, were still elevated as late as 5 weeks after HI, but lithium treatment normalized these cytokine levels.

Conclusions

Delayed lithium treatment conferred long-term neuroprotection in neonatal rats after HI, and this opens a new avenue for future development of treatment strategies for neonatal brain injury that can be administered after the acute injury phase.