Detection of a Single Identical Cytomegalovirus (CMV) Strain in Recently Seroconverted Young Women

Infection with multiple CMV strains is common in immunocompromised hosts, but its occurrence in normal hosts has not been well-studied.We analyzed CMV strains longitudinally in women who acquired CMV while enrolled in a CMV glycoprotein B (gB) vaccine trial. Sequencing of four variable genes was performed in samples collected from seroconversion and up to 34 months thereafter.199 cultured isolates from 53 women and 65 original fluids from a subset of 19 women were sequenced. 51 women were infected with one strain each without evidence for genetic drift; only two women shed multiple strains. Genetic variability among strains increased with the number of sequenced genetic loci. Nevertheless, 13 of 53 women proved to be infected with an identical CMV strain based on sequencing at all four variable genes. CMV vaccine did not alter the degree of genetic diversity amongst strains.Primary CMV infection in healthy women nearly always involves shedding of one strain that remains stable over time. Immunization with CMVgB-1 vaccine strain is not selective against specific strains. Although 75% of women harbored their unique strain, or a strain shared with only one other woman, 25% shared a single common strain, suggesting that this predominant strain with a particular combination of genetic loci is advantageous in this large urban area

Mechanisms underlying a thalamocortical transformation during active tactile sensation

During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain’s ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior-related computation implemented by the thalamocortical circuit

Neural network model of L4.

<p><b>(a)</b> Diagram of the recurrent model of L4 network. <b>(b)</b> Spike shape of VPM (schematic), L4E and L4I neurons. <b>(c)</b> Temporal dynamics of individual EPSPs for the different synaptic connections (T = VPM; I = L4 FS; E = L4E). The convention is that that the first letter corresponds to the post-synaptic neuron and the second letter to the presynaptic neuron. <b>(d)</b> Thalamic generating function <i>F</i>_T (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.e003" target="_blank">Eq 1</a>). The panels on the right show the same figure in a magnified scale. For simplicity, we assume that all T neurons have the same preferred phase.</p

Summary of experimental results in the object-localization task [37].

<p><b>(a)</b> Top, schematic illustrates measurement of whisker position (azimuthal angle <i>θ</i>), instances of touch and an example trace of whisker position. Protraction corresponds to positive changes in <i>θ</i>. <b>(b)</b> Schematics of the thalamocortical circuit and relevant cell-types. <b>(c)</b> Spike rate aligned to transitions from non-whisking to whisking (adapted from panel 5e in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref037" target="_blank">37</a>]). <b>(d)</b> Average spike rate as a function of whisking amplitude. <b>(e)</b> Average population response aligned to touch (adapted from panel 5c in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref037" target="_blank">37</a>]). Data and figures corresponding to previously reported datasets [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref036" target="_blank">36</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref037" target="_blank">37</a>].</p

Effects of varying intracortical recurrent excitatory conductances <i>g</i>_EE on the function of L4E neurons.

<p><b>(a)</b> The circuit with changing g_EE emphasized in green. <b>(b)</b> ν_E vs. <i>A</i>_T during whisker movements only, for 11 values of <i>g</i>_EE from 0 (light green) to 0.4 mS/cm², that is twice the reference parameter value (dark green). Recurrent excitation <i>g</i>_EE increases ν_E while not affecting the slope of the ν_E-<i>A</i>_T curve far from spiking threshold substantially. <b>(c)</b> <i>R</i>_T, <i>R</i>_E and <i>R</i>_I as functions of <i>g</i>_EE. Other parameters: <i>A</i>_T = 14 spikes/s, <i>C</i>_T = 0.6. <b>(d)</b> PSTH aligned to touch onset for L4E and without recurrent excitation (<i>g</i>_EE = 0 mS/cm²). <b>(e)</b> Same as <b>C</b> for L4I. <b>(f-g)</b> Same as <b>c</b>-<b>d</b> for <i>g</i>_EE = 0.2 mS/cm². <b>(h-i)</b>: Same as <b>c</b>-<b>d</b> for <i>g</i>_EE = 0.35 mS/cm². Beyond <i>~g</i>_EE = 0.4 mS/cm² the network exhibits runaway excitation.</p

Touch response in function of synaptic delay, AMPA receptors’ time constant and parameters defining thalamic input.

<p>In each panel, responses to touch in L4E and L4I neurons (<i>R</i>_E and <i>R</i>_I, in grey and red respectively) are plotted, as well as the thalamic response in black. Spikes per touch were counted up to 25 ms after touch onset, and baseline computed by counting spikes 25 ms before touch is subtracted. Responses to touch are plotted as functions of <b>(a)</b> I-to-E synaptic delay , <b>(b)</b> the AMPA receptor time constant <i>t</i>_AMPA, <b>(c)</b> the thalamic response to touch, <i>C</i>_T, and <b>(d)</b> the thalamic spike rate <i>A</i>_T during whisker movements without touch.</p

Summary of effect of photoinhibition of L4 FS neurons on L4 neurons.

<p><b>(a)</b> Schematic of the Hr⁺ experiment. A subset of L4 FS neurons do not express Hr (Hr^- neurons). <b>(b)</b> Photostimulation of Hr⁺ neurons decreases the activity in L4 FS neurons and increases the activity in L4 excitatory neurons. Black: without photostimulation; orange: with photostimulation. <b>(c)</b> Response of L4 excitatory neurons during whisker movements (adapted from panel 8d in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref037" target="_blank">37</a>]). <b>(d)</b> Response to touch of L4 excitatory neurons. The black circle denotes the mean values (adapted from panel 8e in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.ref037" target="_blank">37</a>]).</p

Effect of varying thalamocortical conductances on the function of L4E neurons.

<p>Symblols and lines are as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005576#pcbi.1005576.g009" target="_blank">Fig 9</a>. <b>(a)</b> Changing <i>g</i>_ET. <b>(b)</b> ν_E vs. <i>A</i>_T during whisker movements only. <b>(c)</b> R_E vs. <i>C</i>_T. <b>(d)</b> Changing <i>g</i>_IT. <b>(e-f)</b> Same as <b>b-c</b>.</p

A neural network model of L4 explains suppression of whisker movement signals in L4 excitatory neurons.

<p>The colors black, grey and red denote T, L4E and L4I neuronal populations respectively. <b>(a)</b> Example L4E and L4I membrane potential during simulated whisking (green). <b>(b)</b> The population- and time average spike rates ν_E and ν_I of the L4E and L4I neurons respectively as function of the thalamic input <i>A</i>_T in the absence of touch. L4I neurons follow linearly the thalamic input while L4E neurons increase only weakly with <i>A</i>_T beyond firing threshold. Inset, zoom in. <b>(c)</b> Membrane potential for an example neuron during whisking and touch (black dots). <b>(d)</b> Population PSTH aligned to touch onset. Inset, zoom in.</p

Simulated light activation of halorhodopsin expressed in L4I-Hr⁺ neurons.

<p>Simulations with <i>f</i>_halo = 0.5 reveals a reduction in the whisking suppression and an enhancement of touch responses by L4E neurons. <b>(a)</b> Halorhodopsin activation in L4I-Hr⁺ causes an average increase in response of L4E during whisking and no touch, with a wide distribution of halorhodopsin—induced modifications. <b>(b)</b> Most L4I-Hr⁺ neurons reduce their activity during whisking while L4I-Hr^- neurons increase it. <b>(c)</b> Increase in the touch responses in L4E neurons during suppression of L4I-Hr⁺. <b>(d)</b> Increase in the touch responses in L4I neurons. The increase in touch responses is only seen in Hr⁺ cells. <b>(e</b>,<b>f)</b> Population PSTH of L4E (<b>e</b>) and L4I (<b>f</b>) neurons with and without L4I-Hr⁺ activity suppression. <b>(g)</b> Reduction of L4I-Hr⁺ activity diminishes the whisking suppression effect in L4E neurons. Black line: T neurons; solid grey line: L4E neurons without halorhodopsin activation; dashed grey line: L4E neurons during halorhodopsin activation. <b>(h)</b> Reduction of L4I-Hr⁺ activity diminishes the whisking response in L4I-Hr⁺ neurons. Solid red line: L4I-Hr⁺ neurons without halorhodopsin activation; dashed red line: L4I-Hr⁺ neurons during halorhodopsin activation. Dashed blue line: L4I-Hr^- neurons during halorhodopsin activation.</p