Faculty Bibliography

Objective: Individuals with ADHD are often characterized as inconsistent across many contexts. ADHD is also associated with deficits in executive function. We examined the relationships between response time (RT) variability on five brief computer tasks to parents' ratings of ADHD-related features and executive function in a group of children with a broad range of ADHD symptoms from none to full diagnosis. Methods: We tested 98 children (mean age 9.9 +/- 1.4 years; 66 boys) from community clinics on short tasks of executive control (TEC) and the Eriksen Flanker task, while a parent completed the Conners' Parent Rating Scale and Behavior Rating Inventory of Executive Function. Results: Variability for two of the TEC tasks explained significant proportions of the variance of all five ADHD-related Conners' subscales and several executive function subscales. By contrast, variability on the flanker task or mean RTs for any task were not associated with any rating scale. Conclusion: The significant dimensional relationships observed between variability measures and parent ratings supported the utility of RT variability as an objective measure in ADHD and aspects of executive functioning that is superior to RT means or accuracy measures

Sensory neurons exhibit two universal properties: sensitivity to multiple stimulus dimensions, and adaptation to stimulus statistics. How adaptation affects encoding along primary dimensions is well characterized for most sensory pathways, but if and how it affects secondary dimensions is less clear. We studied these effects for neurons in the avian equivalent of primary auditory cortex, responding to temporally modulated sounds. We showed that the firing rate of single neurons in field L was affected by at least two components of the time-varying sound log-amplitude. When overall sound amplitude was low, neural responses were based on nonlinear combinations of the mean log-amplitude and its rate of change (first time differential). At high mean sound amplitude, the two relevant stimulus features became the first and second time derivatives of the sound log-amplitude. Thus a strikingly systematic relationship between dimensions was conserved across changes in stimulus intensity, whereby one of the relevant dimensions approximated the time differential of the other dimension. In contrast to stimulus mean, increases in stimulus variance did not change relevant dimensions, but selectively increased the contribution of the second dimension to neural firing, illustrating a new adaptive behavior enabled by multidimensional encoding. Finally, we demonstrated theoretically that inclusion of time differentials as additional stimulus features, as seen so prominently in the single-neuron responses studied here, is a useful strategy for encoding naturalistic stimuli, because it can lower the necessary sampling rate while maintaining the robustness of stimulus reconstruction to correlated noise.

Fluorescent dextran tracers of varying sizes have been used to assess paranodal permeability in myelinated sciatic nerve fibers from control and three 'myelin mutant' mice, Caspr-null, cst-null, and shaking. We demonstrate that in all of these the paranode is permeable to small tracers (3 kDa and 10 kDa), which penetrate most fibers, and to larger tracers (40 kDa and 70 kDa), which penetrate far fewer fibers and move shorter distances over longer periods of time. Despite gross diminution in transverse bands (TBs) in the Caspr-null and cst-null mice, the permeability of their paranodal junctions is equivalent to that in controls. Thus, deficiency of TBs in these mutants does not increase the permeability of their paranodal junctions to the dextrans we used, moving from the perinodal space through the paranode to the internodal periaxonal space. In addition, we show that the shaking mice, which have thinner myelin and shorter paranodes, show increased permeability to the same tracers despite the presence of TBs. We conclude that the extent of penetration of these tracers does not depend on the presence or absence of TBs but does depend on the length of the paranode and, in turn, on the length of 'pathway 3,' the helical extracellular pathway that passes through the paranode parallel to the lateral edge of the myelin sheath. (c) 2011 Wiley-Liss, Inc

OBJECTIVES/HYPOTHESIS: Vestibular neuritis is a common cause of both acute and chronic vestibular dysfunction. Multiple pathologies have been hypothesized to be the causative agent of vestibular neuritis; however, whether herpes simplex type I (HSV1) reactivation occurs within the vestibular ganglion has not been demonstrated previously by experimental evidence. We developed an in vitro system to study HSV1 infection of vestibular ganglion neurons (VGNs) using a cell culture model system. STUDY DESIGN: basic science study. RESULTS: Lytic infection of cultured rat VGNs was observed following low viral multiplicity of infection (MOI). Inclusion of acyclovir suppressed lytic replication and allowed latency to be established. Upon removal of acyclovir, latent infection was confirmed with reverse-transcription polymerase chain reaction and by RNA fluorescent in situ hybridization for the latency-associated transcript (LAT). A total of 29% cells in latently infected cultures were LAT positive. The lytic ICP27 transcript was not detected by reverse-transcription polymerase chain reaction (RT-PCR). Reactivation of HSV1 occurred at a high frequency in latently infected cultures following treatment with trichostatin A (TSA), a histone deactylase inhibitor. CONCLUSIONS: VGNs can be both lytically and latently infected with HSV1. Furthermore, latently infected VGNs can be induced to reactivate using TSA. This demonstrates that reactivation of latent HSV1 infection in the vestibular ganglion can occur in a cell culture model, and suggests that reactivation of HSV1 infection a plausible etiologic mechanism of vestibular neuritis

Endocytic system dysfunction is one of the earliest disturbances that occur in Alzheimer's disease (AD), and may underlie the selective vulnerability of cholinergic basal forebrain (CBF) neurons during the progression of dementia. Herein we report that genes regulating early and late endosomes are selectively upregulated within CBF neurons in mild cognitive impairment (MCI) and AD. Specifically, upregulation of rab4, rab5, rab7, and rab27 was observed in CBF neurons microdissected from postmortem brains of individuals with MCI and AD compared to age-matched control subjects with no cognitive impairment (NCI). Upregulated expression of rab4, rab5, rab7, and rab27 correlated with antemortem measures of cognitive decline in individuals with MCI and AD. qPCR validated upregulation of these select rab GTPases within microdissected samples of the basal forebrain. Moreover, quantitative immunoblot analysis demonstrated upregulation of rab5 protein expression in the basal forebrain of subjects with MCI and AD. The elevation of rab4, rab5, and rab7 expression is consistent with our recent observations in CA1 pyramidal neurons in MCI and AD. These findings provide further support that endosomal pathology accelerates endocytosis and endosome recycling, which may promote aberrant endosomal signaling and neurodegeneration throughout the progression of AD

We have developed a novel technique of using fluorescent tRNA for translation monitoring (FtTM). FtTM enables the identification and monitoring of active protein synthesis sites within live cells at submicron resolution through quantitative microscopy of transfected bulk uncharged tRNA, fluorescently labeled in the D-loop (fl-tRNA). The localization of fl-tRNA to active translation sites was confirmed through its co-localization with cellular factors and its dynamic alterations upon inhibition of protein synthesis. Moreover, fluorescence resonance energy transfer (FRET) signals, generated when fl-tRNAs, separately labeled as a FRET pair occupy adjacent sites on the ribosome, quantitatively reflect levels of protein synthesis in defined cellular regions. In addition, FRET signals enable detection of intra-populational variability in protein synthesis activity. We demonstrate that FtTM allows quantitative comparison of protein synthesis between different cell types, monitoring effects of antibiotics and stress agents, and characterization of changes in spatial compartmentalization of protein synthesis upon viral infection.

Orienting responses are physiological and active behavioral reactions evoked by novel stimulus perception and are critical for survival. We explored whether odor orienting responses are impacted throughout both adulthood and normal and pathological aging in mice. Novel odor investigation (including duration and bout numbers) and its subsequent habituation as assayed in the odor habituation task were preserved in adult C57BL/6J mice up to 12mo of age with <6% variability between age groups in investigation time. Separately, using whole-body plethysmography we found that both spontaneous respiration and odor-evoked sniffing behaviors were strikingly preserved in wildtype (WT) mice up to 26mo of age. In contrast, mice accumulating amyloid-beta protein in the brain by means of overexpressing mutations in the human amyloid precursor protein gene (APP) showed preserved spontaneous respiration up to 12mo, but starting at 14mo showed significant differences from WT. Similar to WTs, odor-evoked sniffing was not impacted in APP mice up to 26mo. These results show that odor-orienting responses are minimally impacted throughout aging in mice, and suggest that the olfactomotor network is mostly spared of insults due to aging

It has been shown recently that a significant portion of brain electrical field potentials consists of scale-free dynamics. These scale-free brain dynamics contain complex spatiotemporal structures and are modulated by task performance. Here we show that the fMRI signal recorded from the human brain is also scale free; its power-law exponent differentiates between brain networks and correlates with fMRI signal variance and brain glucose metabolism. Importantly, in parallel to brain electrical field potentials, the variance and power-law exponent of the fMRI signal decrease during task activation, suggesting that the signal contains more long-range memory during rest and conversely is more efficient at online information processing during task. Remarkably, similar changes also occurred in task-deactivated brain regions, revealing the presence of an optimal dynamic range in the fMRI signal. The scale-free properties of the fMRI signal and brain electrical field potentials bespeak their respective stationarity and nonstationarity. This suggests that neurovascular coupling mechanism is likely to contain a transformation from nonstationarity to stationarity. In summary, our results demonstrate the functional relevance of scale-free properties of the fMRI signal and impose constraints on future models of neurovascular coupling.

BACKGROUND: . Unique identifier: NCT00798122