Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+ healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

Ultra-low-level measurements of airborne fission products from the Fukushima Daiichi reactor accident using high volume collection systems at Savannah River National Laboratory.

Ultra-low-level measurements of radionuclides in air have been conducted at the Savannah River National Laboratory (SRNL) to determine the atmospheric concentration of fission products released following the Fukushima Daiichi reactor accident on March 11, 2011. Air filter samples were acquired from two high-volume collection systems (a traditional filter-based system and an electrostatic precipitator-based system) to monitor airborne radionuclide concentrations in the period covering from 2 weeks to 3 years after the disaster. The world-wide spread of low-level concentrations of airborne fission products from the Fukushima event provided a unique opportunity to demonstrate SRNL's electrostatic particle collection technology and other improvements in environmental monitoring developed at the Savannah River Site (SRS). Detecting and analyzing the release allowed a comprehensive test of SRS systems for monitoring environmental radioactivity. Gamma-ray-emitting fission products (131,132I, 134,136,137Cs, and 129,132Te) and cosmogenic isotopes (7Be and 22Na) in air were detected and quantified by high-resolution gamma-ray spectroscopy at concentrations as low as 0.07 µBq per standard cubic meter (SCM) (50 mBq total 137Cs), while plutonium content was quantified by thermal ionization mass spectrometry (TIMS) at concentrations as low as 6.5 × 10-21 g/SCM (3.0 fg 239+240Pu). Isotope concentrations measured at SRNL from gamma-ray spectroscopy were compared to independent measurements from Chapel Hill, NC, located approximately 370 km (230 mi) NE of SRNL. Meteorological modeling was also used to predict radionuclide transport from the location of release to both measurement locations.

Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor dysfunction in a transgenic mouse.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease caused by an expanded polyglutamine tract in the ubiquitously expressed huntingtin protein. Clinically, HD is characterized by motor, cognitive and psychiatric deficits. Striking degeneration of the striatum is observed in HD with the medium spiny neurons (MSNs) being the most severely affected neuronal subtype. Dysfunction of MSNs is marked by characteristic changes in gene expression which precede neuronal death. The ubiquitous expression of the huntingtin protein raises the question as to whether the selective vulnerability of the MSN is cell-autonomous, non-cell-autonomous, or a combination thereof. In particular, growing evidence suggests that abnormalities of the cortex and corticostriatal projections may be primary causes of striatal vulnerability. To examine this issue, we developed transgenic mice that, within the forebrain, selectively express a pathogenic huntingtin species in the MSNs, specifically excluding the neocortex. These mice develop a number of abnormalities characteristic of pan-cellular HD mouse models, including intranuclear inclusion bodies, motor impairment, and changes in striatal gene expression. As this phenotype develops in the presence of normal levels of brain-derived neurotrophic factor and its major striatal receptor, tropomyosin-related kinase B, these data represent the first demonstration of in vivo cell-autonomous transcriptional dysregulation in an HD mouse model. Furthermore, our findings suggest that therapies targeted directly to the striatum may be efficacious at reversing some of the molecular abnormalities present in HD.

Cognition, blinks, eye-movements, and pupillary movements during performance of a running memory task.

INTRODUCTION: Blinks, saccades, and pupil diameter changes are studied for their application as tools to unobtrusively monitor aspects of performance. METHODS: Subjects performed a running memory task for a 60-min period. To evaluate changes in the relationship of blinks to saccades as a function of time on task, the ratio of blinks occurring with and without saccade was calculated for the second following stimulus termination plus the last 0.2 s of stimulus presentation, and also the second preceding stimulus onset plus the initial 0.2 s of stimulus presentation. Changes in pupil diameter following blinks with and without saccades were measured at the beginning, middle, and late in the experiment. RESULTS: Blink frequency increased during both periods as a function of time on task (p < 0.0001). The ratio of blinks concurrent with saccades during the post-stimulus period increased as a function of time on task (p < 0.0001). Pupil diameter increased following blink termination (p < 0.05), regardless of time on task, blink duration, or the presence of a saccade during the blink. CONCLUSION: Our results suggest that the increase in blinking associated with saccades as a function of time on task, and the pupillary dilation following a blink are associated with aspects of information processing. These results provide a framework for future studies assessing higher-order cognitive function in operational environments based on measurements of blink, pupil, and saccades.

Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons.

BACKGROUND: The high affinity tyrosine kinase receptor, TrkB, is the primary receptor for brain derived neurotrophic factor (BDNF) and plays an important role in development, maintenance and plasticity of the striatal output medium size spiny neuron. The striatal BDNF/TrkB system is thereby implicated in many physiologic and pathophysiologic processes, the latter including mood disorders, addiction, and Huntington's disease. We crossed a mouse harboring a transgene directing cre-recombinase expression primarily to postnatal, dorsal striatal medium spiny neurons, to a mouse containing a floxed TrkB allele (fB) mouse designed for deletion of TrkB to determine its role in the adult striatum. RESULTS: We found that there were sexually dimorphic alterations in behaviors in response to stressful situations and drugs of abuse. Significant sex and/or genotype differences were found in the forced swim test of depression-like behaviors, anxiety-like behaviors on the elevated plus maze, and cocaine conditioned reward. Microarray analysis of dorsal striatum revealed significant dysregulation in individual and groups of genes that may contribute to the observed behavioral responses and in some cases, represent previously unidentified downstream targets of TrkB. CONCLUSIONS: The data point to a set of behaviors and changes in gene expression following postnatal deletion of TrkB in the dorsal striatum distinct from those in other brain regions.

Detecting phasic lapses in alertness using pupillometric measures.

Small, nonreflexive pupillary changes are robust physiological indicators of cognitive activity. In the present paper, we examined whether measures of pupillary changes could be used to detect phasic lapses in alertness during a vigilance task. A polynomial curve-fitting method for quantifying parameters from single task-evoked pupillary responses (TEPRs) is described. The TEPR parameters associated with long latency responses (indicating low alertness) were compared to the TEPR parameters associated with normal latency responses (indicating an alert state) within a multilevel modeling framework. Three parameters, pupil diameter, linear pupil dilation rate and curvilinear pupil dilation rate, significantly differed between the long latency and normal latency response types. The results provide preliminary evidence that these parameters would be useful neurocognitive markers of operator state in a bio-behavioral alertness monitoring system.