Targeting and Readout Strategies for Fast Optical Neural Control In Vitro and In Vivo

Major obstacles faced by neuroscientists in attempting to unravel the complexity of brain function include both the heterogeneity of brain tissue (with a multitude of cell types present in vivo) and the high speed of brain information processing (with behaviorally relevant millisecond-scale electrical activity patterns). To address different aspects of these technical constraints, genetically targetable neural modulation tools have been developed by a number of groups (Zemelman et al., 2002; Banghart et al., 2004; Karpova et al., 2005; Lima and Miesenbock, 2005; Thompson et al., 2005; Chambers et al., 2006; Tan et al., 2006; Gorostiza et al., 2007; Lerchner et al., 2007; Szobota et al., 2007). One approach recently brought to neurobiology, combining both high speed and genetic targeting, is based on a family of fast light-responsive microbial opsins including halorhodopsins (e.g., NpHR) and channelrhodopsins (e.g., ChR2) (for review, see Zhang et al., 2007b). These microbial opsins are single-component transmembrane conductance regulators encompassing light sensitivity and fast membrane potential control within a single open reading frame, which can be used to achieve fast bidirectional control of specific cell types even in freely moving animals (Adamantidis et al., 2007; Zhang et al., 2007a). Although the basic functioning of these tools has been reviewed previously (Zhang et al., 2007b), here we describe a collection of targeting and readout strategies designed for rapid and flexible application of the microbial opsin system, and provide pointers to the relevant literature. Combinations of these multiple levels of targeting and readout define an evolving toolbox that may open up new possibilities for basic neuroscience investigation

Optical Deconstruction of Parkinsonian Neural Circuitry

Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying mechanisms of DBS. We used optogenetics and solid-state optics to systematically drive or inhibit an array of distinct circuit elements in freely moving parkinsonian rodents and found that therapeutic effects within the subthalamic nucleus can be accounted for by direct selective stimulation of afferent axons projecting to this region. In addition to providing insight into DBS mechanisms, these results demonstrate an optical approach for dissection of disease circuitry and define the technological toolbox needed for systematic deconstruction of disease circuits by selectively controlling individual components

Longitudinal motor system changes from acute to chronic spinal cord injury

BACKGROUND AND PURPOSE In acute spinal cord injury (SCI), magnetic resonance imaging (MRI) reveals tissue bridges and neurodegeneration for 2 years. This 5-year study aims to track initial lesion changes, subsequent neurodegeneration, and their impact on recovery. METHODS This prospective longitudinal study enrolled acute SCI patients and healthy controls who were assessed clinically-and by MRI-regularly from 3 days postinjury up to 60 months. We employed histologically cross-validated quantitative MRI sequences sensitive to volume, myelin, and iron changes, thereby reflecting indirectly processes of neurodegeneration and neuroinflammation. General linear models tracked lesion and remote changes in volume, myelin- and iron-sensitive magnetic resonance indices over 5 years. Associations between lesion, degeneration, and recovery (using the Spinal Cord Independence Measure [SCIM] questionnaire and the International Standards for Neurological Classification of Spinal Cord Injury total motor score) were assessed. RESULTS Patients' motor scores improved by an average of 12.86 (95% confidence interval [CI] = 6.70-19.00) points, and SCIM by 26.08 (95% CI = 17.00-35.20) points. Within 3-28 days post-SCI, lesion size decreased by more than two-thirds (3 days: 302.52 ± 185.80 mm$^{2}$ , 28 days: 76.77 ± 88.62 mm$^{2}$ ), revealing tissue bridges. Cervical cord and corticospinal tract volumes transiently increased in SCI patients by 5% and 3%, respectively, accompanied by cervical myelin decreases and iron increases. Over time, progressive atrophy was observed in both regions, which was linked to early lesion dynamics. Tissue bridges, reduced swelling, and myelin content decreases were predictive of long-term motor score recovery and improved SCIM score. CONCLUSIONS Studying acute changes and their impact on longer follow-up provides insights into SCI trajectory, highlighting the importance of acute intervention while indicating the potential to influence outcomes in the later stages

Coherent, time-shifted patterns of microstructural plasticity during motor-skill learning

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes-and their microstructural underpinnings-remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network

Identification and validation of oncologic miRNA biomarkers for Luminal A-like breast cancer

Introduction: Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Methods: Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n=54) and controls (n=56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n=10 Luminal A-like; n=10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n=44 Luminal A; n=46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated. Results: Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis ( miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652 ). The biomarker potential of 4 miRNAs ( miR-29a, miR-181a , miR-223 and miR-652 ) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p=0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs ( miR-29a, miR-181a and miR-652 ) could reliably differentiate between cancers and controls with an AUC of 0.80. Conclusion: This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype- specific breast tumor detection

The Reliability of Global and Hemispheric Surface Temperature Records

The purpose of this review article is to discuss the development and associated estimation of uncertainties in the global and hemispheric surface temperature records. The review begins by detailing the groups that produce surface temperature datasets. After discussing the reasons for similarities and differences between the various products, the main issues that must be addressed when deriving accurate estimates, particularly for hemispheric and global averages, are then considered. These issues are discussed in the order of their importance for temperature records at these spatial scales: biases in SST data, particularly before the 1940s; the exposure of land-based thermometers before the development of louvred screens in the late 19th century; and urbanization effects in some regions in recent decades. The homogeneity of land-based records is also discussed; however, at these large scales it is relatively unimportant. The article concludes by illustrating hemispheric and global temperature records from the four groups that produce series in near-real time

The Dust in Lyman Break Galaxies

We present our analysis of UV attenuation by internal dust of a large sample (N=906 galaxies) of Lyman Break Galaxies (LBGs). Using spectral energy distributions (SEDs) from the P\'EGASE galaxy spectral evolution model we apply dust attenuation corrections to the G-R colors using the Witt & Gordon (2000) models for radiative transfer in dusty galactic environments to arrive at the UV attenuation factors. We show that the dust in the LBGs exhibit SMC-like characteristics rather than MW-like, and that the dust geometry in these systems is most likely to be represented by a clumpy shell configuration. We show that the attenuation factor exhibits a pronounced dependence on the luminosity of the LBG, a_{1600}\propto (L/L_\sun)^\alpha, where $0.5\leq\alpha\leq1.5$. The exponent $\alpha$ depends on the initial parameters of the stellar population chosen to model the galaxies and the dust properties. We find that the luminosity weighted average attenuation factor is likely to be in the range from $5.7-18.5$, which is consistent with the upper limits to the star formation rate at $2<z<4$ set by the FIR background. This implies that the current UV/optical surveys do detect the bulk of the star formation during the epoch $2<z<4$, but require substantial correction for internal dust attenuation.Comment: 17 pages, 12 figures, uses AASTEX, accepted for publication in the Astrophysical Journa

Dreaming of drams: Authenticity in Scottish whisky tourism as an expression of unresolved Habermasian rationalities

In this paper, the production of whisky tourism at both independently owned and corporately owned distilleries in Scotland is explored by focusing on four examples (Arran, Glengoyne, Glenturret and Bruichladdich). In particular, claims of authenticity and Scottishness of Scottish whiskies through commercial materials, case studies, website-forum discussions and 'independent' writing about such whisky are analysed. It is argued that the globalisation and commodification of whisky and whisky tourism, and the communicative backlash to these trends typified by the search for authenticity, is representative of a Habermasian struggle between two irreconcilable rationalities. This paper will demonstrate that the meaning and purpose of leisure can be understood through such explorations of the tension between the instrumentality of commodification and the freedom of individuals to locate their own leisure lives in the lifeworld that remains. © 2011 Taylor & Francis