A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro

Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing β-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases

Transitioning between preparatory and precisely sequenced neuronal activity in production of a skilled behavior

Precise neural sequences are associated with the production of well-learned skilled behaviors. Yet, how neural sequences arise in the brain remains unclear. In songbirds, premotor projection neurons in the cortical song nucleus HVC are necessary for producing learned song and exhibit precise sequential activity during singing. Using cell-type specific calcium imaging we identify populations of HVC premotor neurons associated with the beginning and ending of singing-related neural sequences. We characterize neurons that bookend singing-related sequences and neuronal populations that transition from sparse preparatory activity prior to song to precise neural sequences during singing. Recordings from downstream premotor neurons or the respiratory system suggest that pre-song activity may be involved in motor preparation to sing. These findings reveal population mechanisms associated with moving from non-vocal to vocal behavioral states and suggest that precise neural sequences begin and end as part of orchestrated activity across functionally diverse populations of cortical premotor neurons

Automatic and reproducible positioning of phase-contrast MRI for the quantification of global cerebral blood flow.

Phase-Contrast MRI (PC-MRI) is a noninvasive technique to measure blood flow. In particular, global but highly quantitative cerebral blood flow (CBF) measurement using PC-MRI complements several other CBF mapping methods such as arterial spin labeling and dynamic susceptibility contrast MRI by providing a calibration factor. The ability to estimate blood supply in physiological units also lays a foundation for assessment of brain metabolic rate. However, a major obstacle before wider applications of this method is that the slice positioning of the scan, ideally placed perpendicular to the feeding arteries, requires considerable expertise and can present a burden to the operator. In the present work, we proposed that the majority of PC-MRI scans can be positioned using an automatic algorithm, leaving only a small fraction of arteries requiring manual positioning. We implemented and evaluated an algorithm for this purpose based on feature extraction of a survey angiogram, which is of minimal operator dependence. In a comparative test-retest study with 7 subjects, the blood flow measurement using this algorithm showed an inter-session coefficient of variation (CoV) of 4.07 ± 3.03%. The Bland-Altman method showed that the automatic method differs from the manual method by between -8% and 11%, for 95% of the CBF measurements. This is comparable to the variance in CBF measurement using manually-positioned PC MRI alone. In a further application of this algorithm to 157 consecutive subjects from typical clinical cohorts, the algorithm provided successful positioning in 89.7% of the arteries. In 79.6% of the subjects, all four arteries could be planned using the algorithm. Chi-square tests of independence showed that the success rate was not dependent on the age or gender, but the patients showed a trend of lower success rate (p = 0.14) compared to healthy controls. In conclusion, this automatic positioning algorithm could improve the application of PC-MRI in CBF quantification

Determination of the scan positioning of the left VA.

<p>Top left panel shows the left VA derivative template, bottom left panel shows the left VA derivative of a subject. Red stars show the turning points and red triangles show the position of the scan plane. Right panel shows the positioning in 3D. The blue curve shows the left VA. The green points show the turning points. The red point and the yellow and green lines show the scan plane.</p

Detection of left and right VAs, left and right ICAs using the middle slice of the thresholded image volume.

<p>The cross sections from the same object are represented by the same color.</p

Subject information in groups and the p values of the Chi-square tests of independence.

<p>Subject information in groups and the p values of the Chi-square tests of independence.</p

Effects of the template on turning points detection.

<p>Top panels show two left VA derivative templates and red stars show the turning points of the templates. Middle panels show the matching between the left VA derivative of a subject and the two templates. Red vertical lines show the rough regions of turning points which are determined by padding around the turning points of the templates. Bottom panels show the regions determined by matching with the templates. Red stars show the turning points detected and red triangles show the position of the scan plane.</p

An ideal case of scan planning.

<p>The ICA scans were placed at the level of foramen magnum, perpendicular to the trajectory of the vessels. The VA scans were placed in the middle of the two turns at the level of cervical vertebra and , perpendicular to the trajectory of the vessels.</p

Illustration of the automatic PC-MRI scan positioning shown on 2D MIP images of the 3D axial TOF angiogram for 4 subjects.

<p>The trace of the VAs are shown in red lines and optimal PC-MRI scanning positions of the four major brain feeding arteries are shown in yellow lines, with artery centers shown as red stars.</p

Comparison between the whole brain blood flow measurements using the automatic positioning algorithm and using manual positioning.

<p>(a) Bland-Altman plot comparing the whole brain cerebral blood flow measurements obtained by the two positioning methods after transformation (, with 2 replicates for each subject). (b) Bland-Altman plot comparing two whole brain cerebral blood flow measurements obtained by the manual positioning method after transformation (). For all the Bland-Altman plots, the solid line indicates the mean difference between two measurements. The dashed lines indicate the 95% confidence interval.</p