Brain activation under right ventricular stimulation.

<p>Coordinates are relative to bregma in the right-left (x), superior-inferior (y), and anterior-posterior (z) directions (mm). Voxels in each cluster are expressed as the number of voxels exceeding the threshold of P<0.05 corrected for multiple comparisons using the false discovery rate in the second-level analysis (Group) and P<0.005 uncorrected for multiple comparisons in the first-level analyses of rats 13–24. Blanks indicate that no voxels exceeded the significance threshold in the right somatosensory cortex.</p

Brain activation under left ventricular stimulation.

<p>Stimulation of the left ventricle induced significant fMRI signal increases in the anterior cingulate cortex (<b>A, B</b>) and in the right somatosensory cortex (<b>C, D</b>), as measured in the second-level analysis (n = 12). Consistent with this group-level result, first-level analyses in three representative rats (rats 4, 6, and 11 quoted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056990#pone-0056990-t001" target="_blank"><b>table 1</b></a>) demonstrated reproducible activations in the anterior cingulate cortex (<b>E, F, I, J, M, N</b>) and in the right somatosensory cortex (<b>G, H, K, L, O, P</b>). The results are displayed on the male Wistar rat template. The color calibration bars in each image represent critical t-score magnitudes for a threshold level of P<0.05 corrected for multiple comparisons using the false discovery rate (<b>A–D</b>) and P<0.005 uncorrected for multiple comparisons (<b>E–P</b>).</p

Brain activation under left ventricular stimulation.

<p>Coordinates are relative to bregma in the right-left (x), superior-inferior (y), and anterior-posterior (z) directions (mm). Voxels in each cluster are expressed as the number of voxels exceeding the threshold of P<0.05 corrected for multiple comparisons using the false discovery rate in the second-level analysis (Group) and P<0.005 uncorrected for multiple comparisons in the first-level analyses of rats 1–12. Blanks indicate that no voxels exceeded the significance threshold in the anterior cingulate cortex or in the right somatosensory cortex.</p

Brain activation under right ventricular stimulation.

<p>Stimulation of the right ventricle induced significant fMRI signal increases in the right somatosensory cortex (<b>A, B</b>), as measured in the second-level analysis (n = 12). Consistent with this group-level result, first-level analyses in three representative rats (rats 17, 20, and 23 quoted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056990#pone-0056990-t002" target="_blank"><b>table 2</b></a>) demonstrated reproducible activations in the right somatosensory cortex (<b>C–H</b>). The results are displayed on the male Wistar rat template. The color calibration bars in each image represent critical t-score magnitudes for a threshold level of P<0.05 corrected for multiple comparisons using the false discovery rate (<b>A, B</b>) and P<0.005 uncorrected for multiple comparisons (<b>C–H</b>).</p

Temporal profiles of fMRI signals under left (LV) and right ventricular (RV) stimulation.

<p>Temporal profiles showing the averaged fMRI signal intensity changes of the anterior cingulate cortex (<b>A</b>, n = 10) and the right somatosensory cortex (<b>B</b>, n = 11) in response to LV stimulation (red lines) and the right somatosensory cortex (<b>C</b>, n = 11) in response to RV stimulation (blue line). The black bars represent the duration of the 2-mA stimulation.</p

Representative echocardiograms of the electrical stimulation catheter inside the left (LV) or right ventricle (RV).

<p>Yellow arrowheads indicate the tip of the catheter from which electrical pulses were administered. The tip of the catheter was positioned at the interventricular septum in LV and the free wall in RV.</p

Volumes of brain regions in the ROI analysis.

<p>Volumes of brain regions in the ROI analysis.</p

Volumes of the neocortical regions in the ROI analysis.

<p>Volumes of the neocortical regions in the ROI analysis.</p

Regional volume decreases in the brain of male <i>rSey</i>^<i>2</i>/+ rats compared to male WT rats.

<p>Colored voxels represent clusters of significant regional volume decreases in the brain of male <i>rSey</i>^<i>2</i>/+ rats (n = 16) compared to male WT rats (n = 16) in the post hoc analysis after ANOVA (FWE, <i>p</i> < 0.05, threshold of 500 voxels), superimposed on the T2-weighted MRI template. rSey²/+, Pax6 heterozygous mutant; WT, wild-type; ANOVA; analysis of variance; FWE, family-wise error.</p

Regional Volume Decreases in the Brain of <i>Pax6</i> Heterozygous Mutant Rats: MRI Deformation-Based Morphometry - Fig 5

<p><b>(A) Expression pattern of <i>Pax6</i> in rat embryo at E10.5.</b> The figure was modified from Kikkawa et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref050" target="_blank">50</a>]. dte, dorsal telencephalon; di, diencephalon; me, mesencephalon; rh, rhombencephalon; vte, ventral telencephalon. <b>(B) Pax6 expression in an E14.5 mouse cortex.</b> Pax6 protein (red) is restricted to the ventricular zone (VZ), where neural progenitor cells reside; in contrast, <i>Pax6</i> is not expressed in the Tuj1-positive (blue) cortical plate (CP). The figure was modified from Osumi and Kikkawa [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref051" target="_blank">51</a>]. <b>(C) Expression pattern of <i>Pax6</i> in the adult mouse based on previously published data (Duan et al., 2013</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref041" target="_blank">41</a>]; <b>Haba et al., 2009</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref052" target="_blank">52</a>]; <b>Kohwi et al., 2005</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref053" target="_blank">53</a>]; <b>Maekawa et al., 2005</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref054" target="_blank">54</a>]). The regions with <i>Pax6</i> expression in the studies of Duan et al. and Haba et al. are shown in green, and the regions in which <i>Pax6</i> was expressed in neural stem cells/progenitor cells in the other studies are shown in red. Nomenclature and illustration of various brain regions are based on <i>The Mouse Brain in Stereotaxic Coordinates</i> (2^nd Edition) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158153#pone.0158153.ref055" target="_blank">55</a>]. AA, anterior amygdaloid area; AO, anterior olfactory nucleus; APT, anterior pretectal nucleus; BM/BL, basomedial/basolateral amygdaloid nucleus; Ce, central amygdaloid nucleus; CG, central gray; DG, hippocampal dentate gyrus; DR, dorsal raphe nucleus; EP, entopeduncular nucleus; EPl, external plexiform layer of the olfactory bulb; F, nucleus of the fields of Forel; GCL, granular cell layer of the cerebellum; Gl, glomerular layer of the olfactory bulb; Gr, granule cell layer of the olfactory bulb; Hb, habenular nucleus; I, intercalated nuclei of the amygdala; InC, interstitial nucleus of Cajal; LH, lateral hypothalamic area; LL, nucleus of the lateral lemniscus; LPO, lateral preoptic area; LSI, lateral septal nucleus, intermediate part; MCPC, magnocellular nucleus of the posterior commissure; Me, Medial amygdaloid nucleus; mRt, mesencephalic reticular formation; MS, medial septal nucleus; PAG, periaqueductal gray; PCom, nucleus of the posterior commissure; PDTg/LDTg, posterodorsal/laterodorsal tegmental nucleus; Pir, Piriform cortex; PL, paralemniscal nucleus; Pn, pontine nuclei; PrC, precommissural nucleus; Rt, reticular thalamic nucleus; RtTg, reticulotegmental nucleus of the pons; SubG, subgeniculate nucleus; SuVe/MVe, superior/medial vestibular nucleus; SPFPC, subparafascicular thalamic nucleus, parvicellular part; SVZ, subventricular zone; Tu, olfactory tubercle; VC/DC, ventral/dorsal cochlear nucleus; VDB/HDB, nucleus of the vertical/horizontal limb of the diagonal band; VP, ventral pallidum; VTT/DTT, ventral/dorsal tenia tecta; X, nucleus X; ZI, zona incerta.</p