- Email: [email protected]
Development of intraparietal sulcus connectivity in late childhood
Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
sound-evoked brain activity; however, there are a number of challenges to neonatal auditory fMRI that first need to be addressed. We demonstrate that all aspects of data acquisition and analysis must be optimized to improve the sensitivity of fMRI for detecting auditory-evoked activations in a group of neonates scanned at approximately term-equivalent age (40 wks). First, we show that the sound presentation equipment affects the quality of fMRI data. Although audiologists use in-ear headphones during infant hearing tests, we have found these to be unreliable for extended MRI sessions (of at least 30 min), and that they evoke weaker fMRI activation than over-the-ear headphones. Next, we compared continuous image acquisition to a “sparse imaging” paradigm – a technique used to prevent the sound of the scanner from masking auditory stimuli. We found that continuous imaging yields more statistical power than sparse imaging. It is also known that neonates have a different hemodynamic response function (HRF) than adults, and here we demonstrate that fMRI analyses significantly benefit from the use of age-specific HRF models. Finally, we show that state-of-the-art “denoising” algorithms (GLMdenoise) can significantly reduce the impact of increased noise associated with neonatal fMRI (e.g., from motion). These results demonstrate that auditory fMRI is feasible in newborn infants, suggest that some results in the literature may be weakened through the use of improper methods, and pave the way for future neuroimaging studies that assess neonatal brain function. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.327 ISDN2014 0409 Development of intraparietal sulcus connectivity in late childhood S.A. Vinette 1,∗ , M. Krongold 1 , C. Lebel 1,2 , S.L. Bray 1,2 1
University of Calgary, Canada Alberta Children’s Hospital Research Institute for Child and Maternal Health, Canada 2
The intraparietal sulcus (IPS) is a functionally heterogeneous brain region important for attention and working memory. The IPS contains a set of regions specifically involved in visual attention and that show a retinotopic organization, labelled IPS0-4. A gradation in structural connectivity along the IPS has been observed, with anterior IPS4 making more probable connections with prefrontal regions, while posterior IPS1 makes more probable connections with occipital regions. The IPS therefore appears central to the visual attention network. Visual attention skills develop across childhood, and developmental increases in IPS connectivity may be necessary for this development. To investigate this hypothesis, cross-sectional data from 84 typically developing (TD) participants 7.7–16.7 years old (average age = 10.8 ± 2.1 years) were entered into seed-based functional connectivity analyses. Data were obtained from the Autism Brain Imaging Data Exchange (ABIDE) database across 4 sites. Wholebrain connectivity analyses were conducted using bilateral seeds in the IPS, in previously reported coordinates for IPS0-4, including age as a covariate. On average, IPS0-4 were functionally connected to the frontoparietal attention network including putative human frontal eye fields (hFEF) and visual regions. An anterior-posterior gradation was observed: anterior IPS exhibited greater connectivity with bilateral hFEF. The posterior IPS demonstrated greater connectivity with ventral visual regions. The right IPS exhibited an age-related increase in connectivity with bilateral lateral occipital regions as
123
well as the right hFEF and supplementary motor area that did not differ between IPS0-4. These results demonstrate an anterior-posterior gradation of functional connectivity in the IPS, similar to previously reported patterns of structural connectivity. The increase in IPS-frontal and IPS-occipital connectivity with age may be important for the development of visual attention. Examining the development of this frontoparietal network in TD children may help to better understand neurodevelopmental disorders marked by impairments in attention. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.328 ISDN2014 0411 CTCF loss results in fate change of Lhx6-positive Interneurons A. Elbert 1,2,∗ , L.A. Watson 1,2 , E. Brûlé 1,2 , N.G. Bérubé 1,2 1 Departments of Biochemistry & Pediatrics, Schulich school of Medicine (Western University), Canada 2 Children’s Health Research Institute, Victoria Hospital, Canada
CCCTC binding factor (CTCF) is a chromatin-organizing protein that influences gene expression. Recently, CTCF mutations were identified in patients with mental retardation, demonstrating the important role for CTCF in neural development. Therefore, we generated conditional whole-brain Ctcf knockout mice using the Nestin-Cre driver line to study CTCF in the developing brain. Transcriptional profiling of E14 control and Ctcf-null forebrain reveals decreased expression of the cortical interneuron marker Lhx6. In situ hybridization (ISH) confirms the reduction of Lhx6 as early as E13.5. Immuno-fluorescence (IF) detection of cleaved caspase-3 indicates that this reduction in Lhx6 is not a result of cell death. In addition, BrdU birth-dating experiments in E12.5 Ctcf-null embryos show no significant change in cell proliferation, suggesting that the reduction in Lhx6 is due to effects on its transcription. We demonstrate that the expression of interneuron migration genes Cxcr4, Cxcr7, Nrp1 and Erbb4 is significantly reduced. This implies that the decrease in Lhx6 is sufficient to affect the expression of downstream genes. To determine whether migration is affected, we performed ISH to visualize the location of Dlx1-positive cells, a marker of GABAergic interneurons. At E16.5, the number of Dlx1-positive interneurons is reduced in the Ctcf-null brain compared to wildtype. In vitro transwell assays support that the Ctcf-null interneurons have impaired migration compared to control. Interestingly, ISH at E15.5 shows a concomitant increase in Lhx8, which is a marker of cholinergic interneurons. Since Lhx8and Lhx6-positive neurons are derived from a common progenitor pool, these results may indicate that loss of CTCF results in a fate-switch from GABAergic to cholinergic interneurons. Our work implicates CTCF as an important regulator of interneuron development. Understanding the function of CTCF in interneuron differentiation will contribute to the success of cell based therapies that require the in vitro generation of interneurons from embryonic stem cells. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.329
sound-evoked brain activity; however, there are a number of challenges to neonatal auditory fMRI that first need to be addressed. We demonstrate that all aspects of data acquisition and analysis must be optimized to improve the sensitivity of fMRI for detecting auditory-evoked activations in a group of neonates scanned at approximately term-equivalent age (40 wks). First, we show that the sound presentation equipment affects the quality of fMRI data. Although audiologists use in-ear headphones during infant hearing tests, we have found these to be unreliable for extended MRI sessions (of at least 30 min), and that they evoke weaker fMRI activation than over-the-ear headphones. Next, we compared continuous image acquisition to a “sparse imaging” paradigm – a technique used to prevent the sound of the scanner from masking auditory stimuli. We found that continuous imaging yields more statistical power than sparse imaging. It is also known that neonates have a different hemodynamic response function (HRF) than adults, and here we demonstrate that fMRI analyses significantly benefit from the use of age-specific HRF models. Finally, we show that state-of-the-art “denoising” algorithms (GLMdenoise) can significantly reduce the impact of increased noise associated with neonatal fMRI (e.g., from motion). These results demonstrate that auditory fMRI is feasible in newborn infants, suggest that some results in the literature may be weakened through the use of improper methods, and pave the way for future neuroimaging studies that assess neonatal brain function. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.327 ISDN2014 0409 Development of intraparietal sulcus connectivity in late childhood S.A. Vinette 1,∗ , M. Krongold 1 , C. Lebel 1,2 , S.L. Bray 1,2 1
University of Calgary, Canada Alberta Children’s Hospital Research Institute for Child and Maternal Health, Canada 2
The intraparietal sulcus (IPS) is a functionally heterogeneous brain region important for attention and working memory. The IPS contains a set of regions specifically involved in visual attention and that show a retinotopic organization, labelled IPS0-4. A gradation in structural connectivity along the IPS has been observed, with anterior IPS4 making more probable connections with prefrontal regions, while posterior IPS1 makes more probable connections with occipital regions. The IPS therefore appears central to the visual attention network. Visual attention skills develop across childhood, and developmental increases in IPS connectivity may be necessary for this development. To investigate this hypothesis, cross-sectional data from 84 typically developing (TD) participants 7.7–16.7 years old (average age = 10.8 ± 2.1 years) were entered into seed-based functional connectivity analyses. Data were obtained from the Autism Brain Imaging Data Exchange (ABIDE) database across 4 sites. Wholebrain connectivity analyses were conducted using bilateral seeds in the IPS, in previously reported coordinates for IPS0-4, including age as a covariate. On average, IPS0-4 were functionally connected to the frontoparietal attention network including putative human frontal eye fields (hFEF) and visual regions. An anterior-posterior gradation was observed: anterior IPS exhibited greater connectivity with bilateral hFEF. The posterior IPS demonstrated greater connectivity with ventral visual regions. The right IPS exhibited an age-related increase in connectivity with bilateral lateral occipital regions as
123
well as the right hFEF and supplementary motor area that did not differ between IPS0-4. These results demonstrate an anterior-posterior gradation of functional connectivity in the IPS, similar to previously reported patterns of structural connectivity. The increase in IPS-frontal and IPS-occipital connectivity with age may be important for the development of visual attention. Examining the development of this frontoparietal network in TD children may help to better understand neurodevelopmental disorders marked by impairments in attention. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.328 ISDN2014 0411 CTCF loss results in fate change of Lhx6-positive Interneurons A. Elbert 1,2,∗ , L.A. Watson 1,2 , E. Brûlé 1,2 , N.G. Bérubé 1,2 1 Departments of Biochemistry & Pediatrics, Schulich school of Medicine (Western University), Canada 2 Children’s Health Research Institute, Victoria Hospital, Canada
CCCTC binding factor (CTCF) is a chromatin-organizing protein that influences gene expression. Recently, CTCF mutations were identified in patients with mental retardation, demonstrating the important role for CTCF in neural development. Therefore, we generated conditional whole-brain Ctcf knockout mice using the Nestin-Cre driver line to study CTCF in the developing brain. Transcriptional profiling of E14 control and Ctcf-null forebrain reveals decreased expression of the cortical interneuron marker Lhx6. In situ hybridization (ISH) confirms the reduction of Lhx6 as early as E13.5. Immuno-fluorescence (IF) detection of cleaved caspase-3 indicates that this reduction in Lhx6 is not a result of cell death. In addition, BrdU birth-dating experiments in E12.5 Ctcf-null embryos show no significant change in cell proliferation, suggesting that the reduction in Lhx6 is due to effects on its transcription. We demonstrate that the expression of interneuron migration genes Cxcr4, Cxcr7, Nrp1 and Erbb4 is significantly reduced. This implies that the decrease in Lhx6 is sufficient to affect the expression of downstream genes. To determine whether migration is affected, we performed ISH to visualize the location of Dlx1-positive cells, a marker of GABAergic interneurons. At E16.5, the number of Dlx1-positive interneurons is reduced in the Ctcf-null brain compared to wildtype. In vitro transwell assays support that the Ctcf-null interneurons have impaired migration compared to control. Interestingly, ISH at E15.5 shows a concomitant increase in Lhx8, which is a marker of cholinergic interneurons. Since Lhx8and Lhx6-positive neurons are derived from a common progenitor pool, these results may indicate that loss of CTCF results in a fate-switch from GABAergic to cholinergic interneurons. Our work implicates CTCF as an important regulator of interneuron development. Understanding the function of CTCF in interneuron differentiation will contribute to the success of cell based therapies that require the in vitro generation of interneurons from embryonic stem cells. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.329