Adrienne Dorr

High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice

Detailed anatomical atlases can provide considerable interpretive power in studies of both human and rodent neuroanatomy. Here we describe a three-dimensional atlas of the mouse brain, manually segmented into 62 structures, based on an average of 32 mum isotropic resolution T(2)-weighted, within skull images of forty 12 week old C57Bl/6J mice, scanned on a 7 T scanner. Individual scans were normalized, registered, and averaged into one volume. Structures within the cerebrum, cerebellum, and brainstem were painted on each slice of the average MR image while using simultaneous viewing of the coronal, sagittal and horizontal orientations. The final product, which will be freely available to the research community, provides the most detailed MR-based, three-dimensional neuroanatomical atlas of the whole brain yet created. The atlas is furthermore accompanied by ancillary detailed descriptions of boundaries for each structure and provides high quality neuroanatomical details pertinent to MR studies using mouse models in research.

Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study.

Studies of mouse cerebral vasculature to date have focused on the circle of Willis without examining the morphological distribution of blood vessels through the rest of the brain. Since mouse models are frequently used in brain-related studies, there is a need for a comprehensive cerebral vasculature atlas for the mouse with an emphasis on the location of vessels with respect to neuroanatomical structures, the watershed regions associated with specific arteries, as well as a consistent nomenclature of the cerebral vessels. This article describes such an atlas, based on a combination of magnetic resonance and computed tomography technology to yield high-resolution volumetric and vasculature data on CBA mouse. This three-dimensional vasculature dataset provides an anatomical resource for future mouse studies.

Cortical thickness measured from MRI in the YAC128 mouse model of Huntington's disease

A recent study found differences in localised regions of the cortex between the YAC128 mouse model of Huntingtons Disease (HD) and wild-type mice. There are, however, few tools to automatically examine shape differences in the cortices of mice. This paper describes an algorithm for automatically measuring cortical thickness across the entire cortex from MRI of fixed mouse brain specimens. An analysis of the variance of the method showed that, on average, a 50 microm (0.05 mm) localised difference in cortical thickness can be measured using MR scans. Applying these methods to 8-month-old YAC128 mouse model mice representing an early stage of HD, we found an increase in cortical thickness in the sensorimotor cortex, and also revealed regions wherein decreasing striatal volume correlated with increasing cortical thickness, indicating a potential compensatory response.

Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease

Alzheimer’s disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

Quantification of blood flow and volume in arterioles and venules of the rat cerebral cortex using functional micro-ultrasound

Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and blood flow speed are key parameters that characterize cerebral hemodynamics. We used contrast-enhanced functional micro-ultrasound (fMUS) imaging employing a disruption-replenishment imaging sequence to quantify these hemodynamic parameters in the anesthetized rat brain. The method has a spatial resolution of about 100 μm in-plane and around 600 μm through-plane, which is comparable to fMRI, and it has a superior temporal resolution of 40 ms per frame. We found no significant difference in rCBV of cortical and subcortical gray matter (0.89 ± 0.08 and 0.61 ± 0.09 times the brain-average value, respectively). The rCBV was significantly higher in the vascular regions on the pial surface (3.89 ± 0.71) and in the area of major vessels in the subcortical gray matter (2.02 ± 0.31). Parametric images of rCBV, rCBF, and blood flow speed demonstrate spatial heterogeneity of these parameters on the 100 μm scale. Segmentation of the cortex in arteriolar and venular-dominated regions identified through color Doppler imaging showed that rCBV is higher and flow speed is lower in venules than in arterioles. Finally, we show that the dependence of rCBV on rCBF was significantly different in cortical versus subcortical gray matter: the exponent α in the power law relation rCBV=s·rCBF(α) was 0.37 ± 0.13 in cortical and 0.75 ± 0.16 in subcortical gray matter. This work demonstrates that functional micro-ultrasound imaging affords quantification of hemodynamic parameters in the anesthetized rodent brain. This modality is a promising tool for neuroscientists studying these parameters in rodent models of diseases with a cerebrovascular component, such as stroke, neurodegeneration, and venous collagenosis. It is of particular import for studying conditions that selectively affect arteriolar versus venular compartments.

In Vivo Imaging of Cerebral Hemodynamics Using High-Frequency Micro-Ultrasound

Assessment of cerebral vascular response is important in neuroscience research. Some imaging modalities that are commonly used to detect flow and/or vessel diameter changes in the brain include magnetic resonance imaging, positron emission tomography, and optical intrinsic signal imaging. Ultrasound has not typically been used to assess neurovascular response but recent advances in the technology have led to the development of micro-ultrasound systems with significant potential for this application. The state of the art in high frequency (15-50 MHz) micro-ultrasound is based on linear arrays specifically designed for small animal imaging. These systems can achieve axial resolution ranging from 30 to 200 microm. They are capable of quantifying brain hemodynamics in terms of red blood cell (RBC) velocity, flow, and vascular density in real time, up to 35 mm below the cortical surface, and can achieve temporal resolution of up to 1000 frames per second. This protocol describes imaging of the rat brain using various ultrasound imaging modes (power Doppler, color Doppler, pulsed-wave Doppler, and nonlinear contrast-enhanced imaging) to assess the state of cerebral microcirculation.

Neurogliovascular dysfunction in a model of repeated traumatic brain injury

Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period. Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence. Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival. Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.

Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke

Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.

Functional imaging of the rat brain with micro-ultrasound

Linear array based micro-ultrasound provides 40–150um resolution over a significant depth of field at frames rates as high as 1000fps. Current imaging modalities for investigating in vivo brain function are challenged to provide this combination of imaging parameters. The present experiment was carried out to investigate the potential of micro-ultrasound in neuroimaging of rodents in vivo.

IC-101-02: Role of magnetization transfer imaging in early diagnosis of Alzheimer’s disease

mation based morphometry [1] and investigated the relationship between brain structure at baseline and future cognitive decline. Baseline deformation maps were dependent variables in regression analyses, and independent variables included annualized cognitive change, cognitive score at baseline, head size, age, and group. Separate regressions were computed for change in MMSE, CDR, and for the following California Verbal Learning Test subtests: short and long delay cued recall (SDCR and LDCR), and immediate and short delay free recall (IDFR and SDFR). Results: The figure (right brain is image left) shows T-statistic maps overlaid on the group average spatially normalized MRI. A negative association between structure and cognitive change on SDCR is shown in (a), where reduced tissue volumes in the left ERC at baseline are associated with greater performance decline. Smaller tissue volumes in the hippocampus at baseline were also related to greater declines in SDCR, as shown in (b). Associations between structure and LCDR were similar. Panel (c) shows reduced tissue volume in the posterior cingulate cortex at baseline is associated with greater decline in SDFR; adjacent white matter and left ERC were also implicated. These regions were less significantly associated with decline on IDFR. Smaller volumes of frontal and parietal white matter at baseline were associated with MMSE decline. Future declines in CDR were related to smaller baseline volumes of frontal and parietal lobes, particularly in the precuneus region (d). Conclusions: Deformation morphometry reveals focal brain atrophy on MRI that predicts future cognitive decline, and may allow earlier and more precise separation of normal aging from early Alzheimer’s disease. [1] C. Studholme et al, NeuroImage, Vol 21 (2004), pp 1387-1398.