Hippocampal Commissure Research Articles

Molecular regulation of the developing commissural plate

Coordinated transfer of information between the brain hemispheres is essential for function and occurs via three axonal commissures in the telencephalon: the corpus callosum (CC), hippocampal commissure (HC), and anterior commissure (AC). Commissural malformations occur in over 50 human congenital syndromes causing mild to severe cognitive impairment. Disruption of multiple commissures in some syndromes suggests that common mechanisms may underpin their development. Diffusion tensor magnetic resonance imaging revealed that forebrain commissures crossed the midline in a highly specific manner within an oblique plane of tissue, referred to as the commissural plate. This specific anatomical positioning suggests that correct patterning of the commissural plate may influence forebrain commissure formation. No analysis of the molecular specification of the commissural plate has been performed in any species; therefore, we utilized specific transcription factor markers to delineate the commissural plate and identify its various subdomains. We found that the mouse commissural plate consists of four domains and tested the hypothesis that disruption of these domains might affect commissure formation. Disruption of the dorsal domains occurred in strains with commissural defects such as Emx2 and Nfia knockout mice but commissural plate patterning was normal in other acallosal strains such as Satb2(-/-). Finally, we demonstrate an essential role for the morphogen Fgf8 in establishing the commissural plate at later developmental stages. The results demonstrate that correct patterning of the commissural plate is an important mechanism in forebrain commissure formation.

The light of hope: International symposium on Cancer: January 29-31, 2010, Dhaka.

The light of hope: International symposium on Cancer: January 29-31, 2010, Dhaka.

Tractography of the amygdala and hippocampus: anatomical study and application to selective amygdalohippocampectomy

The aim of this study was to evaluate, using diffusion tensor tractography, the white matter fibers crossing the hippocampus and the amygdala, and to perform a volumetric analysis and an anatomical study of the connections of these 2 structures. As a second step, the authors studied the white matter tracts crossing a virtual volume of resection corresponding to a selective amygdalohippocampectomy. Twenty healthy right-handed individuals underwent 3-T MR imaging. Volumetric regions of interest were manually created to delineate the amygdala, the hippocampus, and the volume of resection. White matter fiber tracts were parcellated using the fiber assignment for continuous tracking tractography algorithm. All fibers were registered with the anatomical volumes. In all participants, the authors identified fibers following the hippocampus toward the fornix, the splenium of the corpus callosum, and the dorsal hippocampal commissure. With respect to the fibers crossing the amygdala, the authors identified the stria terminalis and the uncinate fasciculus. The virtual resection disrupted part of the fornix, fibers connecting the 2 hippocampi, and fibers joining the orbitofrontal cortex. The approach created a theoretical frontotemporal disconnection and also interrupted fibers joining the temporal pole and the occipital area. This diffusion tensor tractography study allowed for good visualization of some of the connections of the amygdala and hippocampus. The authors observed that the virtual selective amygdalohippocampectomy disconnected a large number of fibers connecting frontal, temporal, and occipital areas.

The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation

There are three telencephalic commissures which are paleocortical (the anterior commissure), archicortical (the hippocampal commissure), and neocortical. In non-placental mammals, the neocortical commissural fibers cross the midline together with the anterior and possibly the hippocampal commissure, across the lamina reuniens (joining plate) in the upper part of the lamina terminalis. In placental mammals, a phylogenetically new feature emerged, which is the corpus callosum: it results from an interhemispheric fusion line with specialized groups of mildline glial cells channeling the commissural axons through the interhemispheric meninges toward the contralateral hemispheres. This concerns the frontal lobe mainly however: commissural fibers from the temporo-occipital neocortex still use the anterior commissure to cross, and the posterior occipito-parietal fibers use the hippocampal commissure, forming the splenium in the process. The anterior callosum and the splenium fuse secondarily to form the complete commissural plate. Given the complexity of the processes involved, commissural ageneses are many and usually associated with other diverse defects. They may be due to a failure of the white matter to develop or to the commissural neurons to form or to migrate, to a global failure of the midline crossing processes or to a selective failure of commissuration affecting specific commissural sites (anterior or hippocampal commissures, anterior callosum), or specific sets of commissural axons (paleocortical, hippocampal, neocortical commissural axons). Severe hemispheric dysplasia may prevent the axons from reaching the midline on one or both sides. Besides the intrinsically neural defects, midline meningeal factors may prevent the commissuration as well (interhemispheric cysts or lipoma). As a consequence, commissural agenesis is a malformative feature, not a malformation by itself. Good knowledge of the modern embryological data may allow for a good understanding of a specific pattern in a given individual patient, paving the way for better clinical correlation and genetic counseling.

Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental defects in the mouse brain

The microtubule-actin crosslinking factor 1 (MACF1) is a ubiquitous cytoskeletal linker protein with multiple spliced isoforms expressed in different tissues. The MACF1a isoform contains microtubule and actin-binding regions and is expressed at high levels in the nervous system. Macf1−/− mice are early embryonic lethal and hence the role of MACF1 in the nervous system could not be determined. We have specifically knocked out MACF1a in the developing mouse nervous system using Cre/loxP technology. Mutant mice died within 24–36 h after birth of apparent respiratory distress. Their brains displayed a disorganized cerebral cortex with a mixed layer structure, heterotopia in the pyramidal layer of the hippocampus, disorganized thalamocortical and corticofugal fibers, and aplastic anterior and hippocampal commissures. Embryonic neurons showed a defect in traversing the cortical plate. Our data suggest a critical role for MACF1 in neuronal migration that is dependent on its ability to interact with both microfilaments and microtubules.

Activation of the TRPV4 Ion Channel Is Enhanced by Phosphorylation

The TRPV4 (transient receptor potential vanilloid 4) ion channel, a member of the vanilloid subfamily of the transient receptor potential channels, is activated by membrane stretch, by non-noxious warm temperatures, and by a range of chemical activators. In the present study we examined the role of phosphorylation in modulating the activation of TRPV4. We expressed TRPV4 in HEK293 cells and activated the channel by cell swelling in a hypotonic solution. TRPV4 channel activation and serine phosphorylation were enhanced by exposure to the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate or by application of bradykinin, which activates PKC via a G-protein-coupled mechanism. The enhancement was inhibited by the PKC inhibitors staurosporine, bisindolylmaleimide I, and rottlerin or by mutation of the serine/threonine residues Ser(162), Thr(175), and Ser(189). The adenylate cyclase activator forskolin also enhanced activation of TRPV4, and the enhancement was antagonized by the selective cyclic AMP-dependent protein kinase (PKA) inhibitor H89 or by mutation of serine residue Ser(824). Sensitization of TRPV4 by both PKC and PKA depended on the scaffolding protein AKAP79, because channel activation and phosphorylation were enhanced by co-transfection of AKAP79 and were antagonized by removal of AKAP79 using small interfering RNA. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.

Rey Visual Design Learning Test performance correlates with white matter structure.

Studies exploring relation of visual memory to white matter are extensively lacking. The Rey Visual Design Learning Test (RVDLT) is an elementary motion, colour and word independent visual memory test. It avoids a significant contribution from as many additional higher order visual brain functions as possible to visual performance, such as three-dimensional, colour, motion or word-dependent brain operations. Based on previous results, we hypothesised that test performance would be related with white matter of dorsal hippocampal commissure, corpus callosum, posterior cingulate, superior longitudinal fascicle and internal capsule. In 14 healthy subjects, we measured intervoxel coherence (IC) by diffusion tensor imaging as an indication of connectivity and visual memory performance measured by the RVDLT. IC considers the orientation of the adjacent voxels and has a better signal-to-noise ratio than the commonly used fractional anisotropy index. Using voxelwise linear regression analyses of the IC values, we found a significant and direct relationship between 11 clusters and visual memory test performance. The fact that memory performance correlated with white matter structure in left and right dorsal hippocampal commissure, left and right posterior cingulate, right callosal splenium, left and right superior longitudinal fascicle, right medial orbitofrontal region, left anterior cingulate, and left and right anterior limb of internal capsule emphasises our hypothesis. Our observations in healthy subjects suggest that individual differences in brain function related to the performance of a task of higher cognitive demands might partially be associated with structural variation of white matter regions.

Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia

Cuprizone (CPZ) is a neurotoxic agent acting as a copper chelator. In our recent study, C57BL/6 mice given dietary CPZ (0.2%) showed impairments in spatial working memory, social interaction, and prepulse inhibition. These abnormalities are reminiscent of certain schizophrenia symptoms and are not likely due to damage in the whole brain or in any single white matter tract/brain region. We hypothesized that white matter damage resulting from CPZ-treatment may be site-specific rather than universal. We examined the forebrains of C57BL/6 mice given the CPZ-containing diet and compared them with those of controls. We assessed CPZ-induced demyelination in main white matter tracts of the forebrain, evaluated myelin break down in the neuropil of the main olfactory bulb (MOB), cerebral cortex (CTX), caudate putamen (CP), hippocampus (HP), thalamus (TH), and hypothalamus (HY), and counted the number of myelin sheath forming oligodendrocytes (OLs) in CTX, CP, TH, and HY. Obvious demyelination was observed in the corpus callosum, external capsule, CP, and dorsal hippocampal commissure whereas other tracts seemed to be unaffected. The neuropil of CTX, HP and MOB showed myelin break down, which was mild in TH and HY. The number of OLs was decreased in all the above regions of CPZ-treated mice although the degree of OL loss was not consistent across regions. The data provide further support for white matter abnormalities contributing to schizophrenia-like behaviors in mice.

Comparison of key interhemispheric connections and the posterior commissure in normal and hydrocephalic rat fetuses

Background There are a surprising number of interconnecting fibre tracts linking the two cerebral hemispheres, the largest of these being the corpus callosum, but the hippocampal and anterior commissures are also sizable structures. The posterior commissure bridges the upper part of the midbrain and lies adjacent to the posterior end of the third ventricle. Hydrocephalus is known to cause thinning of the corpus callosum but its effect on the other interconnections has not been extensively investigated. On day E18 at the onset of hydrocephalus in the HTx rat development of the corpus callosum is incomplete. The observed thinning of the corpus callosum in fetal onset hydrocephalus is likely to deprive the hemispheres of interconnections. This study was carried out to investigate the effect of hydrocephalus on the other interconnecting fibre tracts and in particular whether adaptive changes occur in any of them.

Partial agenesis of the corpus callosum in spina bifida meningomyelocele and potential compensatory mechanisms

After a review of Arthur Benton's conceptual and methodological contributions to the understanding of normal and pathological development, we discuss agenesis of the corpus callosum (CC), criteria for potential neuroanatomical compensatory mechanisms in CC agenesis, and the results of an examination of magnetic resonance imaging (MRI) data of the CC in 193 children with spina bifida meningomyelocele (SBM). There were 26 CC regional patterns. Although complete agenesis did not occur, partial agenesis was observed in 102 children and within 15 CC regional patterns. Only 4.1% had a normal CC. Quantitative assessment of the area of the CC in 26 NC children and 68 children with SBM revealed that all subgroups with CC anomalies had smaller areas than did a subgroup with a normal CC. Areas were especially small in rostral/splenial agenesis and splenial agenesis but larger with rostral agenesis. Subgroups with normal/hypoplastic regions or complete hypoplasia also had CC areas that were smaller than normal but larger than the areas for the splenial agenesis groups. The relative rarity of anterior commissure enlargement (3.1%) and longitudinal bundles of Probst (0.1%) suggest that these particular fiber tract anomalies are unlikely candidates for structural compensatory mechanisms. The hippocampal commissure, enlarged in 13%, may be a more promising candidate. Overall, however, the functionality of anomalous fiber tracts and commissures in SBM is yet to be determined.

Functional differentiation and cooperation among the hippocampal subregions in rats to effect spatial memory processes

We investigated the roles of the hippocampal subregions and intrahippocampal networks in effecting spatial reference and working processes. The results showed that the dentate gyrus plays a key role in encoding both types of spatial memory. Lesions in the dentate gyrus caused severe impairment in the acquisition of the Morris water maze and delayed matching-to-place tasks as compared to those in the other hippocampal subregions (Exp. 1). Further, there was functional cooperation between CA3 and CA1 via the Schaffer collaterals and the hippocampal commissure in the performance of both types of spatial memory tasks. Among the rats with intact hippocampal commissure, those with both contralateral and ipsilateral CA1/CA3 lesions showed a similar performance (Exp. 2A); however, among the rats with transected hippocampal commissure, those with the contralateral CA1/CA3 lesions showed a more disruptive performance than the rats with the ipsilateral CA1/CA3 lesions (Exp. 2B). This study suggests that the hippocampus is the functional unit for spatial reference and working memory processes, including differential functions and functional cooperation among the hippocampal subregions.

Morphometric abnormalities and hyperanxiety in genetically epileptic rats: A model of psychiatric comorbidity?

BackgroundImaging studies of epilepsy patients with comorbid affective disturbance demonstrate morphometric changes in limbic brain regions implicated in psychiatric disease. Genetic Absence Epilepsy Rats from Strasbourg (GAERS), specifically bred for their epilepsy phenotype, also exhibit elevated anxiety-like behaviors suggesting a common causality. Here we examined whether relevant cerebral morphological alterations exist in this rat strain using volumetric measurements and large deformation high dimensional mapping (HDM-LD), a tool recently validated to produce accurate three-dimensional surface representations of the hippocampus. MethodsVolumetric MRI and the Open Field test of anxiety were performed in adult female GAERS (n=12) and Non-Epileptic Controls (NEC; n=11). The volumes of selected brain regions, including cortex, hippocampus, amygdala, thalamus, hypothalamus and lateral ventricles, were measured using Region-Of-Interest analysis from the MRI data and total volumes compared between the two strains. ResultsGAERS had increased amygdala (right: p=0.003; left p<0.001), cortices (right: p=0.006; left p=0.012) and ventricular volumes (p=0.002) when compared with NEC rats. Further, HDM-LD showed GAERS to have hippocampal volume loss in two regions: the medial hippocampal surface immediately caudal to the hippocampal commissure, and the lateral hippocampal surface over the mid-portion of the septotemporal axis. GAERS exhibited increased anxiety in the Open Field compared with NEC rats: reduced distance traveled (p<0.001) and reduced time in the centre area (p=0.042). ConclusionsMorphometric brain changes in GAERS could be relevant to their hyperanxious and epileptic phenotypes. This model may be useful in illuminating the pathogenesis of affective disorders generally, as well as modeling psychiatric comorbidities of epilepsy.

Depolarization recruits DCC to the plasma membrane of embryonic cortical neurons and enhances axon extension in response to netrin‐1

The netrin-1 receptor Deleted in Colorectal Cancer (DCC) is required for the formation of major axonal projections by embryonic cortical neurons, including the corpus callosum, hippocampal commissure, and cortico-thalamic tracts. The presentation of DCC by axonal growth cones is tightly regulated, but the mechanisms regulating DCC trafficking within neurons are not well understood. Here, we investigated the mechanisms regulating DCC recruitment to the plasma membrane of embryonic cortical neurons. In embryonic spinal commissural neurons, protein kinase A (PKA) activation recruits DCC to the plasma membrane and enhances axon chemoattraction to netrin-1. We demonstrate that PKA activation similarly recruits DCC and increases embryonic cortical neuron axon extension, which, like spinal commissural neurons, respond to netrin-1 as a chemoattractant. We then determined if depolarization might recruit DCC to the plasma membrane. Neither netrin-1 induced axon extension, nor levels of plasma membrane DCC, were altered by depolarizing embryonic spinal commissural neurons with elevated levels of KCl. In contrast, depolarizing embryonic cortical neurons increased the amount of plasma membrane DCC, including at the growth cone, and increased axon outgrowth evoked by netrin-1. Inhibition of PKA, phosphatidylinositol-3-kinase, protein kinase C, or exocytosis blocked the depolarization-induced recruitment of DCC and suppressed axon outgrowth. Inhibiting protein synthesis did not affect DCC recruitment, nor were the distributions of trkB or neural cell adhesion molecule (NCAM) influenced by depolarization, consistent with selective mobilization of DCC. These findings identify a role for membrane depolarization modulating the response of axons to netrin-1 by regulating DCC recruitment to the plasma membrane.

Commissural malformations: Beyond the corpus callosum

Corpus callosum agenesis is frequently only the tip of the iceberg in midline commissural anomalies. Agenesis or hypogenesis of the remaining commissures including the anterior and hippocampal commissures should be excluded. Magnetic resonance imaging is the most sensitive imaging modality to identify commissural anomalies. Diffusion tensor imaging can be helpful to identify hypogenetic or absent commissures even in the preterm neonate.

Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

Intracerebral hemorrhage (ICH) was widely believed to be a monophasic event whereby cell death occurs from the initial space-occupying effects of the hematoma. However, we now know that secondary degenerative events contribute to delayed cell death, functional impairment and clinical deterioration. In three experiments, we further characterized the long-term maturation of injury in the collagenase model of striatal ICH in rat. First, we quantified the volume of tissue lost from 7 to 60 days showing that tissue loss more than doubled over this time. As the volume of tissue lost does not distinguish gray from white matter damage, gold chloride staining was used in a second experiment in ICH rats that survived 7 or 60 days. The mid-sagittal area of the corpus callosum significantly declined (22%) over this period, whereas the hippocampal and anterior commissures were not affected. A third experiment used the Golgi-Cox stain to examine dendritic arborization of peri-hematoma and contralateral medium spiny neurons of the striatum. We found an early and sustained increase in dendritic arborization in the non-lesioned hemisphere, whereas there was initial atrophy of peri-hematoma striatal neurons that eventually recovered to normal. These findings show that tissue loss, including white matter atrophy, continues over extended periods after ICH making it a potential target for cytoprotective agents. Finally, the dendritic alterations in both ipsi- and contralateral striatal neurons likely influence spontaneous recovery and are potential targets to further improve it.

Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. Patients with Wolfram syndrome display considerable clinical pleiomorphism, and symptoms such as neurological complications and psychiatric disorders are common. In the present study we have characterized Wfs1 expression pattern in the mouse central nervous system by using a combination of immunohistochemistry on wild-type mice and X-Gal staining of Wfs1 knockout mice with targeted insertion of the lacZ reporter. We identified a robust enrichment of Wfs1 protein in the central extended amygdala and ventral striatum. Prominent Wfs1 expression was seen in the hippocampal CA1 region, parasubiculum, superficial part of the second and third layers of the prefrontal cortex and proisocortical areas, hypothalamic magnocellular neurosecretory system, and central auditory pathway. Wfs1 expression was also detected in numerous brainstem nuclei and in laminae VIII and IX of the spinal cord. Wfs1-positive nerve fibers were found in the medial forebrain bundle, reticular part of the substantia nigra, globus pallidus, posterior caudate putamen, lateral lemniscus, alveus, fimbria, dorsal hippocampal commissure, subiculum, and to a lesser extent in the central sublenticular extended amygdala, compact part of substantia nigra, and ventral tegmental area. The neuroanatomical findings suggest that the lack of Wfs1 protein function can be related to several neurological and psychiatric symptoms found in Wolfram syndrome. Enrichment of Wfs1 protein in the central extended amygdala suggests a role in the modulation of anxiety and fear.

Impaired fear memory, altered object memory and modified hippocampal synaptic plasticity in split-brain mice

The hippocampus is critical for memory formation. However, the contributions of the hippocampal commissure (HC) and the corpus callosum (CC) are less clear. To elucidate the role of the forebrain commissures in learning and memory, we performed a behavioural and electrophysiological characterization of an inbred mouse strain that displays agenesis of the CC and congenitally reduced HC (BTBR T + tf /J; ‘BTBR’). Compared to a control strain, BTBR mice have severely impaired contextual fear memory, with normal object recognition memory. Interestingly, continuous environmental “enrichment” significantly increased object recognition in BTBR, but not in control C57BL/6 (‘BL/6’) mice. In area CA1 of hippocampal slices, BTBR displayed intact expression of long-term potentiation (LTP), paired-pulse facilitation (PPF) and basal synaptic transmission, compared to BL/6 mice. However, BTBR hippocampal slices show an increased susceptibility to depotentiation (DPT), an activity-induced reversal of LTP. We conclude that the HC and CC are critical for some forms of hippocampal memory and for synaptic resistance to DPT. Agenesis of the CC and HC may unmask some latent ability to encode, store or retrieve certain forms of recognition memory. We suggest that the increased susceptibility to DPT in BTBR may underlie the memory phenotype reported here.

Patterned Neuropathologic Events Occurring in hyh Congenital Hydrocephalic Mutant Mice

Hyh mutant mice develop long-lasting hydrocephalus and represent a good model for investigating neuropathologic events associated with hydrocephalus. The study of their brains by use of lectin binding, bromodeoxyuridine labeling, immunochemistry, and scanning electron microscopy revealed that certain events related to hydrocephalus followed a well-defined pattern. A program of neuroepithelium/ependyma denudation was initiated at embryonic day 12 and terminated at the end of the second postnatal week. After the third postnatal week the denuded areas remained permanently devoid of ependyma. In contrast, a selective group of ependymal areas resisted denudation throughout the lifespan. Ependymal denudation triggered neighboring astrocytes to proliferate. These astrocytes expressed particular glial markers and formed a superficial cell layer replacing the lost ependyma. The loss of the neuroepithelium/ependyma layer at specific regions of the ventricular walls and at specific stages of brain development would explain the fact that only certain brain structures had abnormal development. Therefore, commissural axons forming the corpus callosum and the hippocampal commissure displayed abnormalities, whereas those forming the anterior and posterior commissures did not; and the brain cortex was not homogenously affected, with the cingular and frontal cortices being the most altered regions. All of these telencephalic alterations developed at stages when hydrocephalus was not yet patent at the lateral ventricles, indicating that abnormal neural development and hydrocephalus are linked at the etiologic level, rather than the former being a consequence of the latter. All evidence collected on hydrocephalic hyh mutant mice indicates that a primary alteration in the neuroepithelium/ependyma cell lineage triggers both hydrocephalus and abnormalities in telencephalic development.

Increases of kinin B 1 and B 2 receptors binding sites after brain infusion of amyloid-beta 1–40 peptide in rats

Although numerous inflammation pathways have been implicated in Alzheimer's disease, the involvement of the kallikrein–kinin system is still under investigation. We anatomically localized and quantified the density of kinin B 1 and B 2 receptors binding sites in the rat brain after the infusion of amyloid-β (Aβ) peptide in the right lateral brain ventricle for 5 weeks. The conditioned avoidance test showed a significant reduction of memory consolidation in rats infused with Aβ (68.6 ± 20.9%, P < 0.05) when compared to control group (90.8 ± 4.1%; infused with vehicle). Autoradiographic studies performed in brain samples of both groups using [ 125I]HPP-[des-Arg 10]-Hoe-140 (150 pM, 90 min, 25 °C) showed a significant increase in density of B 1 receptor binding sites in the ventral hippocampal commissure (1.23 ± 0.07 fmol/mg), fimbria (1.31 ± 0.05 fmol/mg), CA1 and CA3 hippocampal areas (1.05 ± 0.03 and 1.24 ± 0.02 fmol/mg, respectively), habenular nuclei (1.30 ± 0.04 fmol/mg), optical tract (1.30 ± 0.05 fmol/mg) and internal capsule (1.26 ± 0.05 fmol/mg) in Aβ group. For B 2 receptors ([ 125I]HPP-Hoe-140, 200 pM, 90 min, 25 °C), a significant increase in density of binding sites was observed in optical tract (2.04 ± 0.08 fmol/mg), basal nucleus of Meynert (1.84 ± 0.18 fmol/mg), lateral septal nucleus – dorsal and intermediary portions (1.66 ± 0.29 fmol/mg), internal capsule (1.74 ± 0.19 fmol/mg) and habenular nuclei (1.68 ± 0.11 fmol/mg). In control group, none of these nuclei showed [ 125I]HPP-Hoe-140 labeling. This significant increase in densities of kinin B 1 and B 2 receptors in animals submitted to Aβ infusion was observed mainly in brain regions related to cognitive behavior, suggesting the involvement of the kallikrein–kinin system in Alzheimer's disease in vivo.

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4–6 h and 24 h post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters – axial diffusivity and relative anisotropy – were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectable on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP stained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.