Uncovering multiple axonal targeting pathways in hippocampal neurons

Neuronal polarity is, at least in part, mediated by the differential sorting of membrane proteins to distinct domains, such as axons and somata/dendrites. We investigated the pathways underlying the subcellular targeting of NgCAM, a cell adhesion molecule residing on the axonal plasma membrane. Following transport of NgCAM kinetically, surprisingly we observed a transient appearance of NgCAM on the somatodendritic plasma membrane. Down-regulation of endocytosis resulted in loss of axonal accumulation of NgCAM, indicating that the axonal localization of NgCAM was dependent on endocytosis. Our data suggest the existence of a dendrite-to-axon transcytotic pathway to achieve axonal accumulation. NgCAM mutants with a point mutation in a crucial cytoplasmic tail motif (YRSL) are unable to access the transcytotic route. Instead, they were found to travel to the axon on a direct route. Therefore, our results suggest that multiple distinct pathways operate in hippocampal neurons to achieve axonal accumulation of membrane proteins

Degree of Collaterals and Not Time Is the Determining Factor of Core Infarct Volume within 6 Hours of Stroke Onset

ABSTRACT BACKGROUND AND PURPOSE: Growth of the core infarct during the first hours of ischemia onset is not well-understood. We hypothesized that factors other than time from onset of ischemia contribute to core infarct volume as measured by MR imaging

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Current imaging studies have concentrated on areas of the brain and spinal cord that contain mixed populations of sensory and motor neurons. In this study, ex vivo magnetic resonance microimaging (MRM) was used to separate motor and sensory components by visualizing individual dorsal and ventral roots in fixed spinal cords. MRM at 15 pm in plane resolution enabled the axons of pure populations of sensory and motor neurons to be measured in the lumbar region of the SOD1 mouse model of ALS. MRM signal intensity increased by 38.3% (p < 0.05) exclusively in the ventral motor nerve roots of the lumbar spinal cord of ALS-affected SOD1 mice compared to wildtype littermates. The hyperintensity was therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were unchanged. Significant decreases in ventral nerve root volume were also detected in the SOD1 mice, which correlated with the axonal degeneration observed by microscopy. These results demonstrate the usefulness of MRM in visualizing the ultrastructure of the mouse spinal cord. The detailed 3D anatomy allowed the processes of pure populations of sensory and motor neurons to be compared. (C) 2011 Elsevier Inc. All rights reserved

Reelin Secreted by GABAergic Neurons Regulates Glutamate Receptor Homeostasis

BACKGROUND: Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons. CONCLUSIONS/SIGNIFICANCE: Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia

Trauma-related emotions and radical acceptance in dialectical behavior therapy for posttraumatic stress disorder after childhood sexual abuse

Background: Posttraumatic Stress Disorder (PTSD) related to childhood sexual abuse (CSA) is often associated with a wide range of trauma-related aversive emotions such as fear, disgust, sadness, shame, guilt, and anger. Intense experience of aversive emotions in particular has been linked to higher psychopathology in trauma survivors. Most established psychosocial treatments aim to reduce avoidance of trauma-related memories and associated emotions. Interventions based on Dialectical Behavior Therapy (DBT) also foster radical acceptance of the traumatic event. Methods: This study compares individual ratings of trauma-related emotions and radical acceptance between the start and the end of DBT for PTSD (DBT-PTSD) related to CSA. We expected a decrease in trauma-related emotions and an increase in acceptance. In addition, we tested whether therapy response according to the Clinician Administered PTSD-Scale (CAPS) for the DSM-IV was associated with changes in trauma-related emotions and acceptance. The data was collected within a randomized controlled trial testing the efficacy of DBT-PTSD, and a subsample of 23 women was included in this secondary data analysis. Results: In a multilevel model, shame, guilt, disgust, distress, and fear decreased significantly from the start to the end of the therapy whereas radical acceptance increased. Therapy response measured with the CAPS was associated with change in trauma-related emotions. Conclusions: Trauma-related emotions and radical acceptance showed significant changes from the start to the end of DBT-PTSD. Future studies with larger sample sizes and control group designs are needed to test whether these changes are due to the treatment. Trial registration: ClinicalTrials.gov, number NCT0048100

A prospective investigation of rumination and executive control in predicting overgeneral autobiographical memory in adolescence

The CaR-FA-X model (Williams et al., 2007), or capture and rumination (CaR), functional avoidance (FA) and impaired executive control (X), is a model of overgeneral autobiographical memory. Two mechanisms of the model, rumination and executive control were examined in isolation and in interaction to investigate overgeneral autobiographical memory over time. Method: Across two time points, six months apart, a total of 149 adolescents (13-16 years) completed a minimal instruction autobiographical memory test, a measure of executive control with emotional and non-emotional stimuli, and measures of brooding rumination and reflective pondering. Results: It was found that executive control for emotional information was negatively associated with OGM, but only when reflective pondering levels were high. Conclusion: In the context of higher levels of reflective pondering, greater switch costs (i.e. lower executive control) when processing emotional information predict a decrease in OGM over time

Multimodal surface-based morphometry reveals diffuse cortical atrophy in traumatic brain injury.

<p>Abstract</p> <p>Background</p> <p>Patients with traumatic brain injury (TBI) often present with significant cognitive deficits without corresponding evidence of cortical damage on neuroradiological examinations. One explanation for this puzzling observation is that the diffuse cortical abnormalities that characterize TBI are difficult to detect with standard imaging procedures. Here we investigated a patient with severe TBI-related cognitive impairments whose scan was interpreted as normal by a board-certified radiologist in order to determine if quantitative neuroimaging could detect cortical abnormalities not evident with standard neuroimaging procedures.</p> <p>Methods</p> <p>Cortical abnormalities were quantified using multimodal surfaced-based morphometry (MSBM) that statistically combined information from high-resolution structural MRI and diffusion tensor imaging (DTI). Normal values of cortical anatomy and cortical and pericortical DTI properties were quantified in a population of 43 healthy control subjects. Corresponding measures from the patient were obtained in two independent imaging sessions. These data were quantified using both the average values for each lobe and the measurements from each point on the cortical surface. The results were statistically analyzed as z-scores from the mean with a p < 0.05 criterion, corrected for multiple comparisons. False positive rates were verified by comparing the data from each control subject with the data from the remaining control population using identical statistical procedures.</p> <p>Results</p> <p>The TBI patient showed significant regional abnormalities in cortical thickness, gray matter diffusivity and pericortical white matter integrity that replicated across imaging sessions. Consistent with the patient's impaired performance on neuropsychological tests of executive function, cortical abnormalities were most pronounced in the frontal lobes.</p> <p>Conclusions</p> <p>MSBM is a promising tool for detecting subtle cortical abnormalities with high sensitivity and selectivity. MSBM may be particularly useful in evaluating cortical structure in TBI and other neurological conditions that produce diffuse abnormalities in both cortical structure and tissue properties.</p

Rejection sensitivity as a vulnerability marker for depressive symptom deterioration in men

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Variables That Best Differentiate In-Patient Acute Stroke from Stroke-Mimics with Acute Neurological Deficits

Introduction. Strokes and stroke-mimics have been extensively studied in the emergency department setting. Although in-hospital strokes are less studied in comparison to strokes in the emergency department, they are a source of significant direct and indirect costs. Differentiating in-hospital strokes from stroke-mimics is important. Thus, our study aimed to identify variables that can differentiate in-hospital strokes from stroke-mimics. Methods. We present here a retrospective analysis of 93 patients over a one-year period (2009 to 2010), who were evaluated for a concern of in-hospital strokes. Results. About two-thirds (57) of these patients were determined to have a stroke, and the remaining (36) were stroke-mimics. Patients with in-hospital strokes were more likely to be obese (p=0.03), have been admitted to the cardiology service (p=0.01), have atrial fibrillation (p=0.03), have a weak hand or hemiparesis (p=0.03), and have a prior history of stroke (p=0.05), whereas, when the consults were called for “altered mental status” but no other deficits (p<0.0001), it is likely a stroke-mimic. Conclusion. This study demonstrates that in-hospital strokes are a common occurrence, and knowing the variables can aid in their timely diagnosis and treatment