Anatomical origins of ocular dominance in mouse primary visual cortex

Ocular dominance (OD) plasticity is a classic paradigm for studying the effect of experience and deprivation on cortical development, and is manifested as shifts in the relative strength of binocular inputs to primary visual cortex (V1). The mouse has become an increasingly popular model for mechanistic studies of OD plasticity and, consequently, it is important that we understand how binocularity is constructed in this species. One puzzling feature of the mouse visual system is the gross disparity between the physiological strength of each eye in V1 and their anatomical representation in the projection from retina to the dorsal lateral geniculate nucleus (dLGN). While the contralateral-to-ipsilateral (C/I) ratio of visually evoked responses in binocular V1 is approximately 2:1, the ipsilateral retinal projection is weakly represented in terms of retinal ganglion cell (RGC) density where the C/I ratio is approximately 9:1. The structural basis for this relative amplification of ipsilateral eye responses between retina and V1 is not known. Here we employed neuroanatomical tracing and morphometric techniques to quantify the relative magnitude of each eye's input to and output from the binocular segment of dLGN. Our data are consistent with the previous suggestion that a point in space viewed by both eyes will activate 9 times as many RGCs in the contralateral retina as in the ipsilateral retina. Nonetheless, the volume of the dLGN binocular segment occupied by contralateral retinogeniculate inputs is only 2.4 times larger than the volume occupied by ipsilateral retinogeniculate inputs and recipient relay cells are evenly distributed among the input layers. The results from our morphometric analyses show that this reduction in input volume can be accounted for by a three-to-one convergence of contralateral eye RGC inputs to dLGN neurons. Together, our findings establish that the relative density of feed-forward dLGN inputs determines the C/I response ratio of mouse binocular V1

Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

<p>Abstract</p> <p>Background</p> <p>We have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. In this study, we sought to determine whether a deficit in the expression of NR2A mRNA was present in the subset of interneurons that contain the calcium buffer parvalbumin (PV) and whether this deficit was associated with a reduction in glutamatergic inputs in the prefrontal cortex (PFC) in schizophrenia.</p> <p>Methods</p> <p>We examined the expression of NR2A mRNA, labeled with a ³⁵S-tagged riboprobe, in neurons that expressed PV mRNA, visualized with a digoxigenin-labeled riboprobe via an immunoperoxidase reaction, in twenty schizophrenia and twenty matched normal control subjects. We also immunohistochemically labeled the glutamatergic axon terminals with an antibody against vGluT1.</p> <p>Results</p> <p>The density of the PV neurons that expressed NR2A mRNA was significantly decreased by 48-50% in layers 3 and 4 in the subjects with schizophrenia, but the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unchanged. In addition, the density of vGluT1-immunoreactive boutons was significantly decreased by 79% in layer 3, but was unchanged in layer 5 of the PFC in schizophrenia.</p> <p>Conclusion</p> <p>These findings suggest that glutamatergic neurotransmission via NR2A-containing NMDA receptors on PV neurons in the PFC may be deficient in schizophrenia. This may disinhibit the postsynaptic excitatory circuits, contributing to neuronal injury, aberrant information flow and PFC functional deficits in schizophrenia.</p

Gene Expression Analysis Implicates a Death Receptor Pathway in Schizophrenia Pathology

An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH

A Tutorial in Connectome Analysis: Topological and Spatial Features of Brain Networks

High-throughput methods for yielding the set of connections in a neural system, the connectome, are now being developed. This tutorial describes ways to analyze the topological and spatial organization of the connectome at the macroscopic level of connectivity between brain regions as well as the microscopic level of connectivity between neurons. We will describe topological features at three different levels: the local scale of individual nodes, the regional scale of sets of nodes, and the global scale of the complete set of nodes in a network. Such features can be used to characterize components of a network and to compare different networks, e.g. the connectome of patients and control subjects for clinical studies. At the global scale, different types of networks can be distinguished and we will describe Erd\"os-R\'enyi random, scale-free, small-world, modular, and hierarchical archetypes of networks. Finally, the connectome also has a spatial organization and we describe methods for analyzing wiring lengths of neural systems. As an introduction for new researchers in the field of connectome analysis, we discuss the benefits and limitations of each analysis approach.Comment: Neuroimage, in pres

Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice

INTRODUCTION: The deposition of the amyloid β protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aβ by Aβ-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages). To test the impact of the B-Aβ stage on Aβ immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aβ-antibody β1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aβ plaque deposition and dendrite degeneration. RESULTS: At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ (representing B-Aβ stage 1) whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified Aβ(N3pE) and phosphorylated Aβ (representing B-Aβ stage 3) were found at 11 months of age in both β1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between β1- and PBS-treated APP23 mice sacrificed with 11 months. CONCLUSIONS: Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3). These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0217-z) contains supplementary material, which is available to authorized users

Cajal and the discovery of a new artistic world: The neuronal forest

The introduction of the staining method of Camillo Golgi in 1873 represented a giant step for neuroscience. Prior to this development, the visualization of neurons with the available histological techniques had been incomplete; it was only feasible to observe the cell body and the proximal portions of the dendrites and axon. However, with the Golgi method it was possible to observe neurons and glia with all their parts (cell body, dendrites, and axon in the case of neurons; cell body and processes in the case of glia). Due to the advantages of this method, all of a sudden it was possible to begin studying one of the great mysteries and critical issues of the organization of the nervous system-the tracing of the connections between neurons. Nevertheless, this method was not fully exploited until Santiago Ramón y Cajal arrived on the scene in 1888. It should be noted that, in Cajal's day, drawing was the most common method of describing microscopic images in the absence of the highly developed microphotography and other imaging techniques commonly available in today's laboratories. As a consequence, most scientific figures presented by the early neuroanatomists were their own drawings, providing an outlet for these scientists to express and develop their artistic talent. In the hands of Cajal, the Golgi method represented not only the principal tool that was to change the course of the history of neuroscience but also the discovery of a new artistic world, the neuronal forest. © 2013 Elsevier B.V.Peer Reviewe