Anatomical Reconstruction and Functional Imaging Reveal an Ordered Array of Skylight Polarization Detectors in Drosophila.

UNLABELLED: Many insects exploit skylight polarization as a compass cue for orientation and navigation. In the fruit fly, Drosophila melanogaster, photoreceptors R7 and R8 in the dorsal rim area (DRA) of the compound eye are specialized to detect the electric vector (e-vector) of linearly polarized light. These photoreceptors are arranged in stacked pairs with identical fields of view and spectral sensitivities, but mutually orthogonal microvillar orientations. As in larger flies, we found that the microvillar orientation of the distal photoreceptor R7 changes in a fan-like fashion along the DRA. This anatomical arrangement suggests that the DRA constitutes a detector for skylight polarization, in which different e-vectors maximally excite different positions in the array. To test our hypothesis, we measured responses to polarized light of varying e-vector angles in the terminals of R7/8 cells using genetically encoded calcium indicators. Our data confirm a progression of preferred e-vector angles from anterior to posterior in the DRA, and a strict orthogonality between the e-vector preferences of paired R7/8 cells. We observed decreased activity in photoreceptors in response to flashes of light polarized orthogonally to their preferred e-vector angle, suggesting reciprocal inhibition between photoreceptors in the same medullar column, which may serve to increase polarization contrast. Together, our results indicate that the polarization-vision system relies on a spatial map of preferred e-vector angles at the earliest stage of sensory processing. SIGNIFICANCE STATEMENT: The fly's visual system is an influential model system for studying neural computation, and much is known about its anatomy, physiology, and development. The circuits underlying motion processing have received the most attention, but researchers are increasingly investigating other functions, such as color perception and object recognition. In this work, we investigate the early neural processing of a somewhat exotic sense, called polarization vision. Because skylight is polarized in an orientation that is rigidly determined by the position of the sun, this cue provides compass information. Behavioral experiments have shown that many species use the polarization pattern in the sky to direct locomotion. Here we describe the input stage of the fly's polarization-vision system.

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.

Back seat driving: hindlimb corticospinal neurons assume forelimb control following ischaemic stroke.

Whereas large injuries to the brain lead to considerable irreversible functional impairments, smaller strokes or traumatic lesions are often associated with good recovery. This recovery occurs spontaneously, and there is ample evidence from preclinical studies to suggest that adjacent undamaged areas (also known as peri-infarct regions) of the cortex 'take over' control of the disrupted functions. In rodents, sprouting of axons and dendrites has been observed in this region following stroke, while reduced inhibition from horizontal or callosal connections, or plastic changes in subcortical connections, could also occur. The exact mechanisms underlying functional recovery after small- to medium-sized strokes remain undetermined but are of utmost importance for understanding the human situation and for designing effective treatments and rehabilitation strategies. In the present study, we selectively destroyed large parts of the forelimb motor and premotor cortex of adult rats with an ischaemic injury. A behavioural test requiring highly skilled, cortically controlled forelimb movements showed that some animals recovered well from this lesion whereas others did not. To investigate the reasons behind these differences, we used anterograde and retrograde tracing techniques and intracortical microstimulation. Retrograde tracing from the cervical spinal cord showed a correlation between the number of cervically projecting corticospinal neurons present in the hindlimb sensory-motor cortex and good behavioural recovery. Anterograde tracing from the hindlimb sensory-motor cortex also showed a positive correlation between the degree of functional recovery and the sprouting of neurons from this region into the cervical spinal cord. Finally, intracortical microstimulation confirmed the positive correlation between rewiring of the hindlimb sensory-motor cortex and the degree of forelimb motor recovery. In conclusion, these experiments suggest that following stroke to the forelimb motor cortex, cells in the hindlimb sensory-motor area reorganize and become functionally connected to the cervical spinal cord. These new connections, probably in collaboration with surviving forelimb neurons and more complex indirect connections via the brainstem, play an important role for the recovery of cortically controlled behaviours like skilled forelimb reaching.

Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.

ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer's disease.

OBJECTIVE: We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results. RESULTS: We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes). CONCLUSIONS: We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported. METHODS: We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions.

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease.

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for ß-amyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity.

PURPOSE: Valproate is one of the most commonly used anticonvulsive drugs. Despite its significant benefits, the teratogenicity of valproate is a relevant problem in the treatment of women of childbearing age. In addition to major congenital malformations, such as neural tube defects, reduced intelligence and attention after intrauterine valproate exposure are reported. Until now the mechanisms of teratogenicity of VPA are poorly understood and concepts how to reduce valproate teratogenicity are lacking. METHODS: In a rat model of valproate teratogenicity we examined hippocampal cell structure in 4 week old animals with a stereological approach. As potential mechanisms of VPA teratogenicity we examined histone acetylation by western blotting and metabolites of the folate metabolism as well as global DNA methylation by tandem mass spectrometry in the brain and liver tissue of newborn pups (p0). RESULTS: We found an increase in the number of neurons in the hippocampal areas CA1/2 (p=0.018) and CA3 (p=0.022), as well as a decreased number of astrocytes in CA1/2 (p=0.004) and CA3 (p=0.003) after intrauterine VPA exposure, as a possible indication of altered cell differentiation during intrauterine VPA exposure. Valproate exposure was also associated with an increase in 5-methyl-tetrahydrofolate (THF) (p=0.002) and a decrease in 5-10-methenyl-THF in the brain of newborn pups, as well as a reduced homocysteine plasma level (p<0.001). The described changes in hippocampal cell numbers and folate metabolism were only significant after high-dose intrauterine VPA exposure indicating a dose-dependent effect. VPA exposure was not associated with changes in histone acetylation or global DNA methylation in brain tissue in newborn pups. CONCLUSION: This study shows that intrauterine VPA exposure is associated with changes in hippocampal cell numbers in the CA1/2 and CA3 region and in folate metabolism.

High-Impact, Self-Motivated Training Within an Enriched Environment With Single Animal Tracking Dose-Dependently Promotes Motor Skill Acquisition and Functional Recovery.

Functional recovery following central nervous system injuries is strongly influenced by rehabilitative training. In the clinical setting, the intensity of training and the level of motivation for a particular task are known to play important roles. With increasing neuroscience studies investigating the effects of training and rehabilitation, it is important to understand how the amount and type of training of individuals influences outcome. However, little is known about the influence of spontaneous "self-training" during daily life as it is often uncontrolled, not recorded, and mostly disregarded. Here, we investigated the effects of the intensity of self-training on motor skill acquisition in normal, intact rats and on the recovery of functional motor behavior following spinal cord injury in adult rats. We used a custom-designed small animal tracking system, "RatTrack," to continuously record the activity of multiple rats, simultaneously in a complex Natural Habitat-enriched environment. Naïve, adult rats performed high-intensity, self-motivated motor training, which resulted in them out-performing rats that were conventionally housed and trained on skilled movement tasks, for example, skilled prehension (grasping) and ladder walking. Following spinal cord injury the amount of self-training was correlated with improved functional recovery. These data suggest that high-impact, self-motivated training leads to superior skill acquisition and functional recovery than conventional training paradigms. These findings have important implications for the design of animal studies investigating rehabilitation and for the planning of human rehabilitation programs.

Rehabilitative training following unilateral pyramidotomy in adult rats improves forelimb function in a non-task-specific way.

Spontaneous functional recovery following injury to the adult central nervous system can be enhanced with increased and focused activity, either through altered behaviour (skill learning, exercise or training) or by artificial stimulation (magnetic or electrical). In terms of training, the choice of paradigm plays a key role in the recovered behaviour. Here we show that task-specific training leads to improved forelimb function that can be translated to a novel forelimb task. Adult Long-Evans rats received a unilateral pyramidotomy and we studied the effects of different post-lesion training paradigms for their ability to recover function in the impaired limb. We trained rats on either the single pellet grasping or the horizontal ladder task. Rats were tested on both tasks regardless of the training paradigm and also on a related, but novel forelimb task, the Staircase. Horizontal ladder training led to full recovery of this task, and also limited recovery on the familiar but untrained single pellet grasping task. In comparison, single pellet grasping training led to a smaller improvement on the horizontal ladder, but interestingly the same degree of recovery on the single pellet grasping task as horizontal ladder trained animals. Both training groups performed equally well on a novel, untrained forelimb grasping task. These results show that task-specific forelimb training can lead to functional recovery also in non-trained, complex, forelimb movements. Anatomically, only single pellet grasping training was associated with enhanced sprouting of the intact corticospinal tract across the cervical spinal cord midline to innervate the denervated side of the spinal cord.