Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.color vision ͉ cone mosaic ͉ photopigment ͉ retinal imaging ͉ rhodopsin N ormal human color vision is trichromatic and derives from the presence of three spectrally distinct cone types: long-, middle-, and short-wavelength-sensitive (L, M, and S). Redgreen color vision defects are characterized by the absence of either L or M cone function and they affect about one in 12 Caucasian males. Inherited red-green defects can be linked to disruptions at the X-chromosome opsin gene locus, where the Land M-cone opsin genes reside in a head-to-tail array (1). Most of these disruptions involve gross gene rearrangements (2-6). However, it is becoming appreciated that missense mutations underlie a significant proportion of red-green defects (5-8). This raises the question of what impact these missense mutations have on the viability of the cones.Some insight comes from rhodopsin. There are Ͼ130 distinct rhodopsin mutations, involving at least 89 sites within the molecule (data compiled from refs. 9-17.) With rare exception (e.g., refs. 9 and 18), each of these mutations has been associated with either retinitis pigmentosa (RP) or congenital stationary night blindness. Rhodopsin and the cone opsins have structural similarities and similar functional demands. Thus, it is reasonable to hypothesize that mutations in the cone opsins homologous to those in rhodopsin that cause retinitis pigmentosa would affect the viability of the cones.The most common missense mutation in the cone opsins is a substitution of cytosine for thymine at nucleotide position 1101, which corresponds to a substitution of arginine for cysteine at amino acid position 203 (C203R) (Fig. S1). The corresponding mutation in rhodopsin (C187Y) disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentos...

Tractography is a powerful technique capable of non-invasively reconstructing the structural connections in the brain using diffusion MRI images, but the validation of tractograms is challenging due to lack of ground truth. Owing to recent developments in mapping the mouse brain connectome, high-resolution tracer injection-based axonal projection maps have been created and quickly adopted for the validation of tractography. Previous studies using tracer injections mainly focused on investigating the match in projections and optimal tractography protocols. Being a complicated technique, however, tractography relies on multiple stages of operations and parameters. These factors introduce large variabilities in tractograms, hindering the optimization of protocols and making the interpretation of results difficult. Based on this observation, in contrast to previous studies, in this work we focused on quantifying and ranking the amount of performance variation introduced by these factors. For this purpose, we performed over a million tractography experiments and studied the variability across different subjects, injections, anatomical constraints and tractography parameters. By using N-way ANOVA analysis, we show that all tractography parameters are significant and importantly performance variations with respect to the differences in subjects are comparable to the variations due to tractography parameters, which strongly underlines the importance of fully documenting the tractography protocols in scientific experiments. We also quantitatively show that inclusion of anatomical constraints is the most significant factor for improving tractography performance. Although this critical factor helps reduce false positives, our analysis indicates that anatomy-informed tractography still fails to capture a large portion of axonal projections.

We report novel 5-HT1BR-induced behaviors and striatal activation that were alleviated only by clinically effective pharmacological OCD treatment. Studying the mechanisms underlying these effects could provide insight into OCD pathophysiology.

The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD.