Behavioral Phenotyping of Bbs6 and Bbs8 Knockout Mice Reveals Major Alterations in Communication and Anxiety.

The primary cilium is an organelle with a central role in cellular signal perception. Mutations in genes that encode cilia-associated proteins result in a collection of human syndromes collectively termed ciliopathies. Of these, the Bardet-Biedl syndrome (BBS) is considered one of the archetypical ciliopathies, as patients exhibit virtually all respective clinical phenotypes, such as pathological changes of the retina or the kidney. However, the behavioral phenotype associated with ciliary dysfunction has received little attention thus far. Here, we extensively characterized the behavior of two rodent models of BBS, Bbs6/Mkks, and Bbs8/Ttc8 knockout mice concerning social behavior, anxiety, and cognitive abilities. While learning tasks remained unaffected due to the genotype, we observed diminished social behavior and altered communication. Additionally, Bbs knockout mice displayed reduced anxiety. This was not due to altered adrenal gland function or corticosterone serum levels. However, hypothalamic expression of Lsamp, the limbic system associated protein, and Adam10, a protease acting on Lsamp, were reduced. This was accompanied by changes in characteristics of adult hypothalamic neurosphere cultures. In conclusion, we provide evidence that behavioral changes in Bbs knockout mice are mainly found in social and anxiety traits and might be based on an altered architecture of the hypothalamus.

Influence of regional cerebral blood volume on voxel-based morphometry.

The investigation of structural brain alterations is one focus in research of brain diseases like depression. Voxel-based morphometry (VBM) based on high-resolution 3D MRI images is a widely used non-invasive tool for such investigations. However, the result of VBM might be sensitive to local physiological parameters such as regional cerebral blood volume (rCBV) changes. In order to investigate whether rCBV changes may contribute to variation in VBM, we performed analyses in a study with the congenital learned helplessness (cLH) model for long-term findings. The 3D structural and rCBV data were acquired with T2 -weighted rapid acquisition with relaxation enhancement (RARE) pulse sequences. The group effects were determined by standard statistical parametric mapping (SPM) and biological parametric mapping (BPM) and examined further using atlas-based regions. In our genetic animal model of depression, we found co-occurrence of differences in gray matter volume and rCBV, while there was no evidence of significant interaction between both. However, the multimodal analysis showed similar gray matter differences compared with the standard VBM approach. Our data corroborate the idea that two group VBM differences might not be influenced by rCBV differences in genetically different strains. Copyright © 2016 John Wiley & Sons, Ltd.

Beyond correlation: functional OPTO-MAgnetic Integration Concept (OPTOMAIC) to reveal the brain-wide signature of local neuronal signals-of-interest.

Significance: Due to the vascular origin of the fMRI signal, the spatiotemporally precise interpretation of the blood oxygen level-dependent (BOLD) response as brain-wide correlate of neuronal activity is limited. Optical fiber-based neuronal calcium recordings provide a specific and temporally highly resolved signal yet lacking brain-wide coverage. The cross-modal integration of both modalities holds the potential for unique synergies. Aim: The OPTO-MAgnetic Integration Concept (OPTOMAIC) extracts the very fraction of the BOLD response that reacts to optically recorded neuronal signals-of-interest. Approach and Results: First, OPTOMAIC identifies the trials containing neuronal signal-of-interest (SoI) in the optical recordings. The long duration of the BOLD response is considered by calculating and thresholding neuronal interevent intervals. The resulting optical regression vector is probed for a positive BOLD response with single-event and single-voxel resolution, generating a BOLD response matrix containing only those events and voxels with both a neuronal SoI and a positive fMRI signal increase. Last, the onset of the BOLD response is being quantified, representing the section of the BOLD response most reliably reporting at least components of the neuronal signal. Conclusions: The seven OPTOMAIC steps result in a brain-wide BOLD signature reflecting the underlying neuronal SoI with utmost cross-modal integration depth and taking full advantage of the specific strengths of each method.

Comparison of the quantitative first pass myocardial perfusion MRI with and without prospective slice tracking: comparison between breath-hold and free-breathing condition.

Physiologic motion of the heart is one of the major problems of myocardial blood flow quantification using first pass perfusion-MRI method. To overcome these problems, a perfusion pulse sequence with prospective slice tracking was developed. Cardiac motion was monitored by a navigator directly positioned at heart's basis to overcome no additional underlying model calculations connecting diaphragm and cardiac motion. Additional prescans were used before the perfusion measurement to detect slice displacements caused by remaining cardiac motion between navigator and the perfusion slice readout. The pulse sequence and subsequent quantification of myocardial blood flow was tested in healthy pigs with and without prospective slice tracking under both free-breathing and breath-hold conditions. To avoid influences by residual contrast agent concentration time courses were analyzed. Median myocardial blood flow values and interquartile ranges with prospective slice tracking under free-breathing and in a breath-hold were (1.04, interquartile range = 0.58 mL/min/g) and (1.20, interquartile range = 0.59 mL/min/g), respectively. This is in agreement with published positron emission tomography values. In measurements without prospective slice tracking (1.15, interquartile range = 1.58 mL/min/g), the interquartile range is significantly (P < 0.012) larger because of residual cardiac motion. In conclusion, prospective slice tracking reduces motion-induced variations of myocardial blood flow under both during breath-hold and under conditions of free-breathing.

Functionally altered neurocircuits in a rat model of treatment-resistant depression show prominent role of the habenula.

Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. To investigate disease-related alterations of brain function we used a genetic animal model of TRD, congenital learned helplessness (cLH), and functional magnetic resonance imaging as a translational tool. High-resolution regional cerebral blood volume (rCBV) and resting-state functional connectivity measurements were acquired at 9.4T to determine regional dysfunction and interactions that could serve as vulnerability markers for TRD. Effects of cLH on rCBV were determined by statistical parametric mapping using 35 atlas-based regions of interest. Effects of cLH on functional connectivity were assessed by seed region analyses. Significant bilateral rCBV reductions were observed in the lateral habenula, dentate gyrus and subiculum of cLH rats. In contrast, focal bilateral increase in rCBV was observed in the bed nucleus of stria terminalis (BNST), a component of the habenular neurocircuitry. Functional connectivity was primarily enhanced in cLH rats, most notably with respect to serotonergic projections from the dorsal raphe nucleus to the forebrain, within the hippocampal-prefrontal network and between the BNST and lateral frontal regions. Dysregulation of neurocircuitry similar to that observed in depressed patients was detected in cLH rats, supporting the validity of the TRD model and suitability of high-field fMRI as a translational technology to detect and monitor vulnerability markers. Our findings also define neurocircuits that can be studied for TRD treatment in patients, and could be employed for translational research in rodent models.

Haloperidol modulates midbrain-prefrontal functional connectivity in the rat brain.

Dopamine D2 receptor antagonists effectively reduce positive symptoms in schizophrenia, implicating abnormal dopaminergic neurotransmission as an underlying mechanism of psychosis. Despite the well-established, albeit incomplete, clinical efficacies of D2 antagonists, no studies have examined their effects on functional interaction between brain regions. We hypothesized that haloperidol, a widely used antipsychotic and D2 antagonist, would modulate functional connectivity in dopaminergic circuits. Ten male Sprague-Dawley rats received either haloperidol (1 mg/kg, s.c.) or the same volume of saline a week apart. Resting-state functional magnetic resonance imaging data were acquired 20 min after injection. Connectivity analyses were performed using two complementary approaches: correlation analysis between 44 atlas-derived regions of interest, and seed-based connectivity mapping. In the presence of haloperidol, reduced correlation was observed between the substantia nigra and several brain regions, notably the cingulate and prefrontal cortices, posterodorsal hippocampus, ventral pallidum, and motor cortex. Haloperidol induced focal changes in functional connectivity were found to be the most strongly associated with ascending dopamine projections. These included reduced connectivity between the midbrain and the medial prefrontal cortex and hippocampus, possibly relating to its therapeutic action, and decreased coupling between substantia nigra and motor areas, which may reflect dyskinetic effects. These data may help in further characterizing the functional circuits modulated by antipsychotics that could be targeted by innovative drug treatments.