Altered fronto-striatal functions in the Gdi1 -null mouse model of X-linked Intellectual Disability

RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients

A novel anesthesia regime enables neurofunctional studies and imaging genetics across mouse strains

Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders

Rat brain parcellation scheme.

<p>Thirty six anatomically defined brain regions of interest, colored differently, are overlaid on the in-house rat MRI template. Distance to Bregma (in mm) is given at the top of each slice.</p

How female mice attract males:A urinary volatile amine activates a trace amine-associated receptor that indices male sexual interest

Individuals of many species rely on odors to communicate, find breeding partners, locate resources and sense dangers. In vertebrates, odorants are detected by chemosensory receptors of the olfactory system. One class of these receptors, the trace amine-associated receptors (TAARs), was recently suggested to mediate male sexual interest and mate choice. Here we tested this hypothesis in mice by generating a cluster deletion mouse (Taar2-9−/−) lacking all TAARs expressed in the olfactory epithelium, and evaluating transduction pathways from odorants to TAARs, neural activity and behaviors reflecting sexual interest. We found that a urinary volatile amine, isobutylamine (IBA), was a potent ligand for TAAR3 (but not TAAR1, 4, 5, and 6). When males were exposed to IBA, brain regions associated with sexual behaviors were less active in Taar2-9−/− than in wild type males. Accordingly, Taar2-9−/− males spent less time sniffing both the urine of females and pure IBA than wild type males. This is the first demonstration of a comprehensive transduction pathway linking odorants to TAARs and male sexual interest. Interestingly, the concentration of IBA in female urine varied across the estrus cycle with a peak during estrus. This variation in IBA concentration may represent a simple olfactory cue for males to recognize receptive females. Our results are consistent with the hypothesis that IBA and TAARs play an important role in the recognition of breeding partners and mate choice

Fisher z-transformed FC matrix of rat brain.

<p>a) Mean FC matrix (40 subjects) showing pairwise partial correlation coefficients obtained for 36 brain regions. b) Standard deviation matrix of the partial correlation coefficients. For abbreviations of brain regions see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#pone-0106156-g001" target="_blank">Figure 1</a>.</p

Modular organization in 4 different groups.

<p>Group plots with high modular similarity (low variability) in subjects randomly split into four groups (a–d) visualized on schematic mid sagittal sections of the rat brain. Network hubs are depicted by larger circles. The colors used for the sub-networks of the six functional modules, as identified by the modularity partitioning algorithm (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#s2" target="_blank">methods</a>), are analogue to those used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#pone-0106156-g004" target="_blank">Figure 4c</a>. For abbreviations of brain regions see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#pone-0106156-g001" target="_blank">Figure 1</a>.</p

Reproducibility of FC across subjects.

<p>The histograms (in blue) represent the distribution of the partial correlation coefficients (z-transformed) for each of the four randomly partitioned subject groups. Scatter plots indicating high correlation (r>0.85) of the pair-wise FC values between the groups suggest high reproducibility of FC at a group level.</p

Modular organization of rat FCN and centrality of brain regions.

<p>a) Mean FC matrix rearranged with functional modules labeled along the major diagonal of the matrix. Six functional modules (sub-networks) of brain regions, as identified by the modularity partitioning algorithm (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#s2" target="_blank">methods</a>), are labeled in different colors. b) In the first row brain regions are shown in descending order of their generalized connection strength. Strong (strength>mean) brain areas are shown in red bars; the horizontal line indicates the mean strength. In the second row brain regions are shown in descending order of their generalized diversity value. Here, red bars show brain regions with strong connections as determined in the first row. Network hubs (i.e., nodes that are both strong and diverse) are indicated by green triangles. c) FCN modules are visualized on a schematic mid sagittal section of the rat brain. Network hubs are depicted by larger circles. For abbreviations of brain regions see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106156#pone-0106156-g001" target="_blank">Figure 1</a>. The colors used for the different modules are the same as those used in Figure 4a.</p