6 research outputs found
Local differences on a nodal level in 6-OHDA rats compared to shams.
<p>Glass brains depicting nodes that showed significantly altered (A) node degree, (B) clustering coefficient and (C) node efficiency in 6-OHDA rats compared to shams. Nodes are represented as spheres and located in the glass brain according to their corresponding anatomical region’s centre mass. Blue spheres depict significantly lower, red spheres significantly higher values in 6-OHDA rats compared to shams. Significance was assessed using two-sample t-test by comparing the AUC of these network measures for each node across all network sparsities (0.05</p
Connection-wise comparison reveals significantly reduced connections in 6-OHDA rats compared shams.
<p>Glass brain depicting edges and their associated nodes that showed significantly reduced functional connectivity in 6-OHDA rats in comparison to sham rats. The size of a node represents the number of abnormal connections associated with that node. Significance was assessed using non-parametric permutation tests (N = 10000). A p-value below 0.05 was considered significant (FWER corrected). The results shown were generated at a primary NBS threshold of t = 3.1 with p = 0.0425, FWER corrected. 6-OHDA rats N = 13; sham rats N = 11. Bold L marks the lesion side. R, contralateral side.</p
Global network measures of segregation and integration across different network sparsities in 6-OHDA rats and shams.
<p>(A) Mean clustering coefficient C normalized to a random reference network. (B) Mean characteristic path length L normalized to a random reference network. (C) Small-worldness S. (D) Number of modules. (E) Modularity Q. (F) Global efficiency. Data are expressed as mean ± SEM. 6-OHDA rats N = 13; sham rats N = 11.</p
Rat brain parcellation scheme showing 150 ROIs (75 on each hemisphere).
<p>Each bilateral ROI is labelled differently and overlaid onto coronal slices of the rat brain template.</p
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The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats
Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB’s hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB’s ability to enhance cerebral metabolism might be limited
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Erbb4 deletion from inhibitory interneurons causes psychosis-relevant neuroimaging phenotypes
BACKGROUND AND HYPOTHESIS: Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA a5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. STUDY DESIGN: Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. RESULTS: Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. CONCLUSIONS: These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species