Weiterführende Techniken in der Spektroskopischen Bildgebung in vivo durch heteronuklearen Polarisationstransfer und anatomie-basierte Spektrenquantifizierung

31P-NMR-Signalverstärkung durch heteronuklearen Polarisationstransfer wurde an einem mit zwei Hochfrequenzsystemen ausgestatteten Ganzkörper-NMR-Tomographen sowohl an Modell-Lösungen, als auch invivo erreicht. Mit dem RINEPT-Doppelresonanz-Experiment können die viel größeren Unterschiede in den Besetzungszahlen der Zeeman-Energieniveaus der Protonen durch eine Serie von simultan eingestrahlten breitbandigen HF-Pulsen auf das 31P-Spinsystem übertragen werden. RINEPT erlaubt einen Polarisationstransfer aller 1H- auf 31P-Zustände mit äquivalenter skalarer Kopplung und der gleichen Anzahl gebundener Wasserstoffatome. Dadurch werden die Signale der Metaboliten mit skalarer 1H-31P-Kopplung verstärkt, während die Signale der Metaboliten ohne Kopplung in den Spektren unterdrückt werden. Durch Optimierung der Zeitparameter wurde an Modell-Lösungen mit RINEPT eine von der Repetitionszeit (TR) abhängige Verstärkung von 29 ± 3 für Methylendiphosphonsäure (MDPA) und 56 ± 1 für Phosphorylethanolamin (PE) gegenüber Ernstwinkelanregung gemessen. Die Messergebnisse wurden durch Vergleich mit Modellrechnungen bestätigt. Bei In-vivo-Messungen konnte unter Verwendung der optimierten Echozeiten eine maximale 31P-NMR-Signalverstärkung von 55 ± 39 erzielt werden. Darüber hinaus wurde durch Entwicklung von Algorithmen zur Gewebedifferenzierung innerhalb des Messbereichs der spektroskopischen Bildgebung (MRSI) des menschlichen Gehirn die Datennachverarbeitung in der In-vivo-1H- und -31P-NMR-Spektroskopie verbessert. Es wurden Korrekturen der MRSI-Daten eingeführt, die die Varianz der Messwerte beim interpersonellen Vergleich signifikant verringern

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation

Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan Disease

Canavan Disease (CD) is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase (ASPA), an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase (lacZ) gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin (aspalacZ/+) mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous (aspalacZ/lacZ) mutants are ASPA-deficient, show CD-like histopathology and moderate neurological impairment with behavioural deficits that are more pronounced in aspalacZ/lacZ males than females. Non-invasive ultrahigh field proton magnetic resonance spectroscopy revealed increased levels of NAA, myo-inositol and taurine in the aspalacZ/lacZ brain. Spongy degeneration was prominent in hippocampus, thalamus, brain stem, and cerebellum, whereas white matter of optic nerve and corpus callosum was spared. Intracellular vacuolisation in astrocytes coincides with axonal swellings in cerebellum and brain stem of aspalacZ/lacZ mutants indicating that astroglia may act as an osmolyte buffer in the aspa-deficient CNS. In summary, the aspalacZ mouse is an accurate model of CD and an important tool to identify novel aspects of its complex pathology

Interactive tool to create adjustable anatomical atlases for mouse brain imaging

Objective!#!Brain atlases are important research tools enabling researchers to focus their investigations on specific anatomically defined brain regions and are used in many MRI applications, e.g. in fMRI, morphometry, whole brain spectroscopy, et cetera. Despite their extensive use and numerous versions they usually consist of predefined rigid brain regions with a given level of detail often degrading them to a non-ideal tool in special research topics.!##!Result!#!To overcome this intrinsic weakness we present a graphical user interface application which allows researchers to easily create mouse brain atlases with an adjustable user-defined level of detail and coverage to match specific research questions

Relevance of orbitofrontal neurochemistry for the outcome of cognitive-behavioural therapy in patients with obsessive-compulsive disorder

Since the advent of non-invasive methods such as proton magnetic resonance spectroscopy ((1)H-MRS), obsessive-compulsive disorder (OCD) has been increasingly associated with an altered composition of neurometabolites and neurotransmitters in several brain areas. Particularly, Inositol has not only been implicated in OCD pathophysiology, but also shown effective in pilot studies in therapy-refractory OCD patients. However, the relevance of regional brain neurochemistry for therapy outcome has not yet been investigated. Whereas numerous neuroimaging findings support a dysfunction of the orbitofrontal cortex (OFC) in OCD, MR-spectroscopic investigations of this region are missing. (1)H-MRS and psychometric measurements were obtained from twenty unmedicated patients with OCD, subsequently enrolled in a 3-month structured inpatient cognitive-behavioural therapy programme, and from eleven matched control subjects. Multiple regression of symptom score changes (Y-BOCS) on (myo-)inositol concentrations in three areas (right orbitofrontal cortex (OFC), right striatum and anterior cingulate cortex) was performed. The concentration of (myo-)inositol in the OFC only predicted the outcome of subsequent CBT regarding Y-BOCS score reduction (Spearman's r(s) = .81, P > 0.003, corrected). The (myo-)inositol concentration did not differ between OCD patients and healthy controls and did not change during therapy. We provide preliminary evidence for a neurochemical marker that may prove informative about a patient's future benefit from behaviour therapy. Inositol, a metabolite involved in cellular signal transduction and a spectroscopic marker of glial activity, predicted the response to CBT selectively in the OFC, adding to the evidence for OFC involvement in OCD and highlighting neurobiological underpinnings of psychotherapy

Striatal hub of dynamic and stabilized prediction coding in forebrain networks for olfactory reinforcement learning

Identifying the circuits responsible for cognition and understanding their embedded computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach, from behavioral modeling and fMRI in task-performing mice to cellular recordings, in order to disentangle local network contributions to olfactory reinforcement learning. At mesoscale, fMRI identifies a functional olfactory-striatal network interacting dynamically with higher-order cortices. While primary olfactory cortices respectively contribute only some value components, the downstream olfactory tubercle of the ventral striatum expresses comprehensively reward prediction, its dynamic updating, and prediction error components. In the tubercle, recordings reveal two underlying neuronal populations with non-redundant reward prediction coding schemes. One population collectively produces stabilized predictions as distributed activity across neurons; in the other, neurons encode value individually and dynamically integrate the recent history of uncertain outcomes. These findings validate a cross-scale approach to mechanistic investigations of higher cognitive functions in rodents

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3′,5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency