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

Oxytocin induces the formation of distinctive cortical representations and cognitions biased toward familiar mice

Social recognition is essential for the formation of social structures. Many times, recognition comes with lesser exploration of familiar animals. This lesser exploration has led to the assumption that recognition may be a habituation memory. The underlying memory mechanisms and the thereby acquired cortical representations of familiar mice have remained largely unknown, however. Here, we introduce an approach directly examining the recognition process from volatile body odors among male mice. We show that volatile body odors emitted by mice are sufficient to identify individuals and that more salience is assigned to familiar mice. Familiarity is encoded by reinforced population responses in two olfactory cortex hubs and communicated to other brain regions. The underlying oxytocin-induced plasticity promotes the separation of the cortical representations of familiar from other mice. In summary, neuronal encoding of familiar animals is distinct and utilizes the cortical representational space more broadly, promoting storage of complex social relationships

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

A consensus protocol for functional connectivity analysis in the rat brain

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience

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