Alzheimer's disease is a progressive neurodegenerative disorder with a decades-long pre-symptomatic phase, substantiating the need for prodromal biomarker development and early intervention. To deconstruct the processes underlying disease progression and identify potential biomarkers, we used neuroimaging techniques with high translational potential to human clinical studies in the TgF344-AD rat model which recapitulates the full spectrum of Alzheimer’s neuropathology (progressive amyloid deposition, tauopathy, frank neuronal loss, gliosis, and cognitive dysfunction). We employed longitudinal magnetic resonance imaging and spectroscopy in conjunction with behavioural testing to characterize multiple facets of disease pathology in male and female TgF344-AD rats (n=26, 14M/12F) relative to wildtype littermates (n=24, 12M/12F). Testing was performed at 4-, 10-, 16-, and 18-months, covering much of the adult rat lifespan and multiple stages of disease progression. The TgF344-AD model demonstrated impaired spatial reference memory in the Barnes Maze by 4 months of age, followed by neurochemical abnormalities in the hippocampus by 10 months and major structural changes by 16 months. Specifically, TgF344-AD rats displayed increased total choline and lactate, and decreased total creatine, taurine, and N-acetylaspartate to myo-inositol ratio, dentate gyrus hypertrophy, and atrophy in the hippocampus, hypothalamus, and nucleus accumbens. Overall, these findings support the use of magnetic resonance imaging and spectroscopy for the development of non-invasive biomarkers of disease progression, clarify the timing of pathological feature presentation in this model, and contribute to the validation of the TgF344-AD rat as a highly relevant model for preclinical Alzheimer's disease research.

Background Preclinical neuroimaging allows for the assessment of brain anatomy, connectivity and function in laboratory animals, such as mice and rats. Most of these studies are performed under anesthesia to avoid movement during the scanning sessions. Method Due to the limitations associated with anesthetized imaging, recent efforts have been made to conduct rodent imaging studies in awake animals, habituated to the restraint systems used in these instances. As of now, only one such system is commercially available for mouse scanning (Animal Imaging Research, Boston, MA, USA) integrating the radiofrequency coil electronics with the restraining element, an approach which, although effective in reducing head motion during awake imaging, has some limitations. In the current report, we present a novel mouse restraining system that addresses some of these limitations. Results/Comparison to other methods The effectiveness of the restraining system was evaluated in terms of three-dimensional linear head movement across two consecutive functional MRI scans (total 20 min) in 33 awake mice. Head movement was minimal, recorded in roughly 12% of the time-series. Respiration rate during the acclimation procedure dropped while the bolus count remained unchanged. Body movement during functional acquisitions did not have a significant effect on magnetic field (B0) homogeneity. Conclusion/novelty Compared to the commercially available system, the benefit of the current design is two-fold: 1) it is compatible with a range of commercially-available coils, and 2) it allows for the pairing of neuroimaging with other established techniques involving intracranial cannulation (i.e. microinfusion and optogenetics).

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were ‘odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists.

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studies from other species 12,13 , we have freely released all data and the generated code.