Axel Mathieu

A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat

Hippocampal shrinkage is a commonly found neuroanatomical change in stress‐related mood disorders such as depression and post‐traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress‐induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression. In this study, we examined the contribution of either innate hippocampal volume differences or hippocampal susceptibility to stress‐induced shrinkage to the formation of stress‐related psychopathology using longitudinal MRI measurements of hippocampal volume in inbred C57 mice before and after chronic social defeat stress. We found that only half of the stressed C57 mice were susceptible to stress and developed psychopathological behaviors such as social avoidance. The other half was resilient to stress and exhibited no social avoidance. Before exposure to stress, we observed a positive correlation between hippocampal volume and social avoidance. After chronic social defeat stress, we found significant increases in left hippocampal volume in resilient and nonstressed control mice. Intriguingly, this increase in hippocampal volume was not found in susceptible mice, suggesting an arrestment of hippocampal growth in these mice. Our findings suggest that both a susceptibility to stress‐induced hippocampal volume changes and a larger hippocampus before stress exposure confer vulnerability to psychopathology after chronic stress.

Behavioral signs of axial low back pain and motor impairment correlate with the severity of intervertebral disc degeneration in a mouse model

BACKGROUND CONTEXT Chronic low back pain is debilitating and difficult to treat. Depending on the etiology, responses to treatments vary widely. Although chronic low back pain is frequently related to intervertebral disc degeneration, the relationship between disc degeneration severity and clinical symptoms are still poorly understood. In humans, studies investigating the relationship between disc degeneration severity and low back pain are limited by the difficulty of obtaining disc samples from well-characterized patients and pain-free controls. We have previously described the secreted protein, acidic, rich in cysteine (SPARC)-null mouse model of chronic low back pain. SPARC is a matricellular protein involved in regulating the assembly and composition of extracellular matrix. The SPARC-null mice develop age-dependent disc degeneration of increasing severity accompanied by behavioral signs suggestive of axial low back pain, radiating leg pain, and motor impairment. The existence of this model allows for examination of the relationships between clinical symptoms in vivo and pathological signs of disc degeneration ex vivo. PURPOSE The goal of this study was to explore the relationship between behavioral signs of pain and the severity of lumbar disc degeneration using the SPARC-null mouse model of disc degeneration-related low back pain. STUDY DESIGN This study used a cross-sectional, multiple-cohort behavioral and histological study of disc degeneration and behavioral symptoms in a mouse model of low back pain associated with disc degeneration. METHODS SPARC-null and wild-type control mice ranging from 6 to 78 weeks of age were used in this study. The severity of disc degeneration was determined by ex vivo analysis of the lumbar spine using colorimetric histological staining and a scoring system adapted from the Pfirrmann scale. Behavioral signs of axial low back pain, radiating leg pain, and motor impairment were quantified as tolerance to axial stretching in the grip force assay, hypersensitivity to cold or mechanical stimuli on the hindpaw (acetone and von Frey tests), and latency to fall in the rotarod assay, respectively. RESULTS The SPARC-null mice exhibited decreased tolerance to axial stretching, hindpaw cold hypersensitivity, and motor impairment compared with age-matched control mice. The severity of disc degeneration increased with age in both SPARC-null and control mice and by 78 weeks of age, the same proportion of lumbar discs were abnormal in SPARC-null and control mice. However, the degree of degeneration was more severe in the SPARC-null mice. In both SPARC-null and control mice, tolerance to axial stretching but not hindpaw cold sensitivity correlated with disc degeneration severity. Motor impairment correlated with degeneration severity in the SPARC-null mice only. CONCLUSIONS These data suggest that internal disc disruption contributes to axial low back pain and motor impairment but not to radiating leg pain. These results have implications for the optimization of mechanism-based treatments strategies.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimers disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages. SIGNIFICANCE STATEMENT The present study proposes a “back translation” of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.

A non-invasive restraining system for awake mouse imaging

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 20min) 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).

In vivo proton observed carbon edited (POCE) 13C magnetic resonance spectroscopy of the rat brain using a volumetric transmitter and receive‐only surface coil on the proton channel

In vivo carbon‐13 (13C) MR spectroscopy (MRS) is capable of measuring energy metabolism and neuroenergetics, noninvasively in the brain. Indirect (1H‐[13C]) MRS provides sensitivity benefits compared with direct 13C methods, and normally includes a 1H surface coil for both localization and signal reception. The aim was to develop a coil platform with homogenous B1+ and use short conventional pulses for short echo time proton observed carbon edited (POCE) MRS.

Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor

Background: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2‐like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2‐like receptors has yet to be explored. Methods: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9‐weeks using structural magnetic resonance imaging (MRI). Results: Chronic typical APD administration in WT mice was associated with reductions in total brain (p=0.009) and prelimbic area (PL) (p=0.02) volumes following 9‐weeks, and an increase in striatal volume (p=0.04) after six weeks. These APD‐induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (p<0.01), thinner cortices (q<0.05), and enlarged striata (q<0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. Conclusions: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure. HIGHLIGHTSNeuroanatomical changes in schizophrenic patients have been possibly linked to chronic antipsychotic drug (APD) treatment.Different classes of APDs interact with the dopaminergic system as part of their mechanism of action.We observe differential changes in total brain, striatal, and prefrontal cortex anatomy based on type of APD administered.Mice lacking the D2 dopamine receptor have limited changes in brain anatomy in response to APD administration.Knock out of the D2 dopamine receptor recapitulates brain volume changes observed with chronic APD administration.

Minimum echo time PRESS-based proton observed carbon edited (POCE) MRS in rat brain using simultaneous editing and localization pulses

Indirect 13C MRS by proton‐observed carbon editing (POCE) is a powerful method to study brain metabolism. The sensitivity of POCE‐MRS can be enhanced through the use of short TEs, which primarily minimizes homonuclear J‐evolution related losses; previous POCE‐MRS implementations use longer than optimal echo times due to sequence limitations, or short TE image selected in vivo spectroscopy‐based multi‐shot acquisitions for 3D localization. To that end, this paper presents a novel single‐shot point resolved spectroscopy (PRESS)‐localized POCE‐MRS sequence that involves the application of simultaneous editing and localization pulses (SEAL)‐PRESS, allowing the TE to be reduced to a theoretically optimal value of ∼ 1/JHC.

Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress

Early-life stress (ELS) exposure has long-term consequences for both brain structure and function and impacts cognitive and emotional behavior. The basolateral amygdala (BLA) plays an important role in anxiety and fear conditioning through its extensive anatomical and functional connections, in particular to the medial prefrontal cortex (mPFC). However, how ELS affects amygdala function and connectivity in developing rats is unknown. We used the naturalistic limited bedding/nesting (LB) paradigm to induce chronic stress in the pups between postnatal day (PND) 1–10. Male normal bedding (NB, control) or LB offspring underwent structural and resting-state functional MRI (rs-fMRI) on PND18 and in adulthood (PND74–76). Adult male rats were tested for fear conditioning and extinction behavior prior to scanning. Seed-based functional connectivity maps were generated based on four BLA seeds (left, right, anterior and posterior). At both ages, LB induced different effects on anterior and posterior BLA networks, with significant reductions in rs-fMRI connectivity between the anterior BLA and mPFC in LB compared to NB offspring. BLA connectivity was lateralized by preweaning age, with the right hemisphere displaying more connectivity changes than the left. Weak negative volumetric correlations between the BLA and mPFC were also present, mostly in preweaning LB animals. rs-fMRI connectivity and volumetric changes were associated with enhanced fear behaviors in adult LB offspring. Activation of the LB-exposed neonatal amygdala described previously might accelerate the maturation of BLA–mPFC projections and/or modify the activity of reciprocal connections between these structures, leading to a net reduction in rs-fMRI connectivity and increased fear behavior.

A chronic in situ coil system adapted for intracerebral stimulation during MRI in rats

BACKGROUND We describe the fabrication and performance of a chronic in situ coil system designed to allow focal brain stimulation in rats while acquiring functional MRI data. NEW METHOD An implantable receive-only surface radiofrequency coil (iCoil) was designed to be fitted subcutaneously, directly onto to the rat skull surface during the intracerebral cannulation procedure. The coil is fixed in place using acrylic dental cement anchored to four screws threaded into the skull. To demonstrate the use of this coil system in situ, whole-brain functional MRI scans were acquired during various stimuli, including intracranial microinfusions of bicuculline and morphine in the prefrontal cortex and ventral tegmental area, respectively. RESULTS/COMPARISON TO OTHER METHODS SNR performance of the iCoil was superior to three commercially-available coils, in some instances by a factor of two. Widespread BOLD activation was observed in response to bicuculline and morphine microinfusions. CONCLUSION A new approach was demonstrated for high-SNR MR imaging of the brain in rats with intracranial implants using an implantable surface coil. This approach enables mapping the functional response to highly targeted stimuli such as intracranial microinfusions.

AMYLOIDOSIS CHANGES ASSOCIATIONS BETWEEN HIPPOCAMPUS VOLUME AND BRAIN METABOLIC DECLINES

BETWEEN HIPPOCAMPUS VOLUME AND BRAIN METABOLIC DECLINES Min Su Kang, Maxime Parent, Monica Shin, Eduardo Rigon Zimmer, Antonia Aliaga, Axel Mathieu, Sulantha Sanjeewa Mathotaarachchi, Sara Mohades, Sarinporn Manitsirikul, Jean-Paul Soucy, Serge Gauthier, Claudio Cuello, Pedro Rosa-Neto, McGill University, Verdun, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; Douglas Hospital, Verdun, Quebec, Canada; 5 McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 6 McGill Center for Studies in Aging, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada. Contact e-mail: peter.ms.kang@gmail.com