Time Course and Nature of Brain Atrophy in the MRL Mouse Model of Central Nervous System Lupus

Objective. Similar to patients with systemic lupus erythematosus, autoimmune MRL/lpr mice spontaneously develop behavioral deficits and pathologic changes in the brain. Given that the disease-associated brain atrophy in this model is not well understood, the present study was undertaken to determine the time course of morphometric changes in major brain structures of autoimmune MRL/lpr mice. Methods. Computerized planimetry and highresolution magnetic resonance imaging (MRI) were used to compare the areas and volumes of brain structures in cohorts of mice that differ in severity of lupus-like disease. Results. A thinner cerebral cortex and smaller cerebellum were observed in the MRL/lpr substrain, even before severe autoimmunity developed. With progression of the disease, the brain area of coronal sections became smaller and the growth of the hippocampus was retarded, which likely contributed to the increase in the ventricle area:brain area ratio. MRI revealed reduced volume across different brain regions, with the structures in the vicinity of the ventricular system particularly affected. The superior colliculus, periaqueductal gray matter, pons, and midbrain were among the regions most affected, whereas the volumes of the parietal-temporal lobe, parts of the cerebellum, and lateral ventricles in autoimmune MRL/lpr mice were comparable with values in congenic controls. Conclusion. These results suggest that morphologic alterations in the brains of MRL/lpr mice are a consequence of several factors, including spontaneous development of lupus-like disease. A periventricular pattern of parenchymal damage is consistent with the cerebrospinal fluid neurotoxicity, limbic system pathologic features, and deficits in emotional reactivity previously documented in this model. Neuropsychiatric (NP) manifestations are a common and serious complication of systemic lupus erythematosus (SLE). Contemporary imaging techniques have revealed various abnormalities in patients with SLE, including lesions in the periventricular and subcortical regions (1,2), hypoperfusion (3), and regional metabolic abnormalities (4). Brain atrophy is the most frequent observation (5) and is likely a consequence of widespread neuronal and glial damage (6). Consistent with these reports, recent studies on water diffusivity indicate a genuine loss of brain-tissue integrity in patients with NPSLE/central nervous system (CNS) lupus (7). However, the lack of understanding of CNS damage led to development of animal models of acute and chronic lupus and dissection of complex pathogenic circuits (8). MRL/MpJTnfrsf6 lpr (MRL/lpr) mice and MRL/ MpJϩ/ϩ (MRLϩ/ϩ) congenic control mice share more than 99.9% of their genome but differ in the onset of lupus-like manifestations. The 3-4-month difference in the time to onset allows discrimination of autoimmunityinduced functional and structural brain damage from epiphenomena associated with aging and with damage of vital peripheral organs (9). In addition to accelerated development of serologic signs of inflammation and autoimmunity, MRL/lpr mice develop, at an early stage, a constellation of behavioral deficits and neuropathologic changes, operationally termed autoimmune

Zoopharmacognosy in diseased laboratory mice: conflicting evidence.

Zoopharmacognosy denotes a constellation of learned ingestive responses that promote healing and survival of infected or poisoned animals. A similar self-medication phenomenon was reported in diseased laboratory rodents. In particular, a series of studies revealed that autoimmune MRL/lpr mice readily consume solutions paired or laced with cyclophosphamide (CY), an immunosuppressive drug that prevents inflammatory damage to internal organs. However, due to design limitations, it could not be elucidated whether such a response reflects the learned therapeutic effect of CY, or a deficit in sensory input. We presently assess the behavioural effects of prolonged consumption of CY-laced, 16% sucrose solution in a continuous choice paradigm, with tap water available ad lib. Contrary to overall expectation, MRL/lpr mice did not increase their intake of CY with disease progression. Moreover, they ingested lower doses of CY and preferred less CY-laced sucrose solution than age-matched controls. The results obtained could not confirm zoopharmacognosy in diseased MRL/lpr mice, likely due to impaired responsiveness to palatable stimulation, or attenuated survival mechanisms after prolonged inbreeding in captivity. However, by revealing the effectiveness of unrestricted drinking of drug-laced sucrose solution on behavior and immunity, the current study supports broader use of such an administration route in behavioural studies sensitive to external stressors

Daily fluid consumption from 11–22 weeks of age.

<p>(A) Despite fluctuations in daily water intake over the course of the study, Veh MRL +/+ mice consumed the most water in the 2-bottle test. They also drank significantly more than their CY +/+ counterparts, a trend that was not noted in the MRL/lpr substrain. (B) Lacing sweetened solution with CY significantly reduced daily consumption. However, autoimmune MRL/lpr mice consumed significantly less CY solution in comparison to MRL +/+ mice, particularly after the first week of treatment.</p

Mean body weight from 11–22 weeks of age.

<p>Autoimmune MRL/lpr mice were significantly lighter when compared to congenic controls. However, prolonged immunosuppression further reduced their body weight, but not in MRL +/+ mice.</p