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

Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling

Abstract Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders

Behavioural effects of chronic exposure to CY/sucrose solution.

<p>(A) Chronic immunosuppression reduced step-down latency in diseased MRL/lpr mice, but had the opposite effect on congenic controls. (B) In addition to the previously-documented substrain differences in sucrose consumption <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100684#pone.0100684-Sakic3" target="_blank">[24]</a>, CY had a significant detrimental effect on the performance in both groups. (C) Although a trend was noted, CY could not abolish previously-reported differences in overall floating in the forced swim test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100684#pone.0100684-Sakic2" target="_blank">[23]</a>. (D) Prolonged immunosuppression improved spontaneous ambulatory activity in MRL/lpr mice, but had a detrimental effect on MRL +/+ controls. (E) Conversely, CY exposure significantly improved (but did not normalize) running wheel activity in MRL/lpr mice.</p

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

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

BackgroundImmune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration.ObjectiveThe present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology.MethodsA broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age.ResultsAged AD mice displayed severe manifestations of systemic autoimmune/inflammatory dise6ase, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired "cognitive" flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology.ConclusionThe results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD

Weekly preference for sweet solutions.

<p>Initially, CY lpr mice displayed a higher preference for CY/sucrose in comparison to control CY +/+ group at 11 weeks of age. However, this difference was transient and became the lowest of all groups by the end of the study.</p

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

BACKGROUND: Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. OBJECTIVE: The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. METHODS: A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. RESULTS: Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. CONCLUSION: The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD

Weekly CY dose ingested.

<p>Although both substrains received similar CY dose at the starting of the treatment period, voluntary drinking in subsequent weeks was higher in less symptomatic MRL +/+ than in MRL/lpr mice.</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