Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Mortality of septic old and adult male mice correlates with individual differences in premorbid behavioral phenotype and acute-phase sickness behavior

Individual differences in premorbid behaviors and in those exhibited in the course of an infection disease may be useful to explain the individual susceptibility to infections, the underlying neuroimmunological mechanisms and be helpful to design patient oriented treatments with better prediction of pharmacological reactivity/outcome. Age (old) and gender (male) are also considered vulnerability factors. In the present study, the motor, emotional, anxious-like and social phenotypes of adult (6-month-old) and old (18-month-old) male C57BL/6 × 129Sv mice were determined using both a transversal and longitudinal designs prior to the analysis of LPS (150 mg/kg, i.p.)- induced sickness behavior and mortality. The results show: i) Individual premorbid behavioral phenotype had short- and long-term predictive value of hours of survival; ii) Persistence of behavioral traits from adulthood to old age and predictive value on hours of survival; iii) First signs of sickness behavior were also predicting mortality, mostly in old animals; iv) LPS-sickness behavior was the same at both ages but adult animals were able to show attempts of motor recovery; v) The mortality rate over 96 h was 100% in both ages, but old animals showed shorter survival times. In summary, these results confirm the relevance of age/aging but also individual behavioral differences in the premorbid phenotype and the morbidity response to the LPS-induced-sepsis that correlate with the individual's mortality. Thus, this work supports the translational scenarios to study personalized evaluation of risks factors and psycho-neuro-immunological mechanisms relevant for better interventions and prognosis in the critically ill young but specially aged patient population

Fearfulness and sex in F2 Roman rats: males display more fear though both sexes share the same fearfulness traits.

The pattern of sex differences in a large sample (about 400 for each sex) of F2-generation rats, derived from inbred Roman high- and low-avoidance strains differing in fearfulness and brain functioning, was investigated. We obtained measures from responses to a battery of novel/threatening tests [open field (OF), plus maze (PM), hole board (HB), activity (A), and acoustic startle reflex (ASR)] as well as learned fear paradigms [classical fear conditioning (CFC) and shuttlebox avoidance conditioning (SAC)]. The results showed that almost all behaviors assessed fit with a pattern of unidirectional sex effects characterized by male rats as being more fearful than females: males defecated more than females in the OF, PM, HB, ASR, and CFC; ambulated less in the OF, PM, A, and SAC; showed more self-grooming in PM and HB; explored the open arms of the PM and the holes of the HB less; displayed enhanced ASR; and showed poorer performance in the SAC task. We applied two factor analyses to each sex showing that, in general, they shared a common three-factor structure: a Learned Fear Factor comprising SAC and CFC responding, a Fear of Heights/Open Spaces Factor with the highest loadings for open arm behavior in the PM, and an Emotional Reactivity Factor, mainly grouping defecations, ambulation, and self-grooming. These results indicate that the essential components of fearful behavior are similar for both sexes in an inbred but genetically heterogeneous population

Melatonin and physical exercise induce synergistic neuroprotection in the 3xTg-AD mouse

Trabajo presentado en la 43rd European Brain and Behaviour Society Meeting (EBBS), celebrada en Sevilla, España, del 9 al 12 de septiembre de 2011Peer Reviewe

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer's disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12-14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.status: publishe

Anxiety in genetically heterogeneous rats: Towards the identification of quantitative genes for behavioural traits

The use of genetically heterogeneous (outbred) rodents is a unique resource for the identification and fine mapping of genetic loci (QTL) influencing biological and behavioural quantitative phenotypes, allowing the identification of quantitative genes. We present the first study of this kind carried out with genetically heterogeneous rats (N/Nih-HS; derivated from an eight-way cross of inbred strains), whose behaviour is assessed in tests evoking unlearned (Black/white box, Elevated "zero" maze) or learned (context conditioned freezing, two-way active avoidance acquisition in the shuttlebox) anxious/fearful responses. The behavioural profile of N/Nih-HS rats is more similar to that of RLA-I (anxious) rats rather than to RHA-I (low anxious) rats. Significant correlations are found among unconditioned anxiety variables and two-way active avoidance acquisition in the shuttlebox; these are partially confirmed by multiple regression analysis. "High avoider" N/Nih-HS rats show lower unlearned anxiety levels than "low avoiders". Results of this behavioural assessment of the N/Nih-HS rats are discussed in terms of their potential usefulness for present and future neurobehavioural and genetic studies of fearfulness and anxiety. © Copyright 2009: de los Editores de Ansiedad y Estrés