Identifying reliable traits across laboratory mouse exploration arenas: A meta-analysis

This study is a meta-analysis of 367 mice from a collection of behaviour neuroscience and behaviour genetic studies run in the same lab in Zurich, Switzerland. We employed correlation-based statistics to confirm and quantify consistencies in behaviour across the testing environments. All 367 mice ran exactly the same behavioural arenas: the light/dark box, the null maze, the open field arena, an emergence task and finally an object exploration task. We analysed consistency of three movement types across those arenas (resting, scanning, progressing), and their relative preference for three zones of the arenas (home, transition, exploration). Results were that 5/6 measures showed strong individual-differences consistency across the tests. Mean inter-arena correlations for these five measures ranged from +.12 to +.53. Unrotated principal component factor analysis (UPCFA) and Cronbach’s alpha measures showed these traits to be reliable and substantial (32-63% of variance across the five arenas). UPCFA loadings then indicate which tasks give the best information about these cross-task traits. One measure (that of time spent in “intermediate” zones) was not reliable across arenas. Conclusions centre on the use of individual differences research and behavioural batteries to revise understandings of what measures in one task predict for behaviour in others. Developing better behaviour measures also makes sound scientific and ethical sense

A Phytoestrogen-Rich Diet Increases Energy Expenditure and Decreases Adiposity in Mice

BACKGROUND: Obesity is an increasingly prevalent health problem, and natural effective therapeutic approaches are required to prevent its occurrence. Phytoestrogens are plant-derived compounds with estrogenic activities; they can bind to both estrogen receptors alpha and beta and mimic the action of estrogens on target organs. OBJECTIVES: The purpose of this study was to examine the influence of soy-derived phytoestrogens on energy balance and metabolism. METHODS: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet from conception to adulthood. We measured circulating serum isoflavone levels using reverse-phase solid-phase extraction for subsequent liquid chromatography electrospray tandem mass spectrometry analysis. Adult animals were analyzed for body composition by dual-energy X-ray absorptiometry, locomotor activity by running-wheel experiments, respiratory exchange rate by indirect calorimetry, and food intake using metabolic cages. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine the expression of hypothalamic neuropeptide genes. RESULTS: We found that adult mice fed a soy-rich diet had reduced body weight, adiposity, and resistance to cold. This lean phenotype was associated with an increase in lipid oxidation due to a preferential use of lipids as fuel source and an increase in locomotor activity. The modulation of energy balance was associated with a central effect of phytoestrogens on the expression of hypothalamic neuropeptides, including agouti-related protein. CONCLUSION: The data suggest that dietary soy could have beneficial effects on obesity, but they also emphasize the importance of monitoring the phytoestrogen content of diets as a parameter of variability in animal experiments

The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotraum

Modeling Alzheimer’s disease related phenotypes in the Ts65Dn mouse: impact of age on Aβ, Tau, pTau, NfL, and behavior

IntroductionPeople with DS are highly predisposed to Alzheimer’s disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS.MethodsWe undertook studies to characterize age-related changes for AD-relevant markers linked to Aβ, Tau, and phospho-Tau, axonal structure, inflammation, and behavior.ResultsWe found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aβ40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory.DiscussionThese data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes

Emotions are building up in the field of extracellular proteolysis

Activity-dependent remodeling of neural connections might require localized extracellular proteolysis. The tissue-type plasminogen activator (tPA)-plasmin proteolytic system is expressed in different regions of the central nervous system, in the context of a variety of physiological and pathological processes. Accumulating evidence regarding the expression and role of tPA and its inhibitors suggests that extracellular proteolysis is a key player in the biology of memory, emotions and neurodegeneration

Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice

Adult cortical neurons can produce tissue-type plasminogen activator (tPA), an extracellular protease that plays a critical role in fibrinolysis and tissue remodelling processes. There is growing evidence that extracellular proteolysis may be involved in synaptic plasticity, axonal remodelling and neurotoxicity in the adult central nervous system. Here we show that transgenic mice overexpressing tPA in post-natal neurons have increased and prolonged hippocampal long-term potentiation (LTP), and improved performance in spatial orientation learning tasks. Extracellular proteolysis catalysed by tPA may facilitate synaptic micro-remodelling, and thereby play a role in activity-dependent neuronal plasticity and learning

Neuronal overexpression of tissue-type plasminogen activator does not enhance sensory axon regeneration or locomotor recovery following dorsal hemisection of adult mouse thoracic spinal cord

CNS axons rarely regenerate spontaneously back to original targets following spinal cord injury (SCI). Neuronal expression of the serine protease tissue-type plasminogen activator (tPA) enhances axon growth in vitro and following PNS injury. Here we test the hypothesis that neuronal overexpression of tPA in adult transgenic mice promotes CNS axon regeneration and functional recovery following SCI. Adult wild-type and transgenic mouse spinal cords were subjected to dorsal hemisection at the level of the T10/T11 vertebrae. PCR confirmed incorporation of the transgene. Immunolabeling revealed overexpression of tPA in transgenic mice in neurons, including large-diameter neurons in lumbar dorsal root ganglia that contribute axons to the dorsal columns. Immunolabeling also revealed the presence of tPA protein within axons juxtaposing the injury site in transgenics but not wild types. In situ zymography revealed abundant enzymatic activity of tPA in gray matter of thoracic spinal cords of transgenics but not wild types. Rotorod locomotor testing revealed no differences between groups in locomotor function up to 21 days postinjury. Transganglionic tracer was injected into the crushed right sciatic nerve 28 days postinjury, and mice were killed 3 days later. There was no evidence for regrowth of ascending dorsal column sensory axons through or beyond the injury site. In conclusion, despite neuronal overexpression of tPA in injured neurons of transgenics, neither locomotor recovery nor regeneration of ascending sensory axons was observed following thoracic dorsal hemisection

Low intensity exercise attenuates disease progression and stimulates cell proliferation in the spinal cord of a mouse model with progressive motor neuronopathy

Physical exercise has been shown to stimulate neurogenesis, increase resistance to brain trauma and disease, improve learning and increase levels of growth factors. We show that low intensity exercise has profound effects on the phenotype of a mouse mutant with progressive motor neuronopathy. These animals normally die at 47 days of age due to motoneuron loss and muscle atrophy. When mice undergo low intensity exercise, their lifespan increased by 74%, they exhibited a decreased loss of motoneurons, improved muscle integrity and a twofold increase in proliferating cells in the spinal cord. The molecular mechanism of neuroprotection may be related to insulin-like-growth factor 1 (IGF-1) since injections of antibodies to IGF-1 abrogated the effects of exercise on the increased life-span. Thus IGF-1 may act as a possible "exercise-induced" neuroprotective factor

The serpin Spn5 is essential for wing expansion in Drosophila melanogaster

Serpins, a superfamily of protease inhibitors, control proteolytic cascades in many physiological processes. Genomic studies have revealed the presence of a high number of serpin-encoding genes in Drosophila melanogaster, but their functions remain largely unknown. In a biochemical screen designed to detect protease inhibitors that may be implicated in early Drosophila development, we identified in embryos a ligand that forms a 67 kDa SDS-stable complex with the broad spectrum protease trypsin. Characterization of this ligand revealed it to be the recently described serpin, Spn5. Expression analysis by in situ and Northern blot hybridization indicated maternal transmission of the transcript as well as zygotic expression in many larval, pupal and adult tissues. Targeted repression by RNA interference did not alter early embryogenesis but resulted in a complete defect in the unfolding and expansion of the wings of freshly eclosed mutant flies, without other detectable effects on development