SummaryWe generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the β β β β -actin locus. Mice that are hemizygous for this transgene express normal levels of β β β β -actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorierestricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity.

The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse strains, did not modulate the CDP. CDP was triggered by depletion of PrP(C) specifically in neurons, but not in Schwann cells, and was suppressed by PrP(C) expression restricted to neurons but not to Schwann cells. CDP was prevented by PrP(C) variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrP(C) lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance.

Sir2 (silent information regulator 2) is a nicotinamide adenine dinucleotide-dependent deacetylase required for longevity due to calorie restriction in yeast and Drosophila. In mammals, calorie restriction induces a complex pattern of physiological and behavioral changes. Here we report that the mammalian Sir2 ortholog, Sirt1, is required for the induction of a phenotype by calorie restriction in mice.

neural development ͉ neural precursor ͉ subventricular zone ͉ dentate gyrus

Neurobehavioural analysis of mouse phenotypes requires the monitoring of mouse behaviour over long periods of time. In this study, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviours. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviours of two standard inbred and two non-standard mouse strains. From these data, we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor-based automated approaches and enable an adaptable, comprehensive, high-throughput, fi ne-grained, automated analysis of mouse behaviour. A utomated quantitative analysis of mouse behaviour will have a signifi cant role in comprehensive phenotypic analyses -both on the small scale of detailed characterization of individual gene mutants and on the large scale of assigning gene function across the entire mouse genome 1 . One key benefi t of automating behavioural analysis arises from inherent limitations of human assessment, namely, cost, time and reproducibility. Although automation in and of itself is not a panacea for neurobehavioural experiments 2 , it allows for addressing an entirely new set of questions about mouse behaviour and to conduct experiments on time scales that are orders of magnitude larger than those traditionally assayed. For example, reported tests of grooming behaviour span time scales of minutes 3,4 , whereas an automated analysis will allow for analysis of this behaviour over hours or even days and weeks.Indeed, the signifi cance of alterations in home-cage behaviour has recently gained attention as an eff ective means of detecting perturbations in neural circuit function -both in the context of disease detection and more generally to measure food consumption and activity parameters 5 -10 . Previous automated systems (see refs 8, 9, 11, 12 and Supplementary Note ) rely mostly on the use of simple detectors such as infrared beams to monitor behaviour. Th ese sensor-based approaches tend to be limited in the complexity of the behaviour that they can measure, even in the case of costly commercial systems using transponder technologies 13 . Although such systems can be used eff ectively to monitor locomotor activity and perform operant conditioning, they cannot be used to study homecage behaviours such as grooming, hanging, jumping and smaller movements (termed ' micromovements ' below). Visual analysis is a potentially powerful complement to these sensor-based approaches for the recognition of such fi ne animal behaviours.Advances in computer vision and machine learning over the last decade have yielded robust computer vision systems for the recognition of objects 14,15 and human actions (see Moeslund et ...

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Automated analysis of mouse behavior will be vital for elucidating the genetic determinants of behavior, for comprehensive analysis of human disease models, and for assessing the efficacy of various therapeutic strategies and their unexpected side effects. We describe a video-based behavior-recognition technology to analyze home-cage behaviors and demonstrate its power by discovering previously unrecognized features of two already extensively characterized mouse models of neurodegenerative disease. The severe motor abnormalities in Huntington's disease mice manifested in our analysis by decreased hanging, jumping, stretching, and rearing. Surprisingly, behaviors such as resting and grooming were also affected. Unexpectedly, mice with infectious prion disease showed profound increases in activity at disease onset: rearing increased 2.5-fold, walking 10-fold and jumping 30-fold. Strikingly, distinct behaviors were altered specifically during day or night hours. We devised a systems approach for multiple-parameter phenotypic characterization and applied it to defining disease onset robustly and at early time points.home cage ͉ neurodegeneration ͉ prion protein ͉ polyQ

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6L9′S* receptors. α6L9′S mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6α4* pentamers, as α6L9′S mice lacking α4 subunits displayed essentially normal behavior. In α6L9′S mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6L9′S mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6L9′S nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6L9′S, but not WT or α4KO/α6L9′S, mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6L9′S presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system.