Are Underlying Assumptions of Current Animal Models of Human Stroke Correct: from STAIRs to High Hurdles?

Background Stroke is a leading cause of disability worldwide. Focused training of the impaired limb has been shown to improve its functional outcome in animal models. However, most human stroke survivors exhibit persistent motor deficits, likely due to differences in rehabilitation intensity between experimental (animal) and clinical (human) settings. Objective The current study investigated the effect of training intensity on behavioral outcome in a mouse model of stroke. Methods Mice were trained preoperatively on a skilled reaching task. After training, mice received a unilateral photothrombotic stroke. Postoperatively, animals received either daily rehabilitative training (traditional intensity), intermittent rehabilitative training (every other day), or no rehabilitative training (control). Assessment of the impaired limb occurred after 14 training sessions (14 days for the Traditional group; 28 days for the Intermittent group). Results Assessment of the impaired limb illustrated that traditional, daily training resulted in significantly better performance than no training, while intermittent training offered moderate performance gains. Mice receiving intermittent training performed significantly better than control mice but did not exhibit reaching performance as strong as that of animals trained daily. Conclusions The intensity of rehabilitation is important for optimal recovery. Although intermediate intensity offers some benefit, it is not intensive enough to mimic the performance gains traditionally observed in animal models. These results suggest that intensive training, which is often unavailable for human stroke survivors, is necessary to achieve an optimal functional outcome. The lower bounds of training intensity for functional benefit still need to be determined.

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Reprint: Good Laboratory Practice: Preventing Introduction of Bias at the Bench

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.101 ◽

2008 ◽

Vol 29 (2) ◽

pp. 221-223 ◽

Cited By ~ 44

Author(s):

Malcolm R Macleod ◽

Marc Fisher ◽

Victoria O'Collins ◽

Emily S Sena ◽

Ulrich Dirnagl ◽

...

Keyword(s):

Cerebral Ischemia ◽

Animal Models ◽

Animal Experiments ◽

Research Community ◽

Systematic Bias ◽

Laboratory Practice ◽

Improve Outcome ◽

Human Stroke ◽

Good Laboratory ◽

Neuroprotective Efficacy

As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.

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Reductionist thinking and animal models in neuropsychiatric research

Behavioral and Brain Sciences ◽

10.1017/s0140525x18001231 ◽

2019 ◽

Vol 42 ◽

Cited By ~ 1

Author(s):

Nicole M. Baran

Keyword(s):

Animal Models ◽

Mental Disorders ◽

Environmental Factors ◽

Neuropsychiatric Disorders ◽

Model Organisms ◽

Developmental Genetic ◽

Term Study ◽

Genetic And Environmental Factors ◽

Mechanisms Of Plasticity

AbstractReductionist thinking in neuroscience is manifest in the widespread use of animal models of neuropsychiatric disorders. Broader investigations of diverse behaviors in non-model organisms and longer-term study of the mechanisms of plasticity will yield fundamental insights into the neurobiological, developmental, genetic, and environmental factors contributing to the “massively multifactorial system networks” which go awry in mental disorders.

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Inflammational Animal Models for Schizophrenia

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000216 ◽

2015 ◽

Vol 223 (3) ◽

pp. 157-164 ◽

Cited By ~ 1

Author(s):

Georg Juckel

Keyword(s):

Animal Model ◽

Animal Models ◽

Immune Activation ◽

Microglial Activation ◽

Treatment Options ◽

Early Adulthood ◽

Brain Regions ◽

Synaptic Connections ◽

Preventive Interventions ◽

Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

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