Improving the Utility and Translation of Animal Models for Nervous System Disorders Workshop Summary (2013) / Chapter Skim
Currently Skimming:
5 Perspectives on Corresponding Animal and Clinical Endpoints
5 Perspectives on Corresponding Animal and Clinical Endpoints
Pages 45-54
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From page 45... ...
ROLE OF MATCHING ENDPOINTS Invited panelists used specific case examples to discuss the role of corresponding endpoints, and the impact of experimental parameters on corresponding endpoints and bidirectional translation. Neal Swerdlow described prepulse inhibition as an example of the ability to study the same endpoint in both an animal model and humans.
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Prepulse inhibition is defined as the automatic inhibition of the startle reflex, the contraction of the facial and skeletal musculature in response to an intense, abrupt stimulus, when the startling stimulus is preceded by a weak lead stimulus or prepulse. A primary measure of the startle reflex is movement of the orbicularis oculi muscle, or eye blink, often determined using surface electrodes attached to the muscles around the eye.
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Predictive Models Some of the practical uses of prepulse inhibition testing relate to its predictive validity of antipsychotic drug effects. Prepulse inhibition is disrupted by dopamine agonists such as apomorphine.
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A number of developmental animal models will produce a deficit in prepulse inhibition, such as the neonatal ventral hippocampal lesion model. As one example of construct validity of these models, these deficits can be corrected in a dose-dependent manner with clozapine.
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EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS The EAE animal model was first described in 1933 by Rivers and colleagues while they were seeking to understand how some viral infections lead to neurologic reactions. Nearly 80 years later, EAE remains "one of the most enduring models of human disease," said Larry Steinman, professor in the departments of Neurological Sciences and Pediatrics at Stanford University (see Steinman, 2003)
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Clinical Trials The bigger issue, Steinman suggested, is not animal models, but how to facilitate faster, less expensive trials in humans. Animal models will
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The hippocampal circuit most affected in terms of integrity of synaptic connections is the entorhinal cortex layer 2, which sends input to the dentate gyrus and CA3. Electrophysiological recording experiments showed that CA3 pyramidal neurons have elevated firing rates in this animal model.
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. 2 Autoassociative neural networks are feedforward nets trained to produce an approximation of the identity mapping between network inputs and outputs using backpropagation or similar learning procedures (Kramer, 1992)
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Analysis of ADNI data on cortical thickness of the entorhinal cortex shows that during mild cognitive impairment there is ongoing thinning of the entorhinal cortex that might represent the neurodegeneration that has been seen in autopsy. In conclusion, Gallagher noted that this is just one example of how neuroimaging tools have allowed us to understand that the functional components of these circuits are very similar in their core functions across animal models and humans.
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