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Animal models of CNS diseases |
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Alzheimer's disease (AD): |
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Genetically modeling in the mouse: Expression of a human mutant gene or a BAC |
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fragment that is associated with a familial type of AD |
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Pharmacologically/neurosurgically modeling in the rat: Ventricular infusion of |
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β-amyloid with an Osmotic mini pump |
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Fig. 1. An AD model in the mouse: A. Wild-type mice. B. AD mice without β-amyloid deposition. C. AD mice with β-amyloid deposition. D and E. Double staining of β-amyloid deposition. F. I. and L. Wild-type mice. G and H. Neurofibrillary tangle-like structure in AD mice. J and K. tau pathology in AD mice. M. Neuronal degeneration and N. tau pathology in AD model mice. |
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Age-dependent neurodegeneration: |
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Conditional double knockout PS1/PS2 in the mouse: which shows age-dependent neuronal loss and many other AD-like pathologies such as tau |
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hyperphosphorylation, neurofibrillary tangle-like structure, and dementia |
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Parkinson’s Disease (PD): |
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Genetic model in the mouse: Expression of a mutant gene that is associated with a familial autosomal-dominant mutation, or knockout of a gene that is associated with a familial autosomal-recessive mutation for PD |
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Pharmacological/neurosurgical model in the rat: Unilateral intra-striatal injection of 6-OHDA to lesion nigro-striatal dopamine neurons |
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Pharmacological/neurosurgical model in the monkey: Systemic administration of MTPT to lesion dopamine neurons (under development) |
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Fig. 2. PD modeling. A. Neurosurgery for microinjection of 6-OHDA in the rat. B. Forelimb deficits of contralateral forelimb at 6 weeks after surgery C. Quantitative analysis of rotation number after an Apomorphine challenge. D. Quantitative analysis of motor function with a rotarod test. Data are expressed as mean ± SD. |
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Restraint stress in the mouse |
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Tail suspension in the mouse |
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Anxiety: |
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Genetic model in the mouse: Overexpression of the cholecystokinin receptor-2 (CCKR-2) in the forebrain |
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Various stress paradigms: early-life stress, chronic stress, or acute stress |
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PTSD model in the mouse: combination of genetic manipulation and environmental stress |
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Schizophrenia/bipolar disorder: |
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PCP model in the mouse and rat |
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Sleep-deprivation in the rat |
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Drug addiction: |
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Behavioral sensitization |
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Drug of abuse-induced conditioned place preference (CPP) |
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Reinstatement of extinguished CPP |
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Amnesic model: |
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Various compounds such as ketamine-, scopolamine-induced amnesia in the rat and mouse |
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Mental retardation model |
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BDNF knockdown in the mouse |
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Middle cerebral artery occlusion (MCAO) in the rat |
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Forebrain ischemia model in the gerbil |
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Traumatic brain injury model |
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Weight-dropping in the mouse |
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Huntington’s disease model |
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Genetic model in the mouse: Expression of a mutant Huntington gene |
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Pharmacological/neurosurgical model in the rat: Striatal microinjection of quinolinic acid or 3-NY in the rat |
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Nociceptive pain produced by peripheral injection of formalin or capsaicin |
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Inflammatory pain induced by carrageenan |
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Neuropathic pain induced by sciatic nerve ligation, spinal nerve ligation, or streptozotocin-induced diabetic neuropathy |
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Postoperative pain induced by a plantar incision |
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Animal models for studies of the blood-brain barrier (BBB) |
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Experimental approaches |
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Learning and memory: Morris water |
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maze (spatial learning and memory, |
working memory, reference memory, |
reversal learning, hippocampus- |
dependent memory); Barnes maze |
(spatial learning and contextual |
conditioning (hippocampus-dependent), |
cued conditioning (hippocampus- |
independent), long-term memory, short- |
term memory, amygdala-dependent |
memory, fear response. |
Fig. 3. Morris water maze |
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Motor function: Rotarod test, open-field test, walking-beam test, treadmill test |
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(under development). |
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Anxiety-like behavior: Elevated-plus maze, fear-conditioning test, open-field |
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behavior, startle response, and social interaction. |
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Depression-like behavior: Novelty-induced hypophagia, tail suspension test, |
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forced swim test, open-field behavior, social interaction, and learned |
helplessness. |
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Schizophrenia/bipolar-like behavior: Pre-pulse inhibition (PPI; under |
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development), working memory, locomotion/motor activity, social interaction, |
aggressive/mania-like behavior, forced swim test, and nesting behavior. |
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Drug addictive behavior: Drug-seeking behavior (self-administration; under |
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development), behavioral sensitization, conditioned place preference (CPP), and |
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CPP extinction. |
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Pain-related behavior: hot-plate, tail flick (infrared heat/pressure). |
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Homecage behavior and environmental enrichment. |
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Pharmacological/molecular/biochemical assay |
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Distributional and quantitative analysis of gene expression at the mRNA and |
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protein levels: real-time RT-PCR, microarray, in situ hybridization, Western blot, |
immunostaining, and ELISA. |
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in vivo and in vitro isotope-labeled ligand binding/incorporation assay: receptor |
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binding assay, autoradiography |
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Brain regional drug delivery (stereotaxic microinjection) and chronic brain |
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regional drug delivery (Osmotic mini-pump micro-infusion) |
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Spatial and temporal epigenetic analysis: histone modification, DNA methylation, |
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and genome-wide DNA methylation profile. |
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Microdialysis (under development) |
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Histological/morphological studies |
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Gross brain morphometry |
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Colorimetric staining: Nissl staining |
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(neuron), LFB staining (glial myelin), Golgi staining (dendritic spine), Schiff staining, |
HE staining etc. |
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Immunostaining, confocal microscope- |
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Fig. 3. Immunostaining. A and B. NeuN staining shows neuronal loss in a knockout mouse (B), compared to wild-type mouse (A). C and D. GFAP staining in the same mice. |
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(collaboration with local institutes) |
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Adult neurogenesis; |
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Dendritic spine/synapse morphology |
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Subcellular fraction |
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