Animal Models for Human Disorders
Animal models of human disorders are used in research to understand the biological mechanisms that underlie these disorders and to develop new treatments. While it is not always possible to replicate the complexity of human diseases in animals, and especially neurodegenerative and neuropsychiatric disorders, using animals as models allows researchers to test hypotheses and develop treatments in a controlled and ethical manner. They are used to study the causes and effects of diseases, to test potential treatments, and to understand the underlying biology of human disorders. Overall, animal models are a critical tool in medical research and have played an important role in advancing our understanding and treatment of human diseases.
Human APOE 4 knock-in rat for Alzheimer’s Disease
Ekam Imaging uses the human ApoE4 Knock-In Rat developed by HorizonDiscovery®. Apolipoprotein E (ApoE) is a critical lipoprotein in brain lipid metabolism. The 4 allele of ApoE (ApoE4) is a major risk factor for Alzheimer’s disease (AD), with possession of at least one ApoE4 allele in 40–65% of patients with AD and a patient with 2 ApoE4 alleles having up to 20 times the risk of developing AD.
Reference:
Kulkarni, P., S. Grant, T. R. Morrison, X. Cai, S. Iriah, B. S. Kristal, J. Honeycutt, H. Brenhouse, J. C. Hartner, D. Madularu and C. F. Ferris (2020). “Characterizing the human APOE epsilon 4 knock-in transgene in female and male rats with multimodal magnetic resonance imaging.” Brain Res 1747: 147030.
Leaston, J., C. F. Ferris, P. Kulkarni, D. Chandramohan, A. L. van de Ven, J. Qiao, L. Timms, J. Sepulcre, G. El Fakhri, C. Ma, M. D. Normandin and C. Gharagouzloo (2021). “Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities.” PLoS One 16(8): e0256749.
PINK1 transgenic rat for Parkinson’s Disease
Ekam Imaging uses the PINK1 KO rat developed by HorizonDiscovery® in collaboration with the Michael J Fox Foundation. PTEN-induced kinase 1 (PINK1) is a serine/threonine kinase localized to mitochondria and is the second most frequent cause of autosomal recessive PD.
Reference :
Padmakumar, S., P. Kulkarni, C. F. Ferris, B. S. Bleier and M. M. Amiji (2022). “Traumatic brain injury and the development of parkinsonism: Understanding pathophysiology, animal models, and therapeutic targets.” Biomed Pharmacother 149: 112812.
Ferris, C.F., Morrison, T.R., Iriah, S., Malmberg, S., Kulkarni, P., Hartner, J.C. and Trivedi, M., 2018. Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat. Journal of Parkinson’s disease, (Preprint), pp.1-21. https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd171273
Xuezhu Cai, Ju Qiao, Tatiana Knox, Sade Iriah, Praveen Kulkarni, Dan Madularu, Tom Morrison, Barbara Waszczak, Jochen C. Hartner, Craig F. Ferris. In search of early neuroradiological biomarkers for Parkinson’s Disease: Alterations in resting state functional connectivity and gray matter microarchitecture in PINK1 −/− rats, Brain Research, Volume 1706, 2019, Pages 58-67, https://doi.org/10.1016/j.brainres.2018.10.033
Human mutant G2019S LRRK2 transgenic rat for Parkinson’s Disease
Ekam Imaging uses the LRRK2 G2019S Rat (BAC Tg) from Taconic Farms. This transgenic (Tg) rat model overexpresses the human mutant G2019S Lrrk2.The G2019S mutation in leucine-rich repeated kinase 2 (LRRK2), is the most common genetic risk factor for PD. PD associated with LRRK2 mutations is clinically and pathologically indistinguishable from sporadic PD.
Repetitive mild head injury in rat:
Ekam Imaging developed a closed head, momentum exchange model to study repetitive mild injury in fully awake rats. This momentum exchange method was developed to provide biomechanical measures related to impact velocity, head acceleration, change in head velocity, and energy transfer that scale and translate to head injuries in the National Football League
Reference:
Kulkarni Praveen, Morrison Thomas R., Cai Xuezhu, Iriah Sade, Simon Neal, Sabrick Julia, Neuroth Lucas, Ferris Craig F. Neuroradiological Changes Following Single or Repetitive Mild TBI. Frontiers in Systems Neuroscience, Vol 13, 2019, P 34, DOI=10.3389/fnsys.2019.00034 https://www.frontiersin.org/article/10.3389/fnsys.2019.00034
Leaston, J., J. Qiao, I. C. Harding, P. Kulkarni, C. Gharagouzloo, E. Ebong and C. F. Ferris (2021). “Quantitative Imaging of Blood-Brain Barrier Permeability Following Repetitive Mild Head Impacts.” Front Neurol 12: 729464.
Cai, X., I. C. Harding, A. H. Sadaka, B. Colarusso, P. Kulkarni, E. Ebong, J. Qiao, N. R. O’Hare and C. F. Ferris (2021). “Mild repetitive head impacts alter perivascular flow in the midbrain dopaminergic system in awake rats.” Brain Commun 3(4): fcab265.
Development of Type 2 Diabetes in rat
Ekam Imaging uses streptozotocin treatment followed by a diet of high fat/high fructose diet to establish a model for T2DM in rats and uses multimodal imaging to follow changes in brain structure, function and cerebral angiopathy.
Reference:
Lawson, C. M., K. F. G. Rentrup, X. Cai, P. P. Kulkarni and C. F. Ferris (2020). “Using multimodal MRI to investigate alterations in brain structure and function in the BBZDR/Wor rat model of type 2 diabetes.” Animal Model Exp Med 3(4): 285-294.
Qiao, J., C. M. Lawson, K. F. G. Rentrup, P. Kulkarni and C. F. Ferris (2020). “Evaluating blood-brain barrier permeability in a rat model of type 2 diabetes.” J Transl Med 18(1): 256.
Multiple Sclerosis in rat and ferret
Ekam Imaging uses cuprizone model to study the human inflammatory demyelinating disease, multiple sclerosis (MS). With the cuprizone model, two main aspects related to the MS pathology can be investigated: first, mechanisms underlying innate immune cell-driven myelin and axonal degeneration, and second, remyelination of the demyelinated axons.
Drugs of abuse in rat - opioids, cocaine, amphetamines, cannabis
Ekam Imaging in agreement with the DEA and NIDA is using pharmacological MRI in awake rats to fingerprint the effects oxycodone, morphine, fentanyl, cocaine, methamphetamine and vaporized, inhaled cannabis on brain activity and connectivity during acute and chronic exposure.
Reference:
Sadaka AH, Canuel J, Febo M, Johnson CT,Bradshaw HB, Ortiz R, Ciumo F, Kulkarni P,Gitcho MA and Ferris CF (2023) Effects ofinhaled cannabis high in Δ9-THC or CBD onthe aging brain: A translational MRI andbehavioral study.Front. Aging Neurosci. 15:1055433.
Coleman, J. R., D. Madularu, R. J. Ortiz, M. Athanassiou, A. Knudsen, I. Alkislar, X. Cai, P. P. Kulkarni, B. S. Cushing and C. F. Ferris (2022). “Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study.” Addict Biol 27(3): e13169.
Madularu, D., Kulkarni, P., Yee, J.R., Kenkel, W.M., Shams, W.M., Ferris, C.F. and Brake, W.G., 2016. High estrogen and chronic haloperidol lead to greater amphetamine-induced BOLD activation in awake, amphetamine-sensitized female rats. Hormones and behavior, 82, pp.56-63.
Madularu, D., Yee, J.R., Kenkel, W.M., Moore, K.A., Kulkarni, P., Shams, W.M., Ferris, C.F. and Brake, W.G., 2015. Integration of neural networks activated by amphetamine in females with different estrogen levels: A functional imaging study in awake rats. Psychoneuroendocrinology, 56, pp.200-212.
Febo, M., Akbarian, S., Schroeder, F.A. and Ferris, C.F., 2009. Cocaine-induced metabolic activation in cortico-limbic circuitry is increased after exposure to the histone deacetylase inhibitor, sodium butyrate. Neuroscience letters, 465(3), pp.267-271.
Hallucinogens in rat: LSD, psilocybin, mescaline
Ekam Imaging in agreement with the DEA and NIDA is using pharmacological MRI in awake rats to fingerprint the effect of LSD, psilocybin, and mescaline on brain activity and connectivity during acute and chronic exposure.
