Neuroscience
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30817
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Browsing Neuroscience by Author "Davis, Delaney"
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Item Low-dose methotrexate exposure induced long-term cognitive deficits in mice(2022) Trinh, Oanh; Sumien, Nathalie; Vann, Philip; Davis, Delaney; Luedtke, Robert R.; Basha, Riyaz; Singh, MeharvanPurpose: Chemotherapy-related cognitive impairment (CRCI) remains a mysterious morbidity that threatens the quality of life of up to 70% cancer survivors in the United States. Longitudinal studies of CRCI highlighted deficits in memory, learning, attention, motor, and executive functions for up to 20 years after the completion of chemotherapy paradigm. These deficits, especially if happened during childhood, can negatively impact educational achievement, employment, self-independence, and life expectancy of approximately 500,000 adult survivors currently living in the U.S. Given that acute lymphoblastic leukemia (ALL) is the most common diagnosis of childhood cancers worldwide, the folate-inhibitor methotrexate (MTX) has been at the backbone of ALL-treatment with a substantial risk of neurotoxicity. The purpose of this study was to establish a tumor-free mouse model representative of MTX-induced CRCI in childhood ALL survivors and study the long-term effects of chemotherapy treatment on brain function. We hypothesized that MTX administration at a very young age will induce long-term cognitive impairments. Methods: At post-natal day 15, male and female C57BL6/J pups received intraperitoneal injections of either saline (n=12) or MTX (2 mg/kg; n=12) once a day for 3 days. The pups were weaned at post-natal day 21 and allowed to age. At 8-month-old, animals underwent behavioral tests to assess motor, affective and cognitive functions. Results: MTX administration impaired cognitive flexibility in males and impaired spatial learning and memory in females, indicating potential sex- and test-dependent behavioral outcomes. MTX increased performance in coordinated-running test, and increased swimming speed. Anxiety-like behaviors were not affected by the treatment. Conclusions: These preliminary results suggested that low dose MTX-treatment induced sex-dependent cognitive deficits while affective and motor functions were not negatively affected. This study will be repeated, and behaviors will be assessed at other time points to establish complete neurobehavioral profiles of mice affected by MTX chemotherapy.Item The effects of previous exposure to chronic methamphetamine on drug-seeking behavior and neurodegeneration in male and female mice(2022) Davis, Delaney; Metzger, Daniel; Vann, Philip; Wong, Jessica; Shetty, Ritu; Forster, Michael; Sumien, NathaliePurpose: Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade, with amphetamine compounds becoming the second most common illicit drug used in college students. Although amphetamine stimulants have proven to be safe and efficacious in children and adults with Attention Deficit and Hyperactivity Disorder (ADHD) when used as prescribed, these drugs can have significant adverse side effects such as an increased potential of recreational abuse liability, dependence, and neurotoxicity. There are known sex differences in drug abuse, in which women have lower rates of illicit drug use, but use more of the drug, reach dependence faster and have more adverse effects. We hypothesize that females may be more vulnerable to the reinforcing effects of METH as well as METH-induced neurotoxicity and dopaminergic dysregulation. Our study investigated the effects of early chronic exposure to the prototypical stimulant, methamphetamine (METH), at a dose designed to emulate human therapeutic dosing, on abuse potential and biochemical markers of dopaminergic function and neurodegeneration in male and female mice. Methods: Groups of 4-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 4 weeks. METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the reinforcing effects of previous METH exposure. Mice were randomly assigned to either: Experiment I (short-term) in which male and female mice underwent CPP 13 days after injection cessation or Experiment II (long-term) in which female mice underwent CPP 5 months after injection cessation. Following behavioral testing, the animals were euthanized and striatum and midbrain were collected for biochemical testing of dopaminergic function and neurodegeneration. Results: In Experiment I, chronic METH exposure induced drug preference for subsequent doses of METH especially in males, and downregulated dopaminergic markers in males and induced apoptosis in females. In Experiment II, when CPP was performed 5 months after injection cessation, females with prior exposure to METH did not exhibit drug preference to subsequent doses of METH and there were no effects on markers of neurodegeneration or dopaminergic function. Conclusion: Previous exposure to METH induced a heightened sensitivity to subsequent doses of METH especially in males. While the effect in females was smaller, it disappeared in the long-term suggesting that this heightened sensitivity does not last over time. The increase in sensitivity was supported by alterations in the dopaminergic system in males. These outcomes suggest sex differences in response to prior METH exposure, and that these effects may not be long-lasting.