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3004 Effects of Early Life Stress on Adult Behavioral and Neural Outcomes in Rats
- Alexandra Moussa-Tooks, Ken Mackie, John Green, Lisa Bartolomeo, Alex Gimeno, Eric Larson, Heather Bradshaw, Emma Leishman, Brian O’Donnell, William Hetrick
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 9-10
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OBJECTIVES/SPECIFIC AIMS: Early life stress is known to greatly impact neurodevelopment during critical periods, conferring risk for various psychopathologies, including the onset and exacerbation of schizophrenia and anxiety disorders. The endocannabinoid system is highly integrated into the stress response and may be one means by which early life stress produces such deleterious effects. Using a naturalistic, ecologically valid animal model, this study explored interactions between the stress response and endocannabinoid systems within the cerebellum, a region dense with the CB1 endocannabinoid receptors and shown to be susceptible to stress. METHODS/STUDY POPULATION: This study explored behavioral and neural impacts of early life stress in Long-Evans rats reared with or without limited access to bedding material during postnatal day (PND) 2-9. Corticosterone (CORT) levels were measured at PND8 and 70. During PND50-70, rats were assessed on Novel Object Recognition to test memory, Rotarod to evaluate cerebellar integrity, Elevated Plus Maze to assay anxiety, Social Preference, and Eyeblink Conditioning, a cerebellar-dependent and endocannabinoid-mediated task. Lipid analysis was performed on PND70 tissue samples of cerebellar interpositus (IP) nucleus via high-performance liquid chromatography and tandem mass spectrometry. RESULTS/ANTICIPATED RESULTS: Both male and female rats experiencing early life stress exhibited significantly impaired recognition memory (N = 16-20/group). Female rats having undergone stress exhibited decreased social preference compared to normally reared females (N = 11/group). Stressed males showed facilitated eyblink conditioning compared to normally reared males (N = 7-9/group). There were no group differences in rotarod or elevated plus maze performance or CORT levels at PND8 or 70 across rearing groups. At PND70, male rats experiencing early life stress exhibited a significant decrease in 2-arachidonoyl glycerol (2-AG) and arachidonic acid levels in the IP nucleus compared to normally reared males (N = 8-9/group). Compared to normally reared females, those experiencing early life stress exhibited a significant increase in prostaglandin E2 levels in the IP nucleus (N = 6-7/group). DISCUSSION/SIGNIFICANCE OF IMPACT: Early life stress, induced by limited bedding, resulted in sex-specific behavioral and lipid impairments. Results suggest that stress causes long-term alterations in endocannabinoid dynamics in males in the cerebellar IP nucleus and sex-related lipids in female cerebellum. These changes may contribute to observed long-term behavioral aberrations. Moreover, findings suggest these behavioral changes may be the result of negative-feedback dysfunction (as evidenced by decreased endocannabinoids in males) or increased neural inflammation or proliferation (as evidenced by increased prostaglandins in females). Future analysis will quantify mRNA and protein for cannabinoid receptors to better characterize aberrations to this system. Moreover, other neural regions dense with cannabinoid receptors (i.e., PFC, hippocampus) will be investigated. This work provides a basis for understanding stress impacts on the development of cognitive deficits observed in psychotic and anxiety disorders. Specifically, facilitation of eyblink conditioning complements research in humans with anxiety disorders. Broadly, understanding stress-related endocannabinoid dysregulation may provide insights into risks for, and the development of, psychopathology and uncover novel therapeutic targets with high translational power.
Fit for purpose – a regional case study in primary care research partnerships
- Amanda Howe, Heather Leishman, Helen MacDonald
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- Journal:
- Primary Health Care Research & Development / Volume 10 / Issue 1 / January 2009
- Published online by Cambridge University Press:
- 01 January 2009, pp. 7-13
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Aims
To describe the context, mechanisms and outputs of a regional primary care partnership for research facilitation over a three-year period, and evaluate factors which were likely to be worth replicating in the new UK Clinical Research Network (UKCRN) structures.
BackgroundThe revision of NHS research and development structures into the UKCRN has presented organizational challenges to pre-existing partnerships. This raises questions of whether pre-existing arrangements had already delivered effective research facilitation in NHS settings, and makes evaluation of successful practice a crucial part of organizational learning for the current management of research delivery in the UK.
MethodsA mixed methods case study in one R&D consortium (Norfolk and Waveney, England). Using a model of realistic evaluation, we analysed context, mechanisms, working practices, and outcomes for research delivery in the primary care context – covering key priorities of research governance and ethics, hosting and recruiting to studies, and training and support approaches.
FindingsFrom January 2005 to December 2007, 35 general practices opted into a host practice research network, each hosting an average of 10 studies over that period, with 278 projects being active overall. By the last year, an extension of network activity to all practices in Norfolk, Great Yarmouth and Waveney had led to 96% of all practices delivering at least one study, and a turnaround, from application to commencement of approved studies, of 28 days for 74% of studies. This level of activity can act as a baseline for future UKPCRN activities, and the factors associated with it may be helpful for others seeking to provide an effective networking structure. The larger structures of the new UKCRN regional networks will be able to draw on extensive good practice in some areas, and should be sure to preserve these, as they may already be fulfilling the important goals for which UKCRN was created.