%0 PDF %T Influence of Chronic Creatine Supplementation on Neurogenesis, Synaptic Plasticity and Affective Behavior: Implications for Sex-Specific Differences. %A Allen, Patricia. %8 2017-04-24 %R http://localhost/files/7m01bz08b %X Abstract: Rationale: Impairments in creatine metabolism are strongly implicated in the pathophysiology of psychiatric illness. Growing evidence supports the potential for creatine, an antioxidant, neuromodulator and key regulator of energy metabolism, to improve depressive symptoms in humans and animals, especially in females. Objective: The aim of this dissertation was to examine two highly plausible neurobiological mechanisms that may underlie observed antidepressant effects of creatine. Specifically, it was hypothesized that creatine would oppose the negative effects of stress on neurotrophic- and neurogenesis-related activity in hippocampus (HPC) and prefrontal cortex (PFC), akin to conventional antidepressant drugs, and that these positive effects would depend upon the presence of sex steroids. Materials and Methods: Four experiments examined whether creatine supplementation influences gene expression linked to neural growth and survival, particularly brain-derived neurotrophic factor (BDNF), Tyrosine kinase B (TrkB), doublecortin (DCX), calretinin (CALR), and calbindin (CALB) in HPC and PFC following the forced swim test (FST). In the first two experiments, male (Exp. 1) and female (Exp. 2) rats were maintained on chow alone or chow blended with 4% w/w creatine monohydrate for five weeks before random assignment to acute swim stress or no stress conditions. In the last two experiments, male rats (Exp. 3) underwent castration or sham surgery and were assigned to receive either an empty or a testosterone-filled (T) Silastic implant (10-mm releasing surface), and female rats (Exp. 4) were ovariectomized (OVX) or underwent sham surgery and were assigned to receive single weekly injections of estradiol benzoate (EB, 2.5 µg), progesterone (P, 250 µg), EB + P, or sesame oil vehicle. After recovery, rats received either chow alone or chow blended with 2% or 4% w/w creatine monohydrate for five weeks before FST, open field and wire suspension tests, equating to a total of seven weeks of creatine supplementation. For all experiments, plasma and brain tissue were analyzed for creatine levels and mRNA expression using calorimetric and molecular techniques. Results: Creatine was highly bioavailable in the HPC of both males and females, and PFC levels of creatine were consistently higher in females. Contrary to hypothesis, acute swim stress significantly upregulated HPC BDNF, TrkB, DCX, CALR, and CALB mRNA in males (Exp. 1) and HPC TrkB, and CALB mRNA and PFC TrkB in females (Exp. 2). Moreover, creatine downregulated BDNF mRNA in females and marginally reduced HPC TrkB in males and females following acute swim stress (Exp. 1-2). Creatine's molecular effects were more prevalent after 7 weeks (Exp. 3-4), whereby HPC BDNF, TrkB, DCX, CALR, and CALB mRNA were downregulated in sham-operated males fed 4% creatine, and HPC BDNF, DCX, and CALB mRNA were downregulated in sham-operated females given 4% creatine compared to nonsupplemented controls. In contrast, 4% creatine combined with castration + T or OVX + EB + P was associated with a protective effect on HPC BDNF, DCX, and CALR mRNA in males and HPC BDNF and CALB mRNA in females. Corresponding behavioral changes showed that creatine-fed castrates + T displayed marginally significant antidepressant-like trends and creatine-fed OVX + EB + P rats showed significantly greater antidepressant- and anxiolytic-like behaviors. Conclusions: Creatine supplementation produced differential effects on neurobiology and behavior in "healthy" versus "metabolically challenged" rats in a sex-, stress-, and time-dependent manner. Dietary creatine combined with hormone replacement had a neuroprotective effect in castrated and OVX rats. In contrast, creatine downregulated neurotrophic- and neurogenesis-related gene expression in HPC of otherwise healthy, intact rats after 5 and 7 weeks of supplementation, suggesting a U-shape curve for creatine's effects. Nevertheless, it is unclear if downregulated gene expression here is necessarily negative as creatine influences both excitatory glutamate and inhibitory GABA-A receptor activity, which have opposing effects on neurotrophin signaling. However, tissue oversaturation with creatine may cause compensatory changes in energy metabolism that downregulate ATP. All together, these data are consistent with the prediction that sex hormones are necessary, but not sufficient, for creatine's antidepressant properties, and stress signals mediate creatine's molecular effects. Careful dose ranging and efficacy studies in humans and rodents are required to clarify the effects of creatine on neurobiology and behavior and to verify the safety and usefulness of creatine as an adjunctive treatment for depressive disorders.; Thesis (Ph.D.)--Tufts University, 2013.; Submitted to the Dept. of Psychology.; Advisor: Robin Kanarek.; Committee: Kristen D'Anci, Joseph DeBold, Perry Renshaw, Maribel Rios, and Lisa Shin.; Keywords: Psychobiology, Nutrition, and Neurosciences. %[ 2022-10-11 %9 Text %~ Tufts Digital Library %W Institution