Recent work from our laboratory has demonstrated that choline supplementation given to rats during both pre- and postnatal development produces long-term modification of biochemical and neuroanatomical markers of basal forebrain cholinergic function and long-term facilitation of visuospatial memory as indexed by choice accuracy on a radial-arm maze, and appears to protect against age-related decline in memory function. Choline supplementation to male rats produces these organizational changes in memory function only when given during embryonic days (ED) 12-17 or postnatal days (PD) 16-30, but not during PD 1-15 when several potentially important developmental events are occurring in the rat. The major goal of this proposal are 1.) to evaluate possible explanations of these multiple sensitive periods of choline effectiveness and 2.) to examine the ontogeny of the behavioral effects of choline supplementation/deficiency. Three hypotheses will be evaluated: 1.) The Sexual Differentiation Hypothesis predicts that exposure to gonadal steroid hormones during PD 15-30 is required for choline to exert its effects on PD 15-30. Preliminary data has shown that neonatal castration significantly decreases the effectiveness of perinatal choline supplementation on visuospatial memory. Studies are planned to determine the active hormone (testosterone or its metabolite estradiol) for the enhancement of the effect of choline supplementation. 2) The Choline Saturation Hypothesis suggests that pups may be receiving exceptionally high levels of choline from milk during PD 1-15, thus the pups' system may already be saturated with choline and supplementation would have no added effect. This hypothesis will be tested by raising pups with dams that are known to have lower milk choline levels. 3.) The Betaine as Active Agent Hypothesis suggests that choline may be exerting its behavioral effects on memory through its conversion to betaine, a compound that is an important methyl donor for methionine and folate metabolism. Since the conversion of choline to betaine can occur in utero and only develops slowly after birth, little betaine is made from choline during the first postnatal week. To test this hypothesis rats will be treated with betaine at various periods of development of rats ability to use proximal and distal cues to navigate will also be examined in betaine-,and choline-supplemented and choline-deficient rats. These data should provide us with information about the development, hormonal modulation, and natural nutritional control of choline's organizational facilitation of visuospatial memory.
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