Using a rodent model, our previous studies have established that impulsivity is a major behavioral consequence of prenatal protein malnutrition. In humans, evidence is mounting that impulsivity plays a central role in many psychopathological conditions, including attention deficit hyperactivity disorder (ADHD), antisocial and other personality disorders, and also in drug addiction. Importantly, impulsivity may be a common factor in those mental health disorders associated with early childhood malnutrition. In our 35 year follow-up study in Barbados of individuals with a history of malnutrition, we have documented a four-fold increase in the prevalence of ADHD. We are currently assessing in the adults, now 33-38 years of age, mental health outcomes, including attention deficits and impulsivity, associated with childhood malnutrition. The proposed animal research will validate our rat model of prenatal malnutrition and will make use of an innovative multidisciplinary approach to study the neural substrates of impulsivity and inattention. The following aims are based on the overall hypothesis that significant alterations in dopaminergic (DA), noradrenergic (NE) and serotonergic (5-HT) modulation of neurons from the prefrontal cortex (RFC) underlie increased impulsivity and decreased attention. Two highly integrated Specific Aims will test this hypothesis.
In Aim 1, adult rats with and without prenatal protein malnutrition will be assessed with regard to performance on: a) the 5-choice serial reaction time test of impulsivity, response accuracy and perseveration;b) the delayed reward operant test of impulsivity, and;c) the attentional set-shifting test of attention.
In Aim 2 the neural substrates of relevant behaviors measured in Aim 1 will be further examined using in vivo studies in the same animals. All studies of Aim 2 will be performed on behaviorally tested prenatally protein malnourished and well-nourished subjects, and include: a) 2-deoxyglucose examination of metabolic activity in the PFC and other regions of brain and b) in vivo microdialysis assessment of DA, NE and 5-HT release in the PFC. Since prenatal malnutrition is a major public health problem in developing countries and also in Western populations, the validation of our model is likely to lead to research with widespread clinical relevance. As indicated, the proposed project parallels our ongoing human study in Barbados, affording a tremendous and unique advantage to maximize the impact of our translational research.
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