| Popis: |
Neuropsychiatric disorders represent a significant source of disability in the United States and globally. Etiologies of these disorders remain elusive, but there is general consensus that complex interactions between genetic risk factors, environmental stressors, and development are involved. A need exists for research aimed at identifying and understanding contributions of particular risk factors, hopefully leading to the development of novel early interventions. Environmental risk factors may be especially amenable to therapeutic remediation and could be the targets of early intervention strategies. Mounting evidence suggests a deficiency in omega-3 fatty acids (n-3) may be a transdiagnostic environmental risk factor for emergent neuropsychopathology. Particularly, deficiency in docosahexaenoic acid (DHA), the primary n-3 in the mammalian brain. However, specific mechanisms mediating the association between DHA deficiency and neuropsychiatric disorders remain unclear. Therefore, the primary aim of this dissertation research was to investigate the effects of n-3 deficiency on neurodevelopmental mechanisms thought to be relevant to the etiology and pathophysiology of neuropsychiatric disorders. Because n-3 fatty acids are essential nutrients, meaning they must be obtained from dietary sources, we utilized a dietary manipulation in rats to study the impact of n-3 deficiency preconception through adulthood. Our initial experiments investigated the effects of perinatal n-3 deficiency on maternal nurturing and neonatal cortical maturation. We found that dams who received an n-3 deficient diet (DEF) exhibited reduced nurturing behaviors compared with dams receiving a control (CON) diet, suggesting perinatal dietary n-3 intake is an important mediator of maternal nurturing behaviors. Furthermore, we demonstrated that maternal n-3 intake is a major determinant of neonatal DHA accrual. In DEF offspring, reduced DHA accrual plus suboptimal maternal care resulted in a molecular profile consistent with abnormal PFC maturation. Second, we utilized a multimodal approach in male offspring to investigate nerodevelopmental effects of n-3 deficiency on neurochemical, structural, and maturation of the corticolimbic network, as corticolimbic circuit dysfunction is associated with many of the symptoms of neuropsychiatric disorders. The primary findings were that DEF rats exhibited a blunted response to amphetamine treatment during adolescence, and as adults displayed enhanced fear acquisition and impaired fear extinction relative to CON rats, a behavioral phenotype indicative of disrupted functional corticolimbic connectivity. In our final experiments, we investigated the impact of developmental n-3 deficiency on physiological and behavioral measures of stress-responsivity in male and female adolescent and adult offspring. Outcomes in the offspring were the main focus of these experiments, but we also investigated potential mechanisms mediating reduced maternal nurturing behavior previously observed in DEF dams. We found that DEF offspring, male and female, consistently had reduced DHA accrual and heightened behavioral responses to stress relative to CON offspring. Collectively this dissertation research provides novel evidence suggesting developmental n-3 deficiency plus reduced maternal nurturing result in dysregulation of brain networks relevant to the etiology and pathophysiology of neuropsychiatric disorders. Furthermore, they lend general support to the view that n-3 insufficiency may represent a modifiable neurodevelopmental risk factor for psychiatric disorders. |
