Alterations in brain long-chain polyunsaturated fatty acid (LC-PUFA) composition, particularly decreased docosahexaenoic acid (DHA), are implicated as a contributing factor in depression and psychosis. Our preliminary data indicates that pregnancy and lactation can deplete the maternal brain of DHA. Accordingly, these studies are designed to test the HYPOTHESIS that depletion of maternal brain DHA during pregnancy and lactation contributes to postpartum mental illness.
The Specific Aims will use a rat model to: 1. Determine the effects of pregnancy and lactation on levels of maternal brain DHA and other LC-PUFA. Manipulation of dietary fatty acid content will be used to alter maternal brain DHA levels. LC-PUFA will be assessed in four brain regions associated with depression and psychosis, as well as in erythrocytes. These studies will establish a rodent model with which to study the effects of depleted brain DHA levels following pregnancy and lactation on neurochemical parameters associated with depression and psychosis in humans. 2. Determine the effects of reduced brain DHA in the postpartum period on maternal hypothalamic-pituitary-adrenal (HPA) axis activity and regulation. Regulation of the HPA axis will be assessed using a modification of the dexamethasone suppression test. The affinity and density of cerebral cortical corticotrophin releasing factor1 (CRF1) receptors will also be quantified. 3. Determine the effects of reduced brain DHA in the postpartum period on monoamine neurochemistry. The concentrations of serotonin, norepinephrine, and dopamine (and their respective metabolites) will be measured in brain regions relevant to depression or psychosis. The affinity and density of receptors most strongly implicated in depression or psychosis (5-HT1A, 5-TH2A, beta, D2, and D3) will also be quantified. 4. Determine the effects of reduced brain DHA in the postpartum period on expression of brain-derived neurotrophic factor (BDNF) in hippocampus. Hippocampal expression of the BDNF gene, which is decreased in animal models of depression, will be measured by RNAse protectionassay. These experiments will determine whether reproductive activity and the resulting alterations in maternal brain LC-PUFA content are likely to contribute to postpartum mental illness in women. Findings will point to causes of postpartum mental illness and thus the identification of women at risk and the elimination of risk factors. These findings will also suggest novel treatments for such illnesses when they occur.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071599-03
Application #
7091557
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Desmond, Nancy L
Project Start
2004-09-15
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$215,318
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Levant, Beth (2013) N-3 (omega-3) polyunsaturated Fatty acids in the pathophysiology and treatment of depression: pre-clinical evidence. CNS Neurol Disord Drug Targets 12:450-9
Fowler, Stephen C; Zarcone, Troy J; Levant, Beth (2010) Methylphenidate attenuates rats' preference for a novel spatial stimulus introduced into a familiar environment: assessment using a force-plate actometer. J Neurosci Methods 189:36-43
Davis, Paul F; Ozias, Marlies K; Carlson, Susan E et al. (2010) Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status. Nutr Neurosci 13:161-9
Levant, Beth; Ozias, Marlies K; Davis, Paul F et al. (2008) Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: Interactions with reproductive status in female rats. Psychoneuroendocrinology 33:1279-92
Levant, Beth; Ozias, Marlies K; Carlson, Susan E (2007) Diet (n-3) polyunsaturated fatty acid content and parity affect liver and erythrocyte phospholipid fatty acid composition in female rats. J Nutr 137:2425-30
Levant, Beth; Ozias, Marlies K; Carlson, Susan E (2007) Specific brain regions of female rats are differentially depleted of docosahexaenoic acid by reproductive activity and an (n-3) fatty acid-deficient diet. J Nutr 137:130-4
Ozias, Marlies K; Carlson, Susan E; Levant, Beth (2007) Maternal parity and diet (n-3) polyunsaturated fatty acid concentration influence accretion of brain phospholipid docosahexaenoic acid in developing rats. J Nutr 137:125-9
Levant, Beth; Radel, Jeffery D; Carlson, Susan E (2006) Reduced brain DHA content after a single reproductive cycle in female rats fed a diet deficient in N-3 polyunsaturated fatty acids. Biol Psychiatry 60:987-90
Levant, Beth; Ozias, Marlies K; Carlson, Susan E (2006) Diet (n-3) polyunsaturated fatty acid content and parity interact to alter maternal rat brain phospholipid fatty acid composition. J Nutr 136:2236-42