Omega-3 fatty acids upregulate adult neurogenesis

Barbara Beltz

Michael Tlusty

Jeanne Benton

David Sandeman

^{Department of Biological Sciences, Wellesley College, Wellesley MA 02481}

^{Egerton Lab, New England Aquarium, Boston MA 02110}

*Correspondence to: Dr. Barbara Beltz, Biological Sciences, Wellesley College, Wellesley, MA 02481, Phone:(781)283-3048, FAX:(781)283-3642, Email: ude.yelsellew@ztlebb, URL:http://www.wellesley.edu/Biology/Faculty/barbspersonal/Barb_personal.htm

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Abstract

Omega-3 fatty acids play crucial roles in the development and function of the central nervous system. These components, which must be obtained from dietary sources, have been implicated in a variety of neurodevelopmental and psychiatric disorders. Furthermore, the presence of omega-6 fatty acids may interfere with omega-3 fatty acid metabolism. The present study investigated whether changes in dietary ratios of omega-3:omega-6 fatty acids influence neurogenesis in the lobster (Homarus americanus) brain where, as in many vertebrate species, neurogenesis persists throughout life. The factors that regulate adult neurogenesis are highly conserved among species, and the crustacean brain has been successfully utilized as a model for investigating this process. In this study, lobsters were fed one of three diets that differed in fatty acid content. These animals were subsequently incubated in 5-bromo-2′-deoxyuridine (BrdU) to detect cells in S-phase of the cell cycle. A quantitative analysis of the resulting BrdU-labeled cells in the projection neuron cluster in the brain shows that short-term augmentation of dietary omega-3 relative to omega-6 fatty acids results in significant increases in the numbers of S-phase cells, and that the circadian pattern of neurogenesis is also altered. It is proposed that the ratio of omega-3:omega-6 fatty acids may alter neurogenesis via modulatory influences on membrane proteins, cytokines and/or neurotrophins.

Keywords: adult neurogenesis, diet, circadian rhythm, LC-PUFA, α-linolenic acid

Abstract

Long chain polyunsaturated fatty acids (LC-PUFAs), which make up 20% of the brain’s dry weight, are critical for healthy brain development and function because of their roles in membrane structure and cytokine regulation. The large number of LC-PUFAs makes the study of nutritional impacts difficult, because not only the dietary level of specific fatty acids, but also their respective ratios, are often important in modulating the degree of impact [18]. The omega-3 fatty acids EPA (eicosapentaenoic acid, 20:5ω3) and DHA (docosahexaenoic acid, 22:6ω3) are of particular importance in the nervous system [21], and levels of ALA (α-linolenic acid, 18:3ω3), the parent omega-3 molecule, also have been implicated in various aspects of brain function [5]. These molecules must be obtained largely from dietary sources because animals cannot synthesize them de novo. Some fish and crustacean species can convert ALA into DHA and EPA [17], although this mechanism does not appear to contribute significantly to DHA and EPA levels in humans [1].

Research suggests that abnormalities in fatty acid metabolism may play a part in a range of neurodevelopmental and psychiatric disorders [11, 14]. For example, several studies support a connection between dietary intake of omega-3 fatty acids and the prevalence of depressive illnesses [15, 19]. Recently, EPA supplementation has even emerged as a potential treatment for depression [23].

Our interest is the possible connection between depressive disorders and deficiencies in life-long neurogenesis, a link originally proposed by Jacobs et al. [16]. Several lines of evidence support this hypothesis. First, major depression is associated with a loss in volume of the hippocampus [6], one of the sites of neuronal addition throughout life. Second, treatments that have antidepressive effects in patients also influence hippocampal neurogenesis in animal studies (e.g., lithium [7]; physical exercise [29]; serotonin reuptake inhibitors [20]). Finally, factors such as stress that can lead to depression are correlated with decreased neurogenesis [10]. As recent research has established an association between omega-3 fatty acids and major depressive disorder, we were interested in whether there is also a correlation between changes in dietary intake of these molecules and the extent of neuronal proliferation in the brain.

Adult neurogenesis occurs in the brains of many vertebrate and invertebrate species. The factors that influence the birth and survival of adult-born neurons in these organisms are highly conserved [3], and therefore studies in non-vertebrate models can reveal regulatory strategies that are also important in more highly derived species. In the crustacean brain, neuronal birth persists throughout life within two populations of interneurons innervating the olfactory lobe, the functional homolog of the vertebrate olfactory bulb, and the accessory lobe, a higher-order multimodal synaptic area [12]. The somata of these interneuronal populations form two spatially distinct clusters located lateral (cluster 10) and medial (cluster 9) to the lobes. Labeling with cell-cycle markers shows that cell proliferation within each cluster occurs within restricted regions known as the proliferation zones. The crustacean brain therefore provides an accessible and sensitive system for examining the regulation of neurogenesis [3].

In the present study, we asked whether alterations in nutritional LC-PUFA content influence levels of neurogenesis in cluster 10 of the lobster brain, where cell numbers can be accurately assessed in whole mounts of juvenile brains. The fatty acid content of the lobster diet is easily manipulated, and previous studies in lobsters have demonstrated that growth and survival are highly sensitive to dietary LC-PUFA levels [27]. We also assessed the influence of LC-PUFAs on the circadian pattern of neurogenesis [9].

Footnotes

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Footnotes

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