Synergistic effects of stress and omega-3 fatty acid deprivation on emotional response and brain lipid composition in adult rats
Introduction
Docosahexaenoic acid (DHA, 22:6 n-3) is the predominant type of long-chain polyunsaturated fatty acids (PUFA) in the brain and represents around 15% of total fatty acids in that tissue [1]. DHA is contained in the phospholipids that build the structure of neuronal membranes. Most of its accumulation occurs during late prenatal and early postnatal development, coinciding with the formation of synapses [2], [3]. Adequate dietary availability of DHA during this period is essential for optimal central nervous system development and functioning. Inadequate intake of DHA is thus associated with impaired attention and learning performance as well as modifications in emotional status including elevated behavioural indices of anxiety, aggression and depression [4]. We have shown that these effects are partly based in changes of the neurotransmission function. In particular, it has been shown that dietary-induced DHA deficiency leads to a deregulation of the meso-cortico-limbic dopaminergic pathway, which is involved in the emotional and reward processes [5], [6], [7]. Moreover, serotonin and acetylcholine releases in the hippocampus were reduced under neuronal activation in rats receiving a chronically n-3 PUFA deficient diet [1], [8]. The serotoninergic receptor and the muscarinic receptor binding were also influenced by the n-3 PUFA contents of the diet [1], [9], [10], [11]. All this could contribute to the poorer performance on various cognitive tasks observed in n-3 PUFA deficient rats.
A growing body of evidence now suggests that perinatal deficiency in brain DHA accrual may represent a preventable neurodevelopmental risk factor for the subsequent emergence of psychopathology [12]. Epidemiological studies have revealed a comorbidity of reduced DHA levels in red cell membranes and attention-deficit hyperactivity disorder and even depression [13], [14], [15], [16]. A consensual protective effect of n-3 PUFA intake in mood disorders has recently been proven by meta-analyses, which demonstrated significant improvements, particularly in uni- and bi-polar depression [17].
Furthermore, evidence has been provided that early postnatal rearing conditions can exert a sustained modulation over neural systems and influence the predisposition to psychopathology in adulthood. Hence, adverse early life environments including loss of a parent, parental abuse or parental neglect, are also associated with traits of altered physiological and neurobiological functioning and long-term vulnerability to depression. Indeed, the early relationship between mother and infant is critical for optimal development of the offspring [18]. Early maternal separation (MS), by disrupting normal maternal–infant interaction, mimics early life neglect of parents in humans and is considered to be one of the most powerful stressors for rats. The MS paradigm has been suggested to constitute a valid environmental model for early life stress and development of a depression-like syndrome in rats [19].
Maternal separated adults exhibit high stress hormone responsiveness and alterations in emotional and behavioural regulation when challenged in specific experimental environments [20]. Moreover, changes in locomotor sensitization to morphine have been observed, raising the possibility that such subjects have increased vulnerability to drug abuse [21], [22]. Modification of brain neurotransmitter levels are greatly involved in the behavioural effects induced by the chronic disruption of the mother–infant relationship, with specific changes in limbic structures in relation to modifications of the dopamine emotional and reward systems [23], [24]. Most effects can be reversed by antidepressive agents, illustrating a strong predictive validity for the MS model.
In this study, we propose that environmental factors, such as unbalanced nutrition during neurodevelopment and early stressful life events, could act in synergy and initiate permanent and deleterious changes leading to long-lasting depressive-like disorders. We investigated the consequences of 6 h per day MS in rats fed a balanced or a chronically n-3 PUFA deficient diet, in terms of adulthood behaviour relevant to depression and changes in brain lipid composition. We measured the subjects’ motivation for reward with free-sucrose consumption to assess the hedonic state of rats and performance in the forced swim test (FST) was determined. Locomotor reactivity to novelty was used to evaluate anxiety-like behaviours.
Section snippets
Animals and diets
A multigenerational deprivation model of Wistar deficient rat was used, according to published method [1]. Two dietary groups were thus constituted from the second generation of female 2 weeks before mating: a control and an α-linolenic acid (18:3 n-3) deficient group. Both diets contained 6% lipids and differed only in n-3 fatty acid content. The control diet containing a mixture of peanut oil and rapeseed oil provided adequate levels of n-6 and n-3 PUFA (1200 mg 18:2 n-6 and 300 mg of 18:3 n-3
Body weight and food intake
No difference was observed in the rat's body weight between the four experimental groups at birth, at the end of MS procedure and until adulthood. Food intake was identical between control and n-3 PUFA deficient rats, and between handled and separated rats. Thus, at the first week of measuring, the average food intake was around 10.5 g of chow per 100 g of body weight. For the 2 following weeks, values were, respectively, 8.7 and 7.2 g per 100 g of body weight.
Reactivity to novelty in the openfield test (Table 2)
Latency to move from the corner was
Discussion
The major findings of this study were that chronic dietary n-3 PUFA deficiency, as chronic early stress, induced behavioural impulsivity and changed the reward response in adult rats. Moreover, the deficient nutritional status and the stress condition acted in synergy to increase sucrose consumption. Furthermore, n-3 PUFA deficient rats showed increased reactivity to novelty in the openfield test, as expressed by a decline of latency to move and an increase in locomotor activity compared to
Acknowledgements
This work was supported by INRA. We thank Alain Linard and Marie Sylvie Lallemand for technical assistance and Claire Maudet and Patrice Dahirel for animal care. Donald White of the ABIES doctoral school edited the English text. We would add that no conflict of interest, either financial or other, is in any way related to this work.
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