Synergistic effects of stress and omega-3 fatty acid deprivation on emotional response and brain lipid composition in adult rats

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Abstract

The aim was to determine the consequences of multi-generational n-3 polyunsaturated fatty acids (PUFA) deficiency on emotional response in rats subjected to maternal separation (MS) as chronic early life stress. Pups fed a control or an n-3 PUFA deficient diet were daily separated for 2 weeks before weaning. In adult rats, reward response was assessed by sucrose consumption and reactivity to novelty using openfield test. Both n-3 PUFA deficiency and MS increased reward response and impulsivity. Moreover, nutritional deficiency and stress acted in synergy to elevate sucrose intake by 80%, compared to control conditions. n-3 PUFA deprivation induced a depletion of docosahexanoeic acid of brain membranes by 70% compensated by increase in 22:5 n-6 and arachidonic acid (AA) levels. The diet-induced AA increase was, however, significantly higher in MS rats.

This suggests that n-3 PUFA deficit could be an environmental risk increasing vulnerability to depressive-like response induced by chronic stress.

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.

References (55)

  • M. Maes et al.

    Lowered ω3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients

    Psychiatry Res.

    (1999)
  • K. Matthews et al.

    Repeated maternal separation of preweanling rats attenuates behavioral responses to primary and conditioned incentives in adulthood

    Physiol. Behav.

    (1996)
  • P.M. Plotsky et al.

    Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats

    Brain Res. Mol. Brain Res.

    (1993)
  • M.C. Moffett et al.

    Maternal separation alters drug intake patterns in adulthood in rats

    Biochem. Pharmacol.

    (2007)
  • F.S. Hall et al.

    Isolation rearing in rats: pre- and post-synaptic changes in striatal dopaminergic systems

    Pharmacol. Biochem. Behav.

    (1998)
  • K. Matthews et al.

    Sucrose consumption as an hedonic measure following chronic unpredictable mild stress

    Physiol. Behav.

    (1995)
  • J. Folch et al.

    A simple method for the isolation and purification of total lipids from animal tissues

    J. Biol. Chem.

    (1957)
  • P. Green et al.

    Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression

    J. Lipid Res.

    (2005)
  • R.P. Bazinet et al.

    Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder

    Biol. Psychiatry

    (2006)
  • G.P. Smith

    Accumbens dopamine mediates the rewarding effect of orosensory stimulation by sucrose

    Appetite

    (2004)
  • H. Francès et al.

    Nutritional (n-3) polyunsaturated fatty acids influence the behavioral responses to positive events in mice

    Neurosci. Lett.

    (2000)
  • M.E. Carroll et al.

    Nicotine dependence in rats

    Life Sci.

    (1989)
  • S. Vancassel et al.

    Hyperactivity in the rat is associated with spontaneous low level of n-3 polyunsaturated fatty acids in the frontal cortex

    Behav. Brain Res.

    (2007)
  • P.V. Piazza et al.

    Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration

    Brain Res.

    (1991)
  • C. Blondeau et al.

    Dimensional analysis of ADHD subtypes in rats

    Biol. Psychiatry

    (2007)
  • B. Levant et al.

    Decreased brain docosahexaenoic acid during development alters dopamine-related behaviors in adult rats that are differentially affected by dietary remediation

    Behav. Brain Res.

    (2004)
  • S. Vancassel et al.

    Cerebral asymmetry and behavioral lateralization in rats chronically lacking n-3 polyunsaturated fatty acids

    Biol. Psychiatry

    (2005)
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