Abstract
Anxiety disorders and depression are well-documented in subjects exposed to adverse childhood events. Recently, maternal obesity and/or maternal consumption of high-fat diets (HFD) have been also proposed as risk factors for offspring mental health. Here using an animal model in rats, we explored the combinatorial effects of a maternal HFD (40% of energy from fat without impact on maternal weight; during gestation and lactation) and maternal separation (MS) in offspring. In the prefrontal cortex (PFC) of pups, MS led to changes in the expression of several genes such as Bdnf (brain derived neurotrophic factor), 5HT-r1a (serotonin receptor 1a) and Rest4 (neuron-restrictive silencer element, repressor element 1, silencing transcription factor (Rest), splicing variant 4). Surprisingly, perinatal HFD strongly attenuated the developmental alterations induced by MS. Furthermore, maternal HFD totally prevented the endophenotypes (anxiety, spatial memory, social behavior, hypothalamic–pituitary–adrenal (HPA) axis response to stress, hippocampal neurogenesis and visceral pain) associated with MS at adulthood. Finally, we also demonstrated that HFD intake reduced anxiety and enhanced maternal care in stressed dams. Overall, our data suggest that a HFD restricted to gestation and lactation, which did not lead to overweight in dams, had limited effects in unstressed offspring, highlighting the role of maternal obesity, rather than fat exposure per se, on brain vulnerability during development.
Highlights
The etiology of the majority of psychiatric disorders remains unknown
The effect of maternal high-fat diets (HFD) alone was restricted to a decrease of Bdnf expression (HF-control versus mRNA levels of (a) Rest[4], (b) Rest, (c) 5HT-r1a, (d) Bdnf, (e) Adcy[5], (f) Camk2a and (g) Crh in the prefrontal cortex (PFC) of 11-day-old pups after 180-min of separation (n = 8 per group)
Adcy[5], Adenylate cyclase[5]; Bdnf, Brain-derived neurotrophic factor; Camk2a, Calcium/calmodulin-dependent protein kinase 2 α; Crh, Corticotropin-releasing hormone; PFC, prefrontal cortex; Rest, Neural-restrictive silencer element, repressor element 1 (RE1), silencing transcription factor; Rest[4], Rest splicing variant 4; SD, standard diet; 5HT-r1a, Serotonin receptor 1A. *P o 0.05, **P o 0.01 and ***P o 0.001; #P o 0.05, ##P o 0.01 and ###P o 0.001 compared with the standard value of 1 representing mRNA levels in pups killed before the separation
Summary
The etiology of the majority of psychiatric disorders remains unknown. It is, well-accepted that psychosocial adversity in childhood can contribute to an increased risk of depressive and anxiety disorders later in life.[1,2,3,4,5,6] In modern societies, a considerable amount of the population including childbearing women and children is exposed to low-cost energy-dense food with a high content in fat. It has been recently proposed that maternal obesity and/or maternal consumption of fat-rich diets could constitute risk factors for offspring’s mental health.[7] It is crucial to unravel the possible combinatorial effects of perinatal exposure to fat-rich diets and early-life stress on the developing brain. Disruption of the mother–infant relationship in rats leads to a wide range of abnormalities[8,9] that are found in depressive and anxious patients with an history of early-life stress.[6] These include altered hypothalamic–pituitary–adrenal (HPA) axis response to stress,[10,11] reduced hippocampal neurogenesis,[12] altered emotionality,[11,13] increased visceral pain[14] and cognitive impairments.[12,15] beside the wellknown effects on offspring metabolism,[16,17] maternal obesity and/
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