Thesis defense – Flore Marchaland

Venue: BBS

Defense in french

Title

Mechanistic role of polyunsaturated fatty acids in brain development and cognitive trajectory

Abstract

N-3 and n-6 polyunsaturated fatty acids (PUFA) are essential for mammals, as they cannot be synthesized de novo and must therefore be provided by the diet. Once consumed, PUFA are incorporated into cellular membranes, where they play a major structural role. Among PUFA, docosahexaenoic acid (DHA, n-3) and arachidonic acid (ARA, n-6) are long-chain PUFA (LC-PUFA) that are particularly enriched in the brain. They are respectively derived from the metabolism of α-linolenic acid (ALA, n-3) and linoleic acid (LA, n-6), their precursors found in plant-derived foods. LC-PUFA can also be directly supplied by animal-derived foods, primarily marine sources for n-3 and terrestrial sources for n-6. LC-PUFA accumulate in the brain during the perinatal period during which they are transferred from the mother to the infant first via the placenta and subsequently through breast milk. Thus, the supply of LC-PUFA to the infant largely depends on maternal dietary PUFA intake. However, since the late 20th century, changes in dietary habits have led to an increase in n-6 PUFA consumption alongside a decrease in n-3 PUFA intake. Epidemiological and clinical studies have highlighted an inverse correlation between maternal n-3 PUFA dietary intake and children’s cognitive performance. Furthermore, experimental studies in rodents have shown that perinatal n-3 PUFA deficiency impairs cognitive functions as well as neuronal morphology and function in male offspring. However, the underlying mechanisms and potential sex-specific differences remain poorly understood.

In this context, the primary objective of my PhD research was to investigate the cellular and molecular mechanisms underlying the behavioral and neurobiological effects induced by perinatal n-3 PUFA deficiency in both male and female offspring. Additionally, I examined whether maintaining n-3 PUFA through an innovative genetic approach could prevent these alterations.

The results obtained indicate that perinatal n-3 PUFA deficiency affects, in some cases in a sex-dependent manner, 1) brain profiles of PUFA and their oxygenated derivatives (oxylipins) ; 2) the trajectory of physical and motor development ; 3) spatial memory ; and 4) long-term synaptic plasticity in the hippocampus. Genetic maintenance of PUFA in offspring exposed to this perinatal n-3 PUFA deficiency enables 1) the prevention of impairments in spatial memory and long-term synaptic plasticity in the hippocampus ; 2) an increase in mature synapse density, particularly glutamatergic synapses, within the hippocampus ; 3) the promotion of a transcriptional signature associated with synapse and neuronal network maturation ; and 4) the generation of a unique brain oxylipin profile differing by sex. In contrast, genetic modulation of PUFA synthesis specifically in CaMKII neurons, which are predominantly glutamatergic, is not sufficient to prevent alterations in the PUFA profile of hippocampal synaptosomes or to rescue memory deficits induced by perinatal n-3 PUFA deficiency. Finally, this work also shows that perinatal n-3 PUFA deficiency alters the transcriptomic signature of hippocampal microglia only from three weeks after birth, with no significant effects observed earlier in development, in a sex-dependent manner.

Overall, my PhD work has shed light on the mechanisms by which perinatal n-3 PUFA deficiency impairs brain development and cognition, disrupting synaptic and neuronal network maturation in the hippocampus at both the cellular and molecular levels.

Keywords : Development, Behavior, Nutrition, Microglia, Synapse

Publication

Di Miceli, M., Rossitto, M., Martinat, M., Marchaland, F., Kharbouche, S., Graland, M., … & Layé, S. (2024). Modified neuroimmune processes and emotional behaviour in weaned and late adolescent male and female mice born via caesarean section. Scientific Reports, 14(1), 29807.

Jury