Thesis defense – Ivan Marniquet

Thursday 25 September / 14:00

Venue: Centre Broca

Defense in english

Ivan Marniquet
Equipe MutriMind (NutriNeuro)

Thesis supervisor: Jean-Christophe Delpech

Title

Hippocampal cognitive impairment and n-6/n-3 polyunsaturated fatty acids balance modification in adult: sex heterogeneity

Abstract

Cognitive impairment, particularly hippocampal dependent memory deficit, is partly due to environmental factors such as nutrition. Indeed, throughout life, nutrition plays a crucial role in establishing and maintaining an optimal cognitive reserve, defined as our brain’s ability to respond efficiently to any cognitive demand in order to limit cognitive decline. Nutrition, and more specifically the balance of n-6/n-3 polyunsaturated fatty acids (n-6/n-3 PUFAs), has been extensively studied in relation to cognitive impairment throughout life. Clinically, links have been established between accelerated cognitive decline and reduced n-3 PUFA consumption, as well as between n-3 PUFA supplementation and beneficial effects on memory in elderly subjects. Preclinical studies have also demonstrated that n-3 PUFA deficiency from gestation disrupts spatial memory, and induces alterations in hippocampal neuronal functions and in the brain’s resident immune cells, the microglia. Nevertheless, many questions remain unanswered, including a better understanding of the heterogeneity of forms of decline in relation to PUFA intake, and the underlying mechanisms as a function of sex, given that most preclinical work has been carried out in males only.

In this context, the aim on my thesis was initially to evaluate in adulthood cognitive impairment of spatial memory induced by gestational n-3 PUFA deficiency, in both sexes. My hypothesis was that n-3 PUFA deficiency would also induce an alteration in contextual memory, a form of episodic memory, associated with an alteration in neuronal functions of the CA1 of the dorsal hippocampus involved in those memory function. Finally, given that spatial and episodic memory are particularly sensitive to age-related cognitive decline, we hypothesized that a good n-6/n-3 PUFA balance could prevent the deficits observed in a mouse model of accelerated aging.

My results show that a gestational deficiency in n-3 PUFA leads to impairments in spatial and contextual memory in adult males and females, based on the alteration of different parameters according to sex. This heterogeneity is particularly evident in contextual memory performance, with females showing a memory deficit as early as 24 hours after learning, whereas it appears 10 days later in males. At the cellular level, these memory deficits are associated with increased intrinsic excitability of pyramidal CA1 neurons of the dorsal hippocampus in females; and an absence of long-term potentiation, considered to be the substrate of memory, in males. At the protein level, altered activity of protein kinases and synaptic proteins was demonstrated with sex-specific modulation.

In regards to our study on the protective effects of a balanced PUFA diet on cognitive aging, my results indicate that a balanced n-6/n-3 PUFA ratio protects contextual memory associated with a correction of neuroinflammation in the hippocampus.

Overall, these results provide some insight into the mechanisms involved in the optimal functioning of the hippocampus and normal cognitive capacity. These results help to improve our understanding of the importance of a good n-6/n-3 PUFAs intake for the establishment of an optimal cognitive reserve while highlighting the necessity to take sex heterogeneity into account.

Keywords: Memory, PUFA, hippocampus, neuronal excitability