Pierre-Marie Lledo

We are investigating the functional meaning of adult neurogenesis forsensory and cognitive functions. Methodologically, this include morphological, molecular and electrophysiological characterization of new neurons in vitro and in vivo as well as behavioural approaches to investigate the impact of adding new neurons to pre-existing circuits. Special emphases are given to investigate the relative contribution of intrinsic (genetic) and extrinsic (epigenetic) cues regulating this process using genetically manipulated rodents and different environmental paradigms.

Brain aging is associated with a gradual decline of cognitive and regeneration potential, which is directly influenced by the systemic environment and energy state of the organism. In our work that was funded by the Revive consortium we showed that systemic GDF11 couples metabolic regulation to neurogenic and cognitive rejuvenation in aged mice. Systemic GDF11 administration regulated body weight and restored the insulin/IGF-1/FoxO signaling pathway in aged mice. We found that GDF11 levels were linked to the energy state of the organism. Concomitantly, we showed that GDF11 acts on the autophagic pathway to enhance neuronal activity, memory impairments and depression in aged mice. Systemic GDF11 administration restored neurogenesis and autophagy in aged mice. We found that GDF11 specifically acted on neurons to increase autophagy and neuronal activity. However, when autophagy was blocked, the action of GDF11 on neuronal activity was also mitigated, thereby demonstrating that GDF11 acts on neurons via autophagy. Interestingly, when GDF11 was infused intracerebroventricularly, memory impairments and depression were still restored, thereby showing the direct involvement of GDF11 in cognitive processes. Finally, examination of plasma GDF11 levels in major depressive disorder patients demonstrated an inverse correlation between GDF11 circulation in the blood and presence of the disease. Our findings provide evidence that GDF11 could be a potent candidate for future therapeutic strategies to prevent brain and cognitive aging. This work resulted in 2 research articles, one already published (Katsimpardi et al., Aging Cell, 2020), and one currently in submission, one review (Katsimpardi and Lledo, Currrent Opinion in Neurobiology, 2018), as well as a patent with Institut Pasteur.