Adult hippocampal neurogenesis as a process to rejuvenate the aging brain – RejuvBrain

Aging is accompanied by a decline in memory but these alterations are extremely variable between subjects: some individuals preserve memory abilities (Resilient, Res), whereas others show a clear substantial memory decline (Vulnerable, Vul). We believe that understanding the processes underlying such individual differences is a key step in developing new strategies to prevent age-related memory disorders by rejuvenating the brain. One process that could underlie resilience to memory aging is adult neurogenesis (ANg) within the dentate gyrus, a key structure in learning and memory. Importantly, ANg requires interactions of newborn neurons with glial cells, such as astrocytes. Hence, this project aims at deciphering the neurobiological mechanisms of resilience/vulnerability to cognitive aging by focusing on ANg (WP1) and the implication of astrocytes (WP2) in order to rejuvenate memory (WP3).
This project is founded on recent findings on the recruitment of Adu-DGNs generated throughout adult life in Res and Vul rats. In 22-month-old rats, learning-induced activation of Adu-DGNs that were born either 10 or 19 months earlier was studied using the neuronal activity marker, Zif268. It was found that the 2 cohorts of Adu-DGNs (born respectively in 3 and 12 month-old rats) were recruited by learning in Res rats and not in Vul ones. We hypothesize that Adu-DGNs become functionally silent in Vul rats in the course of aging (leading thus to memory deficits). Adu-DGNs silencing may result from a loss of synaptic inputs altering their ability to integrate incoming information. This proposal is divided in 3 work packages:

WP1: Senescence of Adu-DGNs network
We will follow the time course of age-related changes of Adu-DGNs (tag in 3-month old rats) and their connectome. We will investigate the morphology of Adu-DGNs by combining different moloney retrovirus (RV). RV that encode either Syn:GFP or PSD-95:GFP or rabies will be used to analyze Adu-DGNs input and outputs. Senescence will be studied by looking at the expression of lipofuscin, SA-ß-gal, and p16. Then we will characterize the excitability and membrane properties of Adu-DGNs in vitro using patch-clamp recordings in acute hippocampal slices from behaviorally characterized rats.

WP2: Senescence of astrocytes associated to Adu-DGNs
We will follow the time course of age-related changes of astrocytes associated with Adu-DGNs (tag in 3-month old rats). Partner 2 will study the morphology and function of astrocytes that are associated with PSD-95 expressed by Adu-DGNs. Astrocytes will be labeled with an AAV2/DJ-GfaABC1D-TdTomato injected 5 weeks before the analysis. To study calcium activity and function of astrocytes, AAV2/DG.GfaABC1D.lck-GCaMP6f will be injected 5 weeks before the experiment and 2-photons imaging will be performed during electrophysiological recordings.

WP3: Rejuvenating memory through the manipulation of Adu-DGNs/astrocytes
We aim at demonstrating that manipulating the activity of Adu-DGNs (tag in 3-month old rats) and/or astrocytes postpones the appearance of memory dysfunction during aging. This will be done by stimulating Adu-DGNs with optogenetic (RV expressing Channelrhodopsin2) and/or manipulating astrocytes using viruses that we validated recently. In addition as we done in the context of AD, we will implement food with L-serine 2 months before memory tests and we will try to block the rejuvenating effects of L-serine using optogenetic (RV expressing Archaeorhodopsin).

RejuvBrain has the ambitious aim of tackling the role of “new Adu-DGNs/astrocytes” dyad during cognitive aging. Delaying the onset of cognitive decline has been predicted to lead to substantial economy for the health care system and thus our project will have phenomenal applications and a major impact on society and economy by generating new knowledge on healthy aging.