Synapsin-GFP AAV (Serotype 2)

Obesity is often associated with decreased sociability, and stress at puberty can lead to long-term changes in visceral fat deposition and social behavior. Here, researchers found that male mice, but not female mice, subjected to adolescent stress developed both increased adiposity and decreased sociability. Reduced levels of the adipokine nicotinamide phosphoribosyltransferase (NAMPT) in fat and its extracellular form, eNAMPT in the blood, underlie the lifelong decline in sociability caused by peripubertal stress. Using a range of adipose tissue- and brain region-specific loss- and gain-of-function approaches, researchers implicated an impaired nicotinamide adenine dinucleotide (NAD+)/SIRT1 pathway in the nucleus accumbens. Impairments in sociability and excitability of nucleus accumbens neurons were prevented by normalizing eNAMPT levels or by treatment with nicotinamide mononucleotide (NMN), an NAD+-boosting compound. Thus, NAD+-boosting agents could be used to treat social impairments caused by early life stress.

Here, researchers tested the causal contribution of weakened NAD+/SIRT1 pathways in the NAc to changes in sociability in adolescent stressed mice during adulthood. First, bilateral acute intra-NAc injections of NMN (Figure 1A and B), an NAD+-enhancing compound, reversed stress-induced sociability deficits (Figure 1C). EX-527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide), a specific SIRT1 inhibitor (Figure 1D), abolished the rescue of sociability by NMN (Figure 1C). Second, researchers used two adeno-associated viruses (AAVs) to knockout (Figure 1E to H) or overexpress (Figure 1I to L) SIRT1 in NAc neurons. Sirt1^loxP mice were stereotactically injected with AAV2-Syn-GFP (Empty) or AAV2-Syn-Cre-GFP (Cre) in the NAc (Figure 1E). These SIRT1 knockout mice displayed the reduced sociability phenotype of adolescent stressed mice (Figure 1H). Control and stressed mice were stereotactically injected with AAV2-Syn-GFP (Empty) or AAV2-Syn-SIRT1-GFP (SIRT1) in the NAc (Figure 1I). Overexpression of SIRT1 in stressed mice rescued their sociability deficits (Figure 1L). These results are consistent with the ability of eNAMPT to activate the NAD+/SIRT1 pathway in the brain and support the involvement of this pathway in the NAc-mediated link between decreased circulating eNAMPT and decreased sociability in peripubertal stressed mice.

Figure 1. The NAD+/SIRT1 pathway in the NAc mediates sociability deficits induced by peripubertal stress in male mice. (Morató L, et al., 2022)