Synapsin-GFP AAV (Serotype 8)

Regulating neuro-metabolic-inflammatory responses is essential for maintaining physiological homeostasis. However, the molecular mechanisms that coordinate neural, metabolic, and inflammatory responses are largely unknown. Here, researchers show that semaphorin 6D (SEMA6D) coordinates anxiety, metabolic, and inflammatory outputs in the amygdala by maintaining synaptic homeostasis. Using a genome-wide approach, researchers identify SEMA6D as a pleiotropic gene underlying human psychiatric and metabolic traits. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d−/− mice exhibit reduced adiposity and enhanced myelopoiesis compared with control mice, due to higher sympathetic activity through β3-adrenergic receptors. Genetic manipulations and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdala interneurons is responsible for regulating anxiety and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results suggest that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.

Here, to directly determine whether amygdalar SEMA6D is involved in the regulation of anxiety and systemic metabolism, researchers stereotaxically injected AAV8-hSyn-GFP or AAV8-hSyn-Cre-GFP into the CeA of Sema6d^fl/fl mice. CeA-specific SEMA6D deletion reduced exploration time in the OF test and mitigated HFD-induced obesity, indicating that amygdala SEMA6D is responsible for the regulation of anxiety and systemic metabolism (Figures 1I-1K).

Figure 1. Sema6d^fl/fl mice were bilaterally injected with AAV8-hSyn-GFP or AAV8-hSyn-Cre-GFP into the CeA. (Nakanishi Y, et al., 2024)