Amemori, S. | bioRxiv Science

bioRxiv2025

Bridge protein-mediated viral targeting of cells expressing endogenous μ-opioid G protein-coupled receptors in the mouse and monkey brain

Targeting specific cell types is essential for understanding their functional roles in the brain. Although genetic approaches enable cell-type-specific targeting in animals, their application to higher mammalian species, such as nonhuman primates, remains challenging. Here, we developed a nontransgenic method using bridge proteins to direct viral vectors to cells endogenously expressing -opioid receptors (MORs), a G protein-coupled receptor. The bridge protein comprises the avian viral receptor TVB, the MOR ligand {beta}-endorphin ({beta}ed), and an interdomain linker. EnvB-enveloped viruses bind to the TVB component, followed by the interaction of {beta}ed with MORs, triggering viral infection in MOR-expressing cells. We optimized the secretion signals, domain configurations, and interdomain linkers of the bridge proteins to maximize viral targeting efficiency and specificity. Alternative configurations incorporating different ligands and viral receptors also induced viral infection in MOR-expressing cells. The optimized {beta}ed-f2-TVB bridge protein with EnvB-pseudotyped lentiviruses induced infection in MOR-expressing cells in the striatum of mice and monkeys. An intersectional approach combining {beta}ed-f2-TVB with a neuron-specific promoter refined cell-type specificity. This study establishes the foundation for the rational bridge protein design and the feasibility of targeting G protein-coupled receptors beyond tyrosine kinase receptors, thereby expanding targetable cell types in the brain and throughout the body. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/637063v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1fe91org.highwire.dtl.DTLVardef@effe51org.highwire.dtl.DTLVardef@217d73org.highwire.dtl.DTLVardef@b31251_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Multiple types of navigational information is diffusely and independently encoded in the population activities of the dentate gyrus neurons

The dentate gyrus (DG) plays critical roles in cognitive functions such as learning, memory, and spatial coding, and its dysfunction is implicated in various neuropsychiatric disorders. However, it remains largely unknown how information is represented in this region. Here, we recorded neuronal activity in the DG using Ca2+ imaging in freely moving mice and analysed this activity using machine learning. The activity patterns of populations of DG neurons enabled us to successfully decode position, speed, and motion direction in an open field as well as current and future location in a T-maze, and each individual neuron was diversely and independently tuned to these multiple information types. In CaMKII heterozygous knockout mice, which present deficits in spatial remote and working memory, the decoding accuracy of position in the open field and future location in the T-maze were selectively reduced. These results suggest that multiple types of information are independently distributed in DG neurons.

neuroscience↗

bioRxiv2019

Microstimulation of primate neocortex targeting striosomes induces negative decision-making

Affective judgment and decision-making are strongly modulated by the pregenual anterior cingulate (pACC) and caudal orbitofrontal (cOFC) cortical regions. By combining MRI-guided electrical microstimulation with viral tracing methods in non-human primates, we demonstrate that circumscribed pACC and cOFC microstimulation sites that induce negative decision-making preferentially project to striosomes in the anterior striatum. These results outline a behaviorally important circuit from pACC/cOFC to striosomes causally modulating decision-making under emotional conflict.

neuroscience↗