Optogenetic stimulation of cell bodies versus axonal terminals generate comparable activity and functional connectivity patterns in the brain

Optogenetic techniques are often employed to dissect neural pathways with presumed specificity for targeted projections. In this study, we used optogenetic fMRI to investigate the effective landscape of stimulating the cell bodies versus one of its projection terminals. Specifically, we selected a long-range unidirectional projection from the ventral subiculum (vSUB) to the nucleus accumbens shell (NAcSh) and placed two stimulating fibers-one at the vSUB cell bodies and the other at the vSUB terminals in the NAcSh. Contrary to the conventional view that terminal stimulation confines activity to the feedforward stimulated pathway, our findings reveal that terminal stimulation induces brain activity and connectivity patterns remarkably similar to those of vSUB cell body stimulation. This observation suggests that the specificity of optogenetic terminal stimulation may induce antidromic activation, leading to broader network involvement than previously acknowledged.