Archaerhodopsin (ArchT)-mediated photoinhibition of axon terminals is commonly used to test the involvement of specific long-range neural projections in behavior. Although sustained activation of this opsin in axon terminals has the unintended consequence of enhancing spontaneous vesicle release, it is unclear whether this desynchronized signaling is consequential for ArchT’s behavioral effects. Here, we compare axon terminal and cell body photoinhibition of nucleus accumbens (NAc) afferents to test the utility of these approaches for uncovering pathway-specific contributions of neural circuits to behavior. First, in brain slice recordings we confirmed that ArchT photoinhibition of glutamatergic axons reduces evoked synaptic currents and increases spontaneous transmitter release. A further consequence was increased interneuron activity, which served to broadly suppress glutamate input via presynaptic GABA_B receptors. In vivo, axon terminal photoinhibition increased feeding and reward-seeking behavior irrespective of the afferent pathway targeted. These behavioral effects are comparable to those obtained with broad inhibition of NAc neurons. In contrast, cell body inhibition of excitatory NAc afferents revealed a pathway-specific contribution of thalamic input to feeding behavior and amygdala input to reward-seeking under extinction conditions. These findings underscore the off-target behavioral consequences of ArchT-mediated axon terminal inhibition while highlighting cell body inhibition as a valuable alternative for pathway-specific optogenetic silencing.

细菌视紫红质（ArchT）介导的轴突末端的光抑制通常用于测试行为中特定的远程神经投射的参与。尽管该视蛋白在轴突末端的持续激活具有增强自发性囊泡释放的意外结果，但尚不清楚这种失同步的信号是否对ArchT的行为产生影响。在这里，我们比较伏隔核（NAc）传入的轴突末端和细胞体光抑制，以测试这些方法的实用性，以揭示神经回路对行为的通路特异性贡献。首先，在脑切片记录中，我们证实了谷氨酸能轴突的ArchT光抑制作用会降低诱发的突触电流并增加自发性递质的释放。进一步的结果是中间神经元活性增加，通过突触前GABA _B受体。体内，轴突末端的光抑制作用增加了进食和寻求奖励的行为，而与靶向的传入途径无关。这些行为效果可与广泛抑制NAc神经元获得的行为效果相媲美。相比之下，兴奋性NAc传入细胞的细胞抑制显示，在灭绝条件下，丘脑输入对进食行为具有特定的路径贡献，杏仁核输入对寻求奖励的行为具有贡献。这些发现强调了ArchT介导的轴突末端抑制的脱靶行为后果，同时强调了细胞体抑制是途径特异性光遗传沉默的有价值的替代方法。