Anatomical input-output streams within mouse orbitofrontal cortex subdivisions

Abstract

The orbitofrontal cortex (OFC) supports flexible value representation and decision making in primates, where different OFC subdivisions encode rewarding or aversive stimuli, and OFC dysfunction is implicated in depression. Recent anatomical and functional investigations have been performed in mice, but species differences in reward and value encoding physiology calls for deeper investigation of mouse OFC connectivity to better support translational research. Here, we compared density of retrograde inputs, axonal outputs and inter-subdivision connectivity, focusing on MO (medial-orbital), VO (ventral-orbital), (D)LO ((dorso)lateral-orbital) and AI (agranular insula). Central subdivisions (LO,VO) received dominant inputs from mediodorsal and submedius thalamic nuclei and projected respectively to medial prefrontal areas and sensory cortices. The striatal output was directed towards dorsal striatum, with reciprocal brainstem dopaminergic innervation. Input sources were more distributed for MO and AI, with reciprocal outputs to medial prefrontal cortices and amygdala, respectively. Striatal output was mainly to ventral striatum, and AI also received strong serotoninergic innervation. Cluster analysis revealed that VO/LO, and to lesser extent MO/DLO, shared strong similar input distributions, distinct from AI. Output clustering separated VO targeting sensory areas and AI targeting amygdala. Intra-OFC connectivity suggested information flow preferentially from (D)LO (entry nodes), to VO, MO and finally AI (output node). Together these data suggest a model that integrates in-series, information on sensory-motor plans (at (D)LO)), motivational state and cue uncertainty (at VO/LO) and current goals (at MO), via AI modulating the amygdaloidal and ventral striatal outputs, thus proposing an experimentally testable circuit to control emotional reactivity and decision-making in mouse OFC.