Anatomical input-output streams within mouse orbitofrontal cortex subdivisions

The orbitofrontal cortex (OFC) supports flexible value representation and decision making and its dysfunction is implicated in affective disorders. In rodents and primates different OFC subdivisions fulfill different functions, like encoding rewarding/aversive stimuli. Although recent anatomical and functional investigations have been performed in mice, species differences in reward and value-encoding physiology call for deeper investigation of mouse OFC connectivity to better support translational research. Here, we compare 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 connection to/from brainstem dopaminergic areas. Input sources were more distributed for MO and AI, with reciprocal innervation to medial prefrontal cortices and amygdala, respectively. Striatal output was mainly to ventral striatum, and AI also received strong serotonergic 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). We suggest a putative model integrating preferentially in-series, 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 a prototype circuit to control emotional reactivity and decision-making in mouse OFC.