Dissociable Neural Connectome Mapping of Reward and Punishment Responsiveness in Young Adults: Associations with Genetic Variability and Neurotransmitter Profiles

While the hyper- and hypo- reward or punishment sensitivities (RS, PS) have received considerable attention as prominent transdiagnostic features of psychopathology, the lack of an overarching neurobiological characterization currently limits their early identification and neuromodulation. Here we combined microarray data from the Allen Human Brain Atlas with a multimodal fMRI approach to uncover the neurobiological signatures of RS and PS in a discovery-replication design (N=655 healthy participants, 442 Females). Both RS and PS were mapped separately in the brain, with the functional connectome in the fronto-striatal network encoding reward responsiveness, while the fronto-insular system was particularly engaged in punishment sensitivity. These dissociable functional connectome patterns also exhibited high specificity in differentiating decisions driven by social or monetary reward and punishment motivations. Further imaging transcriptomic analyses revealed that functional connectome variations for RS and PS were associated with topography of specific gene sets enriched in ontological pathways, including synaptic transmission, dopaminergic metabolism, immune response and stress adaptation. On the neurotransmitter level, the serotonin neuromodulator emerged as a pivotal hub regulating the intrinsic functional connectome patterns of RS and PS, with its modulatory effects dependent on interactions with the dopaminergic, opioid and GABAergic systems. Overall, these findings indicate dissociable neural connectome mapping of RS and PS, and highlight their linkage with transcriptomic profiles, which may inform future investigations on early identification of vulnerability and risk factors for psychopathological conditions. Significance Statement The hyper- and hypo- reward or punishment sensitivity (RS, PS) has been recognized as a prominent feature across multiple forms of psychopathology. However, an overarching neurobiological characterization of these constructs is lacking. Here we identified distinct large-scale functional connectome patterns associated with RS and PS: RS was linked to enhanced connectivity in fronto-striatal circuitry, while PS showed greater involvement of the fronto-insular system. These neural variations were: (1) associated with gene sets implicated in synaptic transmission, dopaminergic metabolism, immune response and stress adaptation; and (2) further regulated by serotonergic, dopaminergic, opioid and GABAergic pathways. Together, these findings offer a multi-scale perspective on reward- and punishment-related behavioral tendencies, which may inform future efforts toward early identification of vulnerability to psychopathological conditions.