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The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (TH VTA ) neurons, as well as from more global maladaptation in neurocircuit function. However, whether TH VTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated TH VTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of TH VTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of TH VTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of TH VTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct TH VTA input.