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The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species 1 , 2 , 3 . 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 4 . While connectivity among these structures contributes to appetitive behaviours 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 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. Neurons that project from the prefrontal cortex to either the nucleus accumbens or paraventricular thalamus receive different inputs, differentially encode reward-predictive cues, and have opposing effects on reward seeking during cue presentation. Control of reward-seeking behaviour Projections from the prefrontal cortex to the nucleus accumbens and paraventricular thalamus contribute to reward-seeking behaviours, but the type of reward-relevant information that these prefrontal-cortex neurons encode is unknown. Garret Stuber and colleagues show that these two populations of projection neuron receive different inputs, differentially encode reward-predictive cues, and have opposing effects on reward seeking when cues are presented. These findings show how the prefrontal cortex can dynamically control reward-seeking behaviour through the opposing activities of anatomically segregated, projection-specific cell populations.

Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue–reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue–reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue–reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue–reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue–reward associative memory to support behavioral adaptation.Namboodiri, Otis et al. reveal that orbitofrontal cortex acquires and maintains a long-term memory of cue–reward associations to guide multiple aspects of behavioral learning, and that it routes select information to a downstream learning center.

Attentional impairments and exaggerated impulsivity are key features of psychiatric disorders, such as attention-deficit/hyperactivity disorder, schizophrenia, and addiction. These deficits in attentional performance and impulsive behaviors have been associated with aberrant dopamine (DA) signaling, but it remains unknown whether these deficits result from enhanced DA neuronal activity in the midbrain. Here, we took a novel approach by testing the impact of chemogenetically activating DA neurons in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) on attention and impulsivity in the five-choice serial reaction time task (5-CSRTT) in rats. We found that activation of DA neurons in both the VTA and SNc impaired attention by increasing trial omissions. In addition, SNc DA neuron activation decreased attentional accuracy. Surprisingly, enhanced DA neuron activity did not affect impulsive action in this task. These results show that enhanced midbrain DA neuronal activity induces deficits in attentional performance, but not impulsivity. Furthermore, DA neurons in the VTA and SNc have different roles in regulating attention. These findings contribute to our understanding of the neural substrates underlying attention deficits and impulsivity, and provide valuable insights to improve treatment of these symptoms.