The dopamine ontogeny hypothesis for schizophrenia proposes that transient dysregulation of the dopaminergic system during brain development increases the likelihood of this disorder in adulthood. To test this hypothesis in a high-throughput animal model, we have transiently manipulated dopamine signaling in the developing fruit fly Drosophila melanogaster and examined behavioral responsiveness in adult flies. We found that either a transient increase of dopamine neuron activity or a transient decrease of dopamine receptor expression during fly brain development permanently impairs behavioral responsiveness in adults. A screen for impaired responsiveness revealed sleep-promoting neurons in the central brain as likely postsynaptic dopamine targets modulating these behavioral effects. Transient dopamine receptor knockdown during development in a restricted set of ~20 sleep-promoting neurons recapitulated the dopamine ontogeny phenotype, by permanently reducing responsiveness in adult animals. This suggests that disorders involving impaired behavioral responsiveness might result from defective ontogeny of sleep/wake circuits.

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The acquisition of goal-directed action requires the encoding of specific action-outcome associations involving plasticity in the posterior dorsomedial striatum (pDMS). We first investigated the relative involvement of the major inputs to the pDMS argued to be involved in this learning-related plasticity, from prelimbic prefrontal cortex (PL) and from the basolateral amygdala (BLA). Using ex vivo optogenetic stimulation of PL or BLA terminals in pDMS, we found that goal-directed learning potentiated the PL input to direct pathway spiny projection neurons (dSPNs) bilaterally but not to indirect pathway neurons (iSPNs). In contrast, learning-related plasticity was not observed in the direct BLA-pDMS pathway. Using toxicogenetics, we ablated BLA projections to either pDMS or PL and found that only the latter was necessary for goal-directed learning. Importantly, transient inactivation of the BLA during goal-directed learning prevented the PL-pDMS potentiation of dSPNs, establishing that the BLA input to the PL is necessary for the corticostriatal plasticity underlying goal-directed learning.

Performing several actions in swift succession is often necessary to exploit known contingencies in the environment. However, after a change in the contingency rules, the ability to appropriately adapt rapid action sequences must be procured for continued success. By combining analyses of behavioural microstructure with circuit-specific tracing in mice, we report on a relationship between action timing-variability and successful adaptation that relies on post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). We found that M1 hyperdirect pathway projections to the STN also send dense axonal collaterals to external globus pallidus and dorsal striatum, with the highest synaptic volumes found in the DLS. Specific interruption of the M1→DLS circuit reduced the proportion of successful sequences while speeding-up and reducing action timing-variability, revealing a role for M1→DLS circuitry in setting the exploration/exploitation balance that is required for adaptively guiding the timing and success of instrumental action.