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The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards and reward-driven learning. How dopamine supports both functions is unclear. Dopaminecell spiking can encode prediction errors, which arevital learning signals in computational theories of adaptive behaviour. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioural tasks, slower changes in dopamine cell spiking or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues thatindicatean upcoming reward increased both spiking and release. However, NAc core dopamine release also covaried with dynamically evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, whereas local control drives motivation.

The mesolimbic dopamine projection from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is a key pathway for reward-driven learning, and for the motivation to work for more rewards. VTA dopamine cell firing can encode reward prediction errors (RPEs1,2), vital learning signals in computational theories of adaptive behavior. However, NAc dopamine release more closely resembles reward expectation (value), a motivational signal that invigorates approach behaviors3-7. This discrepancy might be due to distinct behavioral contexts: VTA dopamine cells have been recorded under head-fixed conditions, while NAc dopamine release has been measured in actively-moving subjects. Alternatively the mismatch may reflect changes in the tonic firing of dopamine cells8, or a fundamental dissociation between firing and release. Here we directly compare dopamine cell firing and release in the same adaptive decision-making task. We show that dopamine release covaries with reward expectation in two specific forebrain hotspots, NAc core and ventral prelimbic cortex. Yet the firing rates of optogenetically-identified VTA dopamine cells did not correlate with reward expectation, but instead showed transient, error-like responses to unexpected cues. We conclude that critical motivation-related dopamine dynamics do not arise from VTA dopamine cell firing, and may instead reflect local influences over forebrain dopamine varicosities.

Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions.

Genetically modified mice have become standard tools in neuroscience research. Our understanding of the basal ganglia in particular has been greatly assisted by BAC mutants with selective transgene expression in striatal neurons forming the direct or indirect pathways. However, for more sophisticated behavioral tasks and larger intracranial implants, rat models are preferred. Furthermore, BAC lines can show variable expression patterns depending upon genomic insertion site. We therefore used CRISPR/Cas9 to generate two novel knock-in rat lines specifically encoding Cre recombinase immediately after the dopamine D1 receptor (Drd1a) or adenosine 2a receptor (Adora2a) loci. Here, we validate these lines usingin situhybridization and viral vector mediated transfection to demonstrate selective, functional Cre expression in the striatal direct and indirect pathways, respectively. We used whole-genome sequencing to confirm the lack of off-target effects and established that both rat lines have normal locomotor activity and learning in simple instrumental and Pavlovian tasks. We expect these new D1-Cre and A2a-Cre rat lines will be widely used to study both normal brain functions and neurological and psychiatric pathophysiology.

Change history: In this Article, an extraneous label appeared in Fig. 4b, and has been removed in the online version.

Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by distinguishing between medium spiny projection neurons (MSNs) and presumed fast-spiking interneurons (FSIs), in freely moving rats. The response of MSNs to both the stimulant amphetamine (0.5 or 2.5 mg/kg) and the antipsychotic eticlopride (0.2 or 1.0 mg/kg) remained highly heterogeneous, with each drug causing both increases and decreases in the firing rate of many MSNs. By contrast, FSIs showed a far more uniform, dose-dependent response to both drugs. All FSIs had decreased firing rate after high eticlopride. After high amphetamine most FSIs increased firing rate, and none decreased. In addition, the activity of the FSI population was positively correlated with locomotor activity, whereas the MSN population showed no consistent response. Our results show a direct relationship between the psychomotor effects of dopaminergic drugs and the firing rate of a specific striatal cell population. Striatal FSIs may have an important role in the behavioral effects of these drugs, and thus may be a valuable target in the development of novel therapies.

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.