The effects of the dopamine D2/3 agonist quinpirole on incentive value and palatability-based choice in a rodent model of attention-deficit/hyperactivity disorder.

RATIONALE: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. OBJECTIVES: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. METHODS: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01-0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. RESULTS: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. CONCLUSIONS: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD.

Neuropilin 2 Signaling Mediates Corticostriatal Transmission, Spine Maintenance, and Goal-Directed Learning in Mice.

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning, and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore, conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and Semaphorin signaling.SIGNIFICANCE STATEMENT The corticostriatal pathway controls sensorimotor, learning, and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that Neuropilin 2 (Nrp2), a receptor for the axon guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs, and learning in mice. Our findings, coupled with the association of Nrp2 with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 to be a key regulator of corticostriatal development, maintenance, and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

Loss of striatal tyrosine-hydroxylase interneurons impairs instrumental goal-directed behavior.

The striatum mediates a broad range of cognitive and motor functions. Within the striatum, recently discovered tyrosine hydroxylase expressing interneurons (THINs) provide a source of intrastriatal synaptic connectivity that is critical for regulating striatal activity, yet the role of THIN's in behavior remains unknown. Given the important role of the striatum in reward-based behaviors, we investigated whether loss of striatal THINs would impact instrumental behavior in mice. We selectively ablated striatal THINs in TH-Cre mice using chemogenetic techniques, and then tested THIN-lesioned or control mice on three reward-based striatal-dependent instrumental tests: (a) progressive ratio test; (b) choice test following selective-satiety induced outcome devaluation; (c) outcome reinstatement test. Both striatal-THIN-lesioned and control mice acquired an instrumental response for flavored food pellets, and their behavior did not differ in the progressive ratio test, suggesting intact effort to obtain rewards. However, striatal THIN lesions markedly impaired choice performance following selective-satiety induced outcome devaluation. Unlike control mice, THIN-lesioned mice did not adjust their choice of actions following a change in outcome value. In the outcome reinstatement test THIN-lesioned and control mice showed response invigoration by outcome presentation, suggesting the incentive properties of outcomes were not disrupted by THIN lesions. Overall, we found that striatal THIN lesions selectively impaired goal-directed behavior, while preserving motoric and appetitive behaviors. These findings are the first to describe a function of striatal THINs in reward-based behavior, and further illustrate the important role for intrastriatal interneuronal connectivity in behavioral functions ascribed to the striatum more generally.