Pathway-specific control of reward learning and its flexibility via selective dopamine receptors in the nucleus accumbens

Abstract

In the basal ganglia, inputs from the nucleus accumbens (NAc) are transmitted through both direct and indirect pathways and control reward-based learning. In the NAc, dopamine (DA) serves as a key neurotransmitter, modulating these two parallel pathways. This study explored how reward learning and its flexibility are controlled in a pathway-specific and DA receptor-dependent manner. We used two techniques (i) reversible neurotransmission blocking (RNB), in which transmission of the direct (D-RNB) or the indirect pathway (I-RNB) in the NAc on both sides of the hemispheres was selectively blocked by transmission-blocking tetanus toxin; and (ii) asymmetric RNB, in which transmission of the direct (D-aRNB) or the indirect pathway (I-aRNB) was unilaterally blocked by RNB techniques and the intact side of the NAc was infused with DA agonists or antagonists. Reward-based learning was assessed by measuring goal-directed learning ability based on visual cue tasks (VCTs) or response-direction tasks (RDTs). Learning flexibility was then tested by switching from a previously learned VCT to a new VCT or RDT. D-RNB mice and D1 receptor antagonist-treated D-aRNB mice showed severe impairments in learning acquisition but normal flexibility to switch from a previously learned strategy. In contrast, I-RNB mice and D2 receptor agonist-treated I-aRNB mice showed normal learning acquisition but severe impairments not only in the flexibility to the learning switch but also in the subsequent acquisition of learning a new strategy. D1 and D2 receptors thus play distinct but cooperative roles in reward learning and its flexibility in a pathway-specific manner.goal-directed behavior | perseveration | transmission modulation | neurotransmission blockade | striatal neurons T he basal ganglia are the key neural substrates that control reward-based learning and its flexibility to effectively acquire rewards under changing environmental circumstances (1-3). Dysfunction of the basal ganglia leads to severe cognitive and learning impairments as exemplified in Parkinson's disease, schizophrenia, and drug addiction (4-6). In the basal ganglia circuitry, the projection neurons in the striatum and the nucleus accumbens (NAc), which is the ventral part of the striatum, are divided into two subpopulations, i.e., striatonigral neurons of the direct pathway and striatopallidal neurons of the indirect pathway (1,7,8). The outputs of these two parallel pathways converge at the substantia nigra pars reticulata/ventral tegmental area (VTA) and control the dynamic balance of the basal ganglia-thalamocortical circuitry (1, 9). The two types of the striatal projection neurons are morphologically indistinguishable, but the striatonigral and striatopallidal neurons selectively express D1 and D2 dopamine (DA) receptors (1, 10, 11). This difference in expression profile as well as the distinct ligand affinities of these two DA receptors is thought to be critical for modulating transmission of the pathways involved in rewarding behaviors (3,12). However, whether a...

Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

“…1B). As controls, no alteration of locomotion activity was observed in both D-aRNB and I-aRNB mice after treatments with DA agonists and antagonists (17). These results indicated that activation of D1 receptors in the direct pathway is critical for inducing cocaine sensitization.…”

“…All animal handling procedures were approved by the animal research committees of Osaka Bioscience Institute, Kyoto University Graduate School of Medicine, and Kitasato University. The RNB and aRNB mice were generated by the respective bilateral and unilateral injection of the recombinant AAV viruses into four sites of each NAc by stereotaxic techniques (14,17). Virus-injected WT littermates were used as controls.…”

“…After the recombinant virus had been unilaterally injected into the NAc of anesthetized mice, the other side of the NAc was implanted with a cannula aimed toward the NAc for drug infusion as described previously (17). The concentrations of infused drugs were 100 μM SCH23390, 300 μM SKF81297, 1 mM quinpirole, 400 μM eticlopride (all from SIGMA), 100 μM aripiprazole (Toronto Research Chemicals), 25 mM APV, 20 mM MK801 (both from Wako), 100 μM SCH58261 (Tocris), and 300 μM ACEA (abcam).…”

“…We thus extended the RNB technique to an asymmetric RNB (aRNB) technique. In this technique, one side of the NAc was blocked by the RNB technique and the other intact side was treated with an agonist or antagonist specific for a neurotransmitter receptor (17). This aRNB technique allowed us to examine what types of neurotransmitter receptors were responsible for learning in a pathway-specific and learning stage-dependent manner.…”

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions

“…Recent advances in cell-type-specific technologies have provided a wealth of data allowing a more comprehensive understanding of MSNs roles in drug addiction (Durieux et al, 2009;Durieux et al, 2012;Ferguson et al, 2011;Lobo et al, 2010), cognitive functions (Hikida et al, 2010;Hikida et al, 2013;Nishizawa et al, 2012;Tai et al, 2012;Yawata et al, 2012), and parkinsonian physiopathology (Kravitz et al, 2010). Here, we developed a new inducible model of diphtheria toxin (DT) receptor-mediated ablation to further explore the functional implications of striatonigral MSNs of the dorsal striatum.…”