Ventral striatum links motivational and motor networks during operant-conditioned movement in rats
Introduction
Voluntary actions are often initiated to obtain eventual rewards or to avoid punishment. Animals can learn to execute specific voluntary actions, depending on the contingencies across cues, actions, and consequences. This is called operant conditioning, which is a fundamental form of learning goal-directed actions that allows animals to adapt to unfamiliar environments. However, it remains unclear how the motivational processes gain access to the motor execution system in the brain during operant behavior.
The limbic system plays a central role in motivational processes (Ikemoto et al., 2015; Ikemoto and Panksepp, 1996; Jennings et al., 2013; Koob, 1992; Wise, 1978; Wise and Bozarth, 1987). The nucleus accumbens (NAcc) is the core of the ventral striatum (VS), receiving direct afferents from limbic structures. The NAcc in turn projects to limbic areas and the ventral pallidum of the basal ganglia (Ikemoto and Panksepp, 1999). Based on this anatomy, the NAcc is considered a link between the limbic system and the basal ganglia (BG) (Graybiel, 1976; Mogenson et al., 1980; Ikemoto et al., 2015). The ventral pallidum projects to mediodorsal thalamic nuclei (Baleydier and Mauguiere, 1980; Jürgens, 1983), which connect with the medial prefrontal cortex (MPFC) in rats (Morici et al., 2015). In particular, the prelimbic cortex, a part of MPFC in rats, topographically connects with the VS (Berendse et al., 1992) and might encode action-outcome contingencies (Corbit and Balleine, 2003).
The limbic-BG circuit is functionally segregated from the motor-BG circuit (Alexander, 1986). This anatomical model has led to an influential serial processing theory in which motivational information is processed first in the limbic circuit and then transferred to the motor BG circuits. However, recent evidence indicates that fibers from various prefrontal cortical areas overlap substantially within the striatum (Averbeck et al., 2014; Haber et al., 2006; Haber and Knutson, 2010). This anatomical convergence may allow links between reward-related processing and motor-related processing in an integrative rather than serial manner (Kupferschmidt et al., 2017). Collectively, it seems reasonable to assume that the VS plays a pivotal role in operant behavior for motivational processing through interactions with the MPFC and for motor processing through interactions with the motor BG circuits.
However, direct evidence for the hypothesized network organization is scarce. The paucity of evidence partially results from technical difficulty in measuring neural activation at the whole-brain level in animals performing an operant conditioning task. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) is an established imaging technique, which can measure cerebral glucose metabolism as a surrogate marker of overall synaptic and neural activity (Phelps et al., 1981). Once 18F-FDG reaches the brain, 18F-FDG is taken up by astrocytes close to the sites of neural activation (Bélanger et al., 2011). Then, 18F-FDG is phosphorylated by hexokinase as is glucose but cannot be metabolized further because of the lack of hydroxyl group, yielding trapped 18F-FDG within the brain tissue after neural activity for an extended period. This slow kinetics of FDG makes it possible to insert a delay period between tasks and PET scanning (Endepols et al., 2010; Marx et al., 2012; Xi et al., 2013). Thus, 18F-FDG-PET enables us to reveal changes in glucose metabolism during operant behavior via a delayed scanning technique.
Here we combined an operant training system and 18F-FDG PET to reveal changes of glucose metabolism at the whole-brain level during operant behavior in rats. Using this method, we tested a hypothesis that VS might play a pivotal role connecting between motivational and motor systems during operant behavior. We further tested a causal relationship between neural activities in VS and motivational actions, using a pharmacological blocking method.
Section snippets
Experimental design
Sixty-four male Long-Evans rats (8-week-old at the beginning of the training; 228 ± 29 g body weight [mean ± standard deviation (s.d.)]) were used in this study (Institute for Animal Reproduction, Kasumigaura, Japan). The rats were kept under inversed light schedule (lights off at 9:00 a.m. and lights on at 9:00 p.m.) in their home cages and were handled by an experimenter for habituation (10–15 min). All animal experiments were performed under approval of the Animal Care and Use Committee of
Behavioral data
One rat was excluded from the PET analysis according to the exclusion criteria (maximum OCRR was only 37.9% across the 3 learning days). Averaged across the remaining ten rats, maximum OCRRs were 44.6% ± 33.1% (mean ± s.d.) on the 1st training day, 89.8% ± 17.7% on the 2nd training day, and 97.9% ± 4.3% before the FDG injection on the 3rd training day (before the FDG injection) (Fig. 3A). An RM-ANOVA showed significant differences in OCRRs across the training days (F[2,18] = 21.9, p < 0.001).
Discussion
In the present study, we tested a hypothesis that VS plays a pivotal role connecting between motivational processing and motor processing during operant action. For this purpose, we developed a method using 18F-FDG PET combined with an operant training system to evaluate neural activities at the whole-brain level during operant behavior. Using this approach, we revealed that the VS activities likely propagated to MPFC and motor systems through the thalamus. Moreover, muscimol injection into the
Conclusion
In the present study, we have established a procedure for measuring cerebral metabolic changes in rats at the whole brain level during operant-conditioned skilled forelimb movement. we revealed that VS signal reflects the internal motivational state during motivational action, and limbic activities evoked by rewarding stimuli propagated to the primary motor cortex and MPFC through the VS. These results suggest that VS plays a pivotal role as a hub for both motivational processing through
Conflicts of interest
The authors declare no conflict of interest.
Author contribution statement
Conceived and designed the experiments.
YH, NI, TH.
Data acquisition and analysis.
YH, NI, JO, CS.
Interpretation of data.
YH, NI, MH, KK, YI, TH.
Drafting the article.
YH, TH.
Final approval of the version to be published.
YH, NI, JO, CS, MH, KK, YI, TH.
Acknowledgements
The present work was supported in part by the National Center of Neurology and Psychiatry Intramural Research Grant (24-10, 26-9), Grants for Young Scientists (B) (15K21652), and Development of translatable biomarkers for neural circuit disturbance and recovery in cerebrovascular diseases and Parkinson's disease (16dm0207022h0003) carried out under the Brain Mapping by Integrated Neurotechnologies for Disease Studies by the Ministry of Education, Culture, Sports, Science and Technology of Japan
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- 1
YH and NI have contributed equally to this work and are co-first authors. YH is on the leave to RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan. NI is on the leave to University of Tokyo Graduate School of Pharmaceutical Sciences, Bunkyo-ku, Tokyo, Japan.