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The dorsal striatum receives converging excitatory inputs from diverse brain regions, including the cerebral cortex and the intralaminar/ midline thalamic nuclei, and mediates learning processes contributing to instrumental motor actions. However, the roles of each striatal input pathway in these learning processes remain uncertain. We developed a novel strategy to target specific neural pathways and applied this strategy for studying behavioral roles of the pathway originating from the parafascicular nucleus (PF) and projecting to the dorsolateral striatum. A highly efficient retrograde gene transfer vector encoding the recombinant immunotoxin (IT) receptor was injected into the dorsolateral striatum in mice to express the receptor in neurons innervating the striatum. IT treatment into the PF of the vector-injected animals caused a selective elimination of neurons of the PF-derived thalamostriatal pathway. The elimination of this pathway impaired the response selection accuracy and delayed the motor response in the acquisition of a visual cue-dependent discrimination task. When the pathway elimination was induced after learning acquisition, it disturbed the response accuracy in the task performance with no apparent change in the response time. The elimination did not influence spontaneous locomotion, methamphetamine-induced hyperactivity, and motor skill learning that demand the function of the dorsal striatum. These results demonstrate that thalamostriatal projection derived from the PF plays essential roles in the acquisition and execution of discrimination learning in response to sensory stimulus. The temporal difference in the pathway requirement for visual discrimination suggests a stage-specific role of thalamostriatal pathway in the modulation of response time of learned motor actions.

To evaluate mortality reduction from gastric cancer by endoscopic screening, we undertook a population‐based cohort study in which both radiographic and endoscopic screenings for gastric cancer have been carried out. The subjects were selected from the participants of gastric cancer screening in two cities in Japan, Tottori and Yonago, from 2007 to 2008. The subjects were defined as participants aged 40–79 years who had no gastric cancer screening in the previous year. Follow‐up of mortality was continued from the date of the first screening to the date of death or up to December 31, 2013. A Cox proportional hazards model was used to estimate the relative risk (RR) of gastric cancer incidence, gastric cancer death, all cancer deaths except gastric cancer death, and all‐causes death except gastric cancer death. The number of subjects selected for endoscopic screening was 9950 and that for radiographic screening was 4324. The subjects screened by endoscopy showed a 67% reduction of gastric cancer compared with the subjects screened by radiography (adjusted RR by sex, age group, and resident city = 0.327; 95% confidence interval [CI], 0.118–0.908). The adjusted RR of endoscopic screening was 0.968 (95%CI, 0.675–1.387) for all cancer deaths except gastric cancer death, and 0.929 (95%CI, 0.740–1.168) for all‐causes death except gastric cancer death. This study indicates that endoscopic screening can reduce gastric cancer mortality by 67% compared with radiographic screening. This is consistent with previous studies showing that endoscopic screening reduces gastric cancer mortality.

Behavioural flexibility is mediated through the neural circuitry linking the prefrontal cortex and basal ganglia. Here we conduct selective elimination of striatal cholinergic interneurons in transgenic rats by immunotoxin-mediated cell targeting. Elimination of cholinergic interneurons from the dorsomedial striatum (DMS), but not from the dorsolateral striatum, results in enhanced reversal and extinction learning, sparing the acquisition of place discrimination. This enhancement is prevented by infusion of a non-selective muscarinic acetylcholine receptor agonist into the DMS either in the acquisition, reversal or extinction phase. In addition, gene-specific silencing of M4 muscarinic receptor by lentiviral expression of short hairpin RNA (shRNA) mimics the place reversal learning promoted by cholinergic elimination, whereas shRNA-mediated gene silencing of M1 muscarinic receptor shows the normal performance of reversal learning. Our data indicate that DMS cholinergic interneurons inhibit behavioural flexibility, mainly through the M4 muscarinic receptor, suggesting that this role is engaged to the stabilization of acquired reward contingency and the suppression of response switch to changed contingency.

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