Spatial subgoal learning in the mouse: behavioral and computational mechanisms

Here we aim to better understand how animals navigate structured environments. The prevailing wisdom is that they can select among two distinct approaches: querying a mental map of the environment or repeating previously successful trajectories to a goal. However, this dichotomy has been built around data from rodents trained to solve mazes, and it is unclear how it applies to more naturalistic scenarios such as self-motivated navigation in open environments with obstacles. In this project, we leveraged instinctive escape behavior in mice to investigate how rodents use a period of exploration to learn about goals and obstacles in an unfamiliar environment. In our most basic assay, mice explore an environment with a shelter and an obstacle for 5-20 minutes and then we present threat stimuli to trigger escapes to shelter. After 5-10 minutes of exploration, mice took inefficient paths to the shelter, often nearly running into the obstacle and then relying on visual and tactile cues to avoid it. Within twenty minutes, however, they spontaneously developed an efficient subgoal strategy, escaping directly to the obstacle edge before heading to the shelter. Mice escaped in this manner even if the obstacle was removed, suggesting that they had memorized a mental map of subgoals. Unlike typical models of map-based planning, however, we found that investigating the obstacle was not important for updating the map. Instead, learning resembled trajectory repetition: mice had to execute `practice runs' toward an obstacle edge in order to memorize subgoals. To test this hypothesis directly, we developed a closed-loop neural manipulation, interrupting spontaneous practice runs by stimulating premotor cortex. This manipulation successfully prevented subgoal learning, whereas several control manipulations did not. We modelled these results using a panel of reinforcement learning approaches and found that mice behavior is best matched by systems that explore in a non-uniform manner and possess a high-level spatial representation of regions in the arena. We conclude that mice use practice runs to learn useful subgoals and integrate them into a hierarchical cognitive map of their surroundings. These results broaden our understanding of the cognitive toolkit that mammals use to acquire spatial knowledge

Mice identify subgoal locations through an action-driven mapping process

Mammals form mental maps of the environments by exploring their surroundings. Here, we investigate which elements of exploration are important for this process. We studied mouse escape behavior, in which mice are known to memorize subgoal locations-obstacle edges-to execute efficient escape routes to shelter. To test the role of exploratory actions, we developed closed-loop neural-stimulation protocols for interrupting various actions while mice explored. We found that blocking running movements directed at obstacle edges prevented subgoal learning; however, blocking several control movements had no effect. Reinforcement learning simulations and analysis of spatial data show that artificial agents can match these results if they have a region-level spatial representation and explore with object-directed movements. We conclude that mice employ an action-driven process for integrating subgoals into a hierarchical cognitive map. These findings broaden our understanding of the cognitive toolkit that mammals use to acquire spatial knowledge

A Randomised Phase 2 Trial of Intensive Induction Chemotherapy (CBOP/BEP) and Standard BEP in Poor-prognosis Germ Cell Tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604)

AbstractBackgroundStandard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required.ObjectiveTo explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial.Design, setting, and participantsWe conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres.InterventionBEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15 000 IU).Outcome measurements and statistical analysisPrimary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates.Results and limitationsA total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61–85) with CBOP/BEP, 61% with BEP (90% CI, 48–73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33–1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS.ConclusionsThe primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial.Patient summaryIn this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration.Trial registrationISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604

Perspectives on cancer therapy-induced mucosal injury : Pathogenesis, measurement, epidemiology, and consequences for patients

Copyright © 2004 American Cancer SocietyBACKGROUND: A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis. METHODS: The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines. RESULTS: New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before. CONCLUSIONS: Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies.Stephen T. Sonis, Linda S. Elting, Dorothy Keefe, Douglas E. Peterson, Mark Schubert, Martin Hauer-Jensen, B. Nebiyou Bekele, Judith Raber-Durlacher, J. Peter Donnelly, Edward B. Rubenstein, for the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncolog