Optogenetic Mimicry of the Transient Activation of Dopamine Neurons by Natural Reward Is Sufficient for Operant Reinforcement

Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a “reward prediction error” (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function

Correlation of technetium-99m MIBI and thallium-201 retention in solitary cold thyroid nodules with postoperative histopathology

A comparative prospective study of technetium-99m methoxyisobutylisonitrile (MIBI) and thallium-201 with early (15 min) and delayed (90 min for MIBI, 3 h for Tl-201) imaging in the differentiation of thyroid lesions is presented, Forty patients with cold thyroid nodules visualised on Tc-99m-pertechnetate scan and with dyskaryotic or atypical epithelial cells verified by fine-needle aspiration biopsy underwent MIBI and Tl-201 scintigraphy at 3-day intervals. Subsequent thyroidectomies were carried out in all patients. Semiquantitative analysis was performed using a lesion to non-lesion ratio on early (ER) and delayed images (DR). Additionally, a retention index (RI) was calculated using the formula RI=(DR-ER) x 100/ER. The reproducibility of the method for the early and delayed measurements was tested by analysing intra- and inter-observer variability and repeatability coefficients. Histopathologically, the nodules were found to be well-differentiated thyroid cancer in 21 patients and benign in 19 patients. There was no significant difference in the ER between malignant and benign lesions for either Tl-201 or MIBI (P>0.05). However, for both agents significant differences were found between malignant and benign lesions with regard to DR (P0.05) except with regard to DR and RI in malignant nodules (P<0.05). A receiver operating characteristic analysis was performed to determine threshold levels for the differentiation of malignant from benign nodules. Following this analysis, ER, DR and RI levels of 1.03, 1.54 and 2 for MIBI and less than or equal to 1.42, 1.24 and 5 for Tl-201 were selected. Using these threshold levels, the sensitivity, specificity and accuracy of the study were 90.5%, 36.8% and 65% for ER MIBI, 61.9%, 94.7% and 77.5% for DR MIBI, 95.2%, 89.4% and 92.5% for RI MIBI, 85.7%, 47.3% and 67.5% for ER Tl-201 , 80.9%, 73.6% and 77.5% for DR Tl-201, and 90.5%, 4.7% and 92.5% for RI Tl-201. In conclusion, the DR for MIBI and Tl-201 is superior to the ER in detecting malignant nodules, and the RI for both MIBI and Tl-201 is more valuable than the DR in differentiating malignant from benign thyroid nodules

Night Eating Syndrome Frequency in University Students: Association with Impulsivity, Depression, and Anxiety

Objective:The aim of this study was to examine frequency of night eating syndrome and its correlates with depression, anxiety, impulsivity and problematic eating behaviors in a university sample from Turkey

A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins

Cross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins. We developed a method for CLIP data analysis, and applied it to compare CLIP with photoactivatable ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in cross-linking and ribonuclease digestion affect the identified sites. We found only small differences in accuracies of these methods in identifying binding sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a complex binding specificity. We found that cross-link-induced mutations led to single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the expectation from original CLIP publications that RNA-binding proteins do not protect their binding sites sufficiently under the denaturing conditions used during the CLIP procedure, and we show that extensive digestion with sequence-specific RNases strongly biases the recovered binding sites. This bias can be substantially reduced by milder nuclease digestion conditions

Revisiting the global workspace orchestrating the hierarchical organization of the human brain

A central challenge in neuroscience is how the brain organizes the information necessary to orchestrate behaviour. Arguably, this whole-brain orchestration is carried out by a core subset of integrative brain regions, a ‘global workspace’, but its constitutive regions remain unclear. We quantified the global workspace as the common regions across seven tasks as well as rest, in a common ‘functional rich club’. To identify this functional rich club, we determined the information flow between brain regions by means of a normalized directed transfer entropy framework applied to multimodal neuroimaging data from 1,003 healthy participants and validated in participants with retest data. This revealed a set of regions orchestrating information from perceptual, long-term memory, evaluative and attentional systems. We confirmed the causal significance and robustness of our results by systematically lesioning a generative whole-brain model. Overall, this framework describes a complex choreography of the functional hierarchical organization of the human brain.The authors thank D. Chicharro, R. Quian Quiroga, A. Brovelli, J.-P.Changeux and S. Dehaene for their insightful comments on the manuscript, as well as A. Horn and N. Li for their help with diffusion MRI. G.D. is supported by a Spanish research project (ref.PID2019-105772GB-I00 AEI FEDER EU) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI) and European Regional Development Funds (FEDER); HBP SGA3 Human Brain Project Specific Grant Agreement 3 (grant agreement no. 945539), funded by the EU H2020 FET Flagship programme and SGR Research Support Group support (ref. 2017 SGR 1545), funded by the Catalan Agency for Management of University and Research Grants (AGAUR). M.L.K. is supported by the ERC Consolidator Grant: CAREGIVING (no. 615539), Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing funded by the Pettit and Carlsberg Foundations. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscrip