Transient changes in the firing of midbrain dopamine neurons have been closely tied to the unidimensional value-based prediction error contained in temporal difference reinforcement learning models. However, whereas an abundance of work has now shown how well dopamine responses conform to the predictions of this hypothesis, far fewer studies have challenged its implicit assumption that dopamine is not involved in learning value-neutral features of reward. Here, we review studies in rats and humans that put this assumption to the test, and which suggest that dopamine transients provide a much richer signal that incorporates information that goes beyond integrated value.

The major pathological feature of Parkinson 's disease (PD), the second most common neurodegenerative disease and most common movement disorder, is the predominant degeneration of dopaminergic neurons in the substantia nigra, a part of the midbrain. Despite decades of research, the molecular mechanisms of the origin of the disease remain unknown. While the disease was initially viewed as a purely neuronal disorder, results from single-cell transcriptomics have suggested that oligodendrocytes may play an important role in the early stages of Parkinson's. Although these findings are of high relevance, particularly to the search for effective disease-modifying therapies, the actual functional role of oligodendrocytes in Parkinson's disease remains highly speculative and requires a concerted scientific effort to be better understood. This Unsolved Mystery discusses the limited understanding of oligodendrocytes in PD, highlighting unresolved questions regarding functional changes in oligodendroglia, the role of myelin in nigral dopaminergic neurons, the impact of the toxic environment, and the aggregation of alpha-synuclein within oligodendrocytes.

Understanding how corticostriatal circuits mediate behavioral selection and initiation in a naturalistic setting is critical to understanding behavior choice and execution in unconstrained situations. The central striatum (CS) is well poised to play an important role in these spontaneous processes. Using fiber photometry and optogenetics, we identify a role for CS in grooming initiation. However, CS-evoked movements resemble short grooming fragments, suggesting additional input is required to appropriately sustain behavior once initiated. Consistent with this idea, the anterior lateral motor area (ALM) demonstrates a slow ramp in activity that peaks at grooming termination, supporting a potential role for ALM in encoding grooming bout length. Furthermore, optogenetic stimulation of ALM-CS terminals generates sustained grooming responses. Finally, dual-region photometry indicates that CS activation precedes ALM during grooming. Taken together, these data support a model in which CS is involved in grooming initiation, while ALM may encode grooming bout length.

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Recent advances in the field of Voltage Imaging, with a special focus on new constructs and novel implementations.

Work related to place tuning, spatial navigation, orientation and direction. Mainly includes articles on connectivity in the hippocampus, retrosplenial cortex, and related areas.

CXCL12-CXCR4 signaling is involved in a wide variety of homeostatic and pathologic processes, but the role of specific CXCL12 isoforms has remained largely unexplored. We have recently shown that the CXCL12γ isoform, which holds an exceptionally high affinity for heparan sulfate (HS), is produced by human bone marrow stromal cells (BMSCs) and remains cell surface immobilized by HS proteoglycans (HSPGs). This HS-bound CXCL12γ is critical for the adhesion of multiple myeloma cells to BMSCs and for BMSC-mediated drug resistance. In this study, we investigated how CXCL12γ activates and regulates CXCR4 by employing a variety of biosensors in HEK293T cells, endogenous CXCR4-expressing B-lymphoma and myeloma cell lines and primary B cells. We showed that CXCL12γ and CXCL12α bind CXCR4 with a similar affinity and that the cumulative activation of CXCR4 over time is equal for both ligands, although CXCL12α activates CXCR4 more rapidly. Although nonbound CXCL12γ and CXCL12α equally induce CXCR4 internalization, cell- or heparin-bound CXCL12γ hardly induces CXCR4 internalization or desensitization. CXCL12γ presented by HSPGs on the membrane of human bone marrow endothelial cells (HBMECs) induces potent cell adhesion to the endothelium under physiological flow, but cells retain the ability to migrate toward CXCL12α when they encounter HBMEC-bound CXCL12γ. Taken together, our data demonstrate that CXCL12γ and CXCL12α differentially modulate CXCR4 trafficking and that CXCL12γ, when immobilized and presented by HSPGs on the cell surface of HBMECs, can efficiently arrest circulating cells without causing CXCR4 internalization or desensitization, thus enabling subsequent cell migration toward a CXCL12α gradient.