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.

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.

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 concentrations of extracellular and intracellular signaling molecules, such as dopamine and cAMP, change over both fast and slow timescales and impact downstream pathways in a cell-type specific manner. Fluorescence sensors currently used to monitor such signals in vivo are typically optimized to detect fast, relative changes in concentration of the target molecule. They are less well suited to detect slowly-changing signals and rarely provide absolute measurements of either fast and slow signaling components. Here, we developed a system for fluorescence lifetime photometry at high temporal resolution (FLIPR) that utilizes frequency-domain analog processing to measure the absolute fluorescence lifetime of genetically-encoded sensors at high speed but with long-term stability and picosecond precision in freely moving mice. We applied FLIPR to investigate dopamine signaling in two functionally distinct regions in the striatum, the nucleus accumbens core (NAC) and the tail of striatum (TOS). We observed higher tonic dopamine levels at baseline in the TOS compared to the NAC and detected differential and dynamic responses in phasic and tonic dopamine to appetitive and aversive stimuli. Thus, FLIPR enables simple monitoring of fast and slow time-scale neuronal signaling in absolute units, revealing previously unappreciated spatial and temporal variation even in well-studied signaling systems.

Based on the activity of dopamine (DA) neurons during behavioral states, the DA system has long been thought to be foundational in regulating sleep-wake behavior; over the past decade advances in circuit manipulation and recording techniques have strengthened this perspective. Recently, several studies have demonstrated that DA release in regions of the limbic system is important in the promotion of REM sleep. Yet how DA dynamics change within bouts of sleep, how these changes are regulated, and whether they influence future state changes remains unclear. To address these questions, in mice of both sexes we used in vivo fiber photometry and inhibitory optogenetics to identify a specific role of DA transients in the nucleus accumbens (NAcc) in state transitions from NREM sleep. We found that DA transients increase their frequency and amplitude over the duration of NREM sleep and that this increase is more pronounced during NREM bouts that transition into REM sleep. Next, we found that DA transients in NREM sleep are influenced by changes in REM sleep pressure. Finally, we show that transient DA release in the NAcc plays a functional role in regulating the timing of REM sleep entrances, as inhibition of midbrain DA neuron terminals in the NAcc prolonged bouts of NREM sleep and decreased the frequency of bouts of REM sleep. These findings demonstrate that DA release in the NAcc is dynamically regulated by sleep pressure and has a functional role in transitions from NREM sleep, particularly those into REM sleep. Sleep is a central component of daily life and is heavily influenced by midbrain dopamine neurons. Dopamine release in limbic regions, such as the nucleus accumbens, has been implicated in the promotion of REM sleep. However, dopamine release dynamics during sleep and how these influence future changes in state remain unclear. We used a fluorescence-based dopamine biosensor to elucidate the pattern of dopamine release during sleep and inhibitory optogenetics to disrupt dopamine release. Dopamine release increases across the duration of NREM sleep bouts and is sensitive to REM sleep need. Inhibition of dopamine terminals in the nucleus accumbens decreases the frequency of REM sleep. This suggests that phasic dopamine release during NREM sleep functionally influences REM sleep timing.