Striatal dopamine plays key roles in our normal and pathological goal-directed actions. To understand dopamine function, much attention has focused on how midbrain dopamine neurons modulate their firing patterns. However, we identify a presynaptic mechanism that triggers dopamine release directly, bypassing activity in dopamine neurons. We paired electrophysiological recordings of striatal channelrhodopsin2-expressing cholinergic interneurons with simultaneous detection of dopamine release at carbon-fiber microelectrodes in striatal slices. We reveal that activation of cholinergic interneurons by light flashes that cause only single action potentials in neurons from a small population triggers dopamine release via activation of nicotinic receptors on dopamine axons. This event overrides ascending activity from dopamine neurons and, furthermore, is reproduced by activating ChR2-expressing thalamostriatal inputs, which synchronize cholinergic interneurons in vivo. These findings indicate that synchronized activity in cholinergic interneurons directly generates striatal dopamine signals whose functions will extend beyond those encoded by dopamine neuron activity.

In this issue of Neuron, Threlfell et al. (2012) report that synchronous activation of cholinergic interneurons evokes striatal dopamine release by activating presynaptic nicotinic acetylcholine receptors. These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine "feud" over control of striatal circuitry.

The present investigation had two aims: (1) to study responses of dopamine neurons to stimuli with attentional and motivational significance during several steps of learning a behavioral task, and (2) to study the activity of dopamine neurons during the performance of cognitive tasks known to be impaired after lesions of these neurons. Monkeys that had previously learned a simple reaction time task were trained to perform a spatial delayed response task via two intermediate tasks. During the learning of each new task, a total of 25% of 76 dopamine neurons showed phasic responses to the delivery of primary liquid reward, whereas only 9% of 163 neurons responded to this event once task performance was established. This produced an average population response during but not after learning of each task. Reward responses during learning were significantly more numerous and pronounced in area A10, as compared to areas A8 and A9. Dopamine neurons also showed phasic responses to the two conditioned stimuli. These were the instruction cue, which was the first stimulus in each trial and indicated the target of the upcoming arm movement (58% of 76 neurons during and 44% of 163 neurons after learning), and the trigger stimulus, which was a conditioned incentive stimulus predicting reward and eliciting a saccadic eye movement and an arm reaching movement (38% of neurons during and 40% after learning). None of the dopamine neurons showed sustained activity in the delay between the instruction and trigger stimuli that would resemble the activity of neurons in dopamine terminal areas, such as the striatum and frontal cortex. Thus, dopamine neurons respond phasically to alerting external stimuli with behavioral significance whose detection is crucial for learning and performing delayed response tasks. The lack of sustained activity suggests that dopamine neurons do not encode representational processes, such as working memory, expectation of external stimuli or reward, or preparation of movement. Rather, dopamine neurons are involved with transient changes of impulse activity in basic attentional and motivational processes underlying learning and cognitive behavior.

Basal Ganglia Advances is a collection highlighting research on the structure, function, and disorders of the basal ganglia. It features studies spanning neuroscience, clinical insights, and computational models, serving as a hub for advances in movement, cognition, and behavior.

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.

The evolutionary origins of adaptive immune diversification remain a central question in immunology. Using zebrafish as an early vertebrate model, we systematically dissect the distinct diversification strategies of ancient IgM and IgZ antibody repertoires. While both isotypes share a common V gene pool, they exhibit lineage-specific V/J usage biases during independent V(D)J recombination. Heavy-chain rearrangement employs the recombination-activating gene-non-homologous end joining (RAG-NHEJ) pathway, with IgM demonstrating greater junctional diversity than IgZ. Antigen-driven somatic hypermutation (SHM) primarily targets IgM via activation-induced cytidine deaminase (AID)-primed base excision repair/mismatch repair within primitive germinal center-like clusters. However, unbiased targeting across complementarity determining and framework regions, together with constrained CXCR5-CXCL13 signaling, limits mutation frequency and affinity maturation. Notably, we identify an AID-independent SHM pathway mediated by APOBEC2a that specifically targets TCG/CGT motifs. Furthermore, light-chain V-J recombination is uniquely processed via microhomology-mediated end joining, restricting CDR3 diversity compared with heavy-chain. Conversely, IgZ B cells are biased toward plasma cell differentiation, exhibit loosely organized distribution, and undergo minimal antigen-driven SHM, aligning with rapid mucosal defense. Our findings reveal both conserved and distinct diversification mechanisms in teleosts, illuminating layered evolutionary strategies balancing receptor diversity and self-tolerance in early vertebrates.

The Vancouver Island marmot (VIM; Marmota vancouverensis) is a critically endangered sciurid endemic to the subalpine meadows of Vancouver Island, British Columbia, Canada. In response to population declines in the 1980s and 1990s, an intensive conservation breeding and reintroduction program was initiated in 1997. This recovery effort has generated significant health-related data from the captive, captive-release, and wild VIM populations, including results from 153 ex situ and 820 in situ mortalities. There were important differences in surveillance between captive and free-ranging populations (captive release and wild). Ex situ marmots exhibited greater longevity, were monitored with greater intensity, were carefully managed during hibernation, and were safeguarded against predation. These factors facilitated prompt recognition, recovery, and evaluation of mortalities. Cardiomyopathy and neoplasia represented the most significant causes of mortality in captives but were not observed in their in situ counterparts, possibly due to reduced longevity, dissimilar risk patterns, or limited opportunities to evaluate intact carcasses. Intact carcasses of free-ranging marmots were mainly recovered in spring and resulted from hibernation-related, postemergent emaciation. Mortalities of free-ranging VIMs often presented as incomplete remains or were inaccessible in burrows, meaning they were evaluated according to on-site field observations. Investigations indicated that the first wild hibernation was a time of substantial mortality for marmots released from captivity. However, captive releases that survived their first winter displayed a low incidence of hibernation mortality in subsequent winters, a success rate similar to that of their wild-born counterparts. Predators, particularly cougars (Puma concolor), represented the most consequential cause of mortality for both captive-release and wild marmots. No specific infectious agents were identified as presenting a generalized threat to in situ or ex situ populations. Chronic obesity in captives, reduced hibernation survival of first-year captive releases, and pronounced, seasonal predation of free-ranging marmots appear to represent important factors influencing the health and recovery of this critically endangered species.

Grounded theory offers rich possibilities for health-related qualitative research, yet it is frequently misunderstood. Grounded theory is not simply a coding method, but a rigorous methodological approach, with core elements impacting the entire research process, whose goal is to generate a theory that is grounded in the data. Although there is not a unified definition of grounded theory among all its proponents, constructivist grounded theory (CGT) as formulated by Kathy Charmaz is particularly well suited to investigating complex social processes in health care. In this Method/ology article we (1) explain constructivism as a foundational worldview that presumes meaning is coconstructed by individuals through their interactions, (2) outline how the CGT approach grounds both the researcher and their outcomes in the data through an iterative process of data collection and analysis, and (3) describe how the CGT researcher moves beyond descriptive themes to develop a theory or explanatory model of specific social processes. This article highlights common pitfalls in qualitative health care research and provides practical guidance for clinician-researchers interested in pursuing CGT studies.