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.

Understanding coral-climate interactions through deep time is essential for evaluating reef resilience under ongoing climate change. Rejuvenescence is a rare and poorly documented phenomenon in fossil and extant reef-building scleractinian corals, involving polyp contraction followed by regeneration, and has previously been described as a survival strategy for coping with acute thermal stress in a living species. Here, we report evidence of rejuvenescence from a fossil reef in the Makran region of Iran, dated to the Miocene Climatic Optimum, and place it within an ecological and evolutionary framework. Its occurrence in both Miocene Iranian Acanthastrea cf. polygonalis and modern Mediterranean Cladocora caespitosa, despite their phylogenetic, temporal, and biogeographic separation, suggests a recurrent morphogenetic response associated with inferred thermal stress and potentially linked to metabolic downregulation, while its evolutionary origin remains unresolved between deep homology and convergent evolution. This putative role of rejuvenescence in promoting survival appears to be restricted to individual colonies or species and does not translate into thermal resilience at the reef-community scale. Accordingly, current evidence does not support rejuvenescence as a mechanism enhancing coral reef climate resistance but instead identifies it as an indicator of conditions approaching upper thermal tolerance limits in reef ecosystems across geological timescales.

Chronic Kidney Disease (CKD) lacks effective disease-modifying therapies. Retinoic acid (RA) exhibits immunomodulatory and antifibrotic properties; however, its molecular targets and structural mechanisms in CKD remain incompletely understood. We applied an integrative strategy combining network pharmacology, structure-based modeling, and in vivo validation. CKD-associated genes were collected from CTD, GeneCards, MalaCards, and TTD, while RA targets were predicted or curated from PharmMapper, SEA, CTD, and STITCH, followed by UniProt harmonization. Kidney-specific expression was ensured using Human Protein Atlas data (nTPM > 1), and disease-relevant targets were prioritized based on upregulation in GSE142025. Functional enrichment analyses were conducted using GO, KEGG, Reactome, and MSigDB Hallmark datasets (FDR q < 0.05). Protein-protein interaction networks were constructed via STRING and analyzed with CytoHubba to identify hub genes. Molecular docking, 100-ns GROMACS molecular dynamics simulations, and MM-GBSA binding free-energy analysis assessed the predicted stability of the RA-target complexes. Experimental validation was performed in a doxorubicin-induced CKD rat model using protein-level analysis. A total of 2,005 CKD genes and 507 RA targets were identified, with 252 overlapping genes, including 216 kidney-expressed targets. Transcriptomic prioritization yielded 86 upregulated targets enriched in immune-inflammatory signaling, apoptosis, and extracellular matrix remodeling. Network analysis identified five hub genes (AKT1, TP53, TNF, FN1, MMP9). Docking predicted moderate-to-strong binding affinities, particularly for MMP9 (- 9.8 kcal/mol). Molecular dynamics simulations indicated stable complexes, and MM-GBSA binding free energies ranked the hubs MMP9 > TNF > p53 > FN1 > AKT1 (- 26.4 to - 12.3 kcal/mol). In vivo, RA significantly modulated renal expression of all hub proteins. These findings identify RA as a context-dependent regulator of immune-fibrotic networks in CKD, with AKT1, TP53, TNF, FN1, and MMP9 as promising therapeutic targets.

Regular physical activity elicits coordinated molecular adaptations across skeletal muscle, the cardiovascular system, metabolic organs and the brain, underpinning improvements in performance and cardiometabolic health. While classical signaling pathways such as AMPK-PGC‑1α, Ca²⁺/calcineurin, and mTORC1 have been extensively characterized, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of exercise-induced remodeling. Here, we synthesize current evidence on lncRNAs as molecular mediators of exercise adaptations, drawing on mechanistic studies and systems-level transcriptomics. In skeletal muscle, the exercise-induced lncRNAs CYTOR and TUG1 modulate fast-twitch myogenesis, mitochondrial function and fiber-type specification. In the heart, CPhar, lncExACT1 and Mhrt779 discriminate physiological from pathological hypertrophy and encode antihypertrophic "memory," whereas endothelial NEAT1 integrates aerobic training with m⁶A-modulated pyroptosis and atheroprotection. MALAT1 mediates neuroprotection after exercise preconditioning in ischemia/reperfusion models. Omics and network analyses reveal highly modality-, tissue- and cell-type-specific lncRNA programs during human training and across multiple organs. Emerging clinical data support circulating lncRNAs such as MALAT1 and HOTTIP as candidate biomarkers of vascular function and training adaptation. Collectively, lncRNAs constitute a hidden regulatory layer that shapes the quality, magnitude and persistence of exercise-induced adaptations. However, mechanistic evidence is currently limited to a small number of "flagships" lncRNAs, and non-muscle tissues and inter-organ communication remain underexplored. Priorities include functional validation of atlas-derived candidates, dissection of exerkine lncRNAs, and integration of lncRNA biology into precision exercise medicine.