Although learning in response to extrinsic reinforcement is theorized to be driven by dopamine signals that encode the difference between expected and experienced rewards, skills that enable verbal or musical expression can be learned without extrinsic reinforcement. Instead, spontaneous execution of these skills is thought to be intrinsically reinforcing. Whether dopamine signals similarly guide learning of these intrinsically reinforced behaviours is unknown. In juvenile zebra finches learning from an adult tutor, dopamine signalling in a song-specialized basal ganglia region is required for successful song copying, a spontaneous, intrinsically reinforced process. Here we show that dopamine dynamics in the song basal ganglia faithfully track the learned quality of juvenile song performance on a rendition-by-rendition basis. Furthermore, dopamine release in the basal ganglia is driven not only by inputs from midbrain dopamine neurons classically associated with reinforcement learning but also by song premotor inputs, which act by means of local cholinergic signalling to elevate dopamine during singing. Although both cholinergic and dopaminergic signalling are necessary for juvenile song learning, only dopamine tracks the learned quality of song performance. Therefore, dopamine dynamics in the basal ganglia encode performance quality during self-directed, long-term learning of natural behaviours.

Linking activity in specific cell types with perception, cognition, and action, requires quantitative behavioral experiments in genetic model systems such as the mouse. In head-fixed primates, the combination of precise stimulus control, monitoring of motor output, and physiological recordings over large numbers of trials are the foundation on which many conceptually rich and quantitative studies have been built. Choice-based, quantitative behavioral paradigms for head-fixed mice have not been described previously. Here, we report a somatosensory absolute object localization task for head-fixed mice. Mice actively used their mystacial vibrissae (whiskers) to sense the location of a vertical pole presented to one side of the head and reported with licking whether the pole was in a target (go) or a distracter (no-go) location. Mice performed hundreds of trials with high performance (>90% correct) and localized to <0.95 mm (<6 degrees of azimuthal angle). Learning occurred over 1-2 weeks and was observed both within and across sessions. Mice could perform object localization with single whiskers. Silencing barrel cortex abolished performance to chance levels. We measured whisker movement and shape for thousands of trials. Mice moved their whiskers in a highly directed, asymmetric manner, focusing on the target location. Translation of the base of the whiskers along the face contributed substantially to whisker movements. Mice tended to maximize contact with the go (rewarded) stimulus while minimizing contact with the no-go stimulus. We conjecture that this may amplify differences in evoked neural activity between trial types.

The substantia nigra pars reticulata (SNr) functions as the principal inhibitory output of the basal ganglia, with the timing of its spikes critically controlling downstream disinhibition required for movement initiation. The external globus pallidus (GPe) and D1-expressing medium spiny neurons (D1-MSNs) in the striatum provide GABAergic inputs to the SNr that differ in their amplitude and kinetic properties. How these inputs interact with the intrinsic membrane currents that determine SNr firing is only partially understood. Using optogenetics, computational modeling, and electrophysiology in acute mouse brain slices, 47 animals of either sex were used for measurements, and we found an unexpected interaction between GABAergic inputs and hyperpolarization-activated currents (Ih) that tunes inhibitory efficacy in a pathway-specific manner. GPe inputs evoke fast, large IPSCs that transiently suppress SNr firing within a narrow window but whose rapid decay enables depolarization from Ih to restore firing after only a brief pause. In contrast, the slower decay kinetics of striatal IPSCs enables more sustained inhibition that counters the depolarizing drive from Ih to produce longer pauses, despite their lower conductance amplitudes. Pharmacological blockade of Ih with ZD7288 eliminated the rapid recovery of firing after GPe inhibition and equalized the inhibitory efficacy between GPe and striatal pathways. These findings establish an important interplay between synaptic kinetics and intrinsic membrane conductances in establishing pathway-specific inhibitory balance in the basal ganglia. Our study reveals that inhibitory pathways to the substantia nigra pars reticulata are differentially shaped by the interplay between synaptic kinetics and intrinsic membrane conductances. Using optogenetics, electrophysiology, and modeling, we showed that fast-decaying GABAergic inputs from the external globus pallidus are rapidly overcome by Ih, producing only brief pauses in SNr firing, whereas slower striatal inputs generate longer-lasting inhibition. Blocking Ih abolishes this difference, demonstrating that intrinsic currents tune inhibitory efficacy in a pathway-specific manner. These results identify a biophysical mechanism that helps set the balance of basal ganglia output essential for movement control.

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.

How the brain signals prediction errors for non-rewarding, yet significant, sensory events remains a central question. Although the cortical mismatch negativity provides a well-known signature for deviance detection, the contribution of subcortical dopamine remains unclear. This study tested the hypothesis that phasic dopamine in the nucleus accumbens encodes the salience associated with the violation of an ongoing statistical regularity. Using fiber photometry in freely moving rats, we contrasted an auditory oddball paradigm with a many-standards control. Deviant stimuli elicited a significantly amplified dopamine response compared with standard stimuli. Crucially, this dopamine response enhancement was absent in the control condition, demonstrating that the nucleus accumbens dopamine responds specifically to rule violation rather than mere stimulus rarity. The long latency of this signal (~500 ms) relative to the cortical mismatch negativity argues against a direct role in the initial detection of deviance. Instead, our findings support a model in which subcortical dopamine acts as a distinct salience signal, operating in parallel with cortical deviance detection, to evaluate unexpected events and guide subsequent behavioral adjustments.

C57BL/6 mice serve as in vivo-model mimicking acute enteritis caused by Salmonella Typhimurium (S. Tm) but succumb to infection within a week. CBA mice, however, were shown to be clinically resistant to S. Tm-infection, survive the acute phase and are hence suitable to study chronic infection. We performed a comprehensive survey of enteropathogenic loads and immunopathological responses in intestinal compartments during the early and late phase of S. Tm-infection. Upon oral challenge of CBA mice, the enteropathogens colonized the intestines with highest loads in the cecum and colon. Whereas all mice survived the 4-week observation period and did not display any symptoms, marked inflammatory cell damage became overt in the cecum as early as 24 h post-infection (p.i.) that was accompanied by increased numbers of large intestinal innate immune cells including neutrophils, macrophages, and monocytes on days 1 and 14 p.i., whereas recruitment of adaptive immune cells such as T and B lymphocytes and regulatory T cells to the cecum and colon was pronounced on days 14 and 28 p.i. Depending on the time point S. Tm-infection resulted in differential cytokine secretion alongside the intestinal tract. Collectively, our results underscore CBA mice as a model to study chronic S. Tm-infection including long-term fecal pathogen shedding.

Effective extrahepatic activity of therapeutic oligonucleotides remains an unresolved and significant problem in the development of new genetic medicines. Targeted delivery to the heart is of particular interest due to the unmet need to treat an increasing health burden of cardiovascular diseases and the identification of potential genetic therapeutic targets. Drawing inspiration from literature, we investigate the potential of tannic acid (TA) modifications to improve the activity of a model siRNA sequence in the heart. We developed the synthesis of a series of conjugates containing 1-3 (TA) units to study how molecularly defined numbers of TA ligands influence activity. While we observe significant knockdown of the siRNA target gene in the liver, we did not in the heart, suggesting that although TA ligands confer improved function of siRNA in the liver, extrahepatic activity was not enhanced. In addition, hetero-bifunctional siRNA conjugates containing both TA and albumin binding motifs were designed and their synergistic effects explored. Similarly, data suggests that TA ligands do not increase cardiac activity of siRNA in this context; however, we can conclude that both C16 and AlbuTag ligands do significantly improve siRNA activity in the heart. We believe this work provides important bioconjugation insight for polyphenolic molecules, like tannic acid, as well as the synthesis of hetero-bifunctional siRNA conjugates generally. Moreover, our findings will inform the design of novel targeting ligands and nanomaterials, especially for molecules that may possess emergent properties when present in high multiplicity compared to their monomeric forms.