Precisely neuromodulating deep brain regions could bring transformative advancements in both neuroscience and treatment. We demonstrate that non-invasive transcranial ultrasound stimulation (TUS) can selectively modulate deep brain activity and affect learning and decision making, comparable to deep brain stimulation (DBS). We tested whether TUS could causally influence neural and behavioural responses by targeting the nucleus accumbens (NAcc) using a reinforcement learning task. Twenty-six healthy adults completed a within-subject TUS-fMRI experiment with three conditions: TUS to the NAcc, dorsal anterior cingulate cortex (dACC), or Sham. After TUS, participants performed a probabilistic learning task during fMRI. TUS-NAcc altered BOLD responses to reward expectation in the NAcc and surrounding areas. It also affected reward-related behaviours, including win-stay strategy use, learning rate following rewards, learning curves, and repetition rates of rewarded choices. DBS-NAcc perturbed the same features, confirming target engagement. These findings establish TUS as a viable approach for non-invasive deep-brain neuromodulation.

Interval timing is an evolutionarily well-preserved function that presents similar behavioral signatures across different species. However, the neural basis of interval timing remains an open question. For instance, although dopamine has been implicated as a vital component of the internal clock, its precise role is debated due to equivocal findings from various methodologies and their interpretations. We tested this question by optogenetically exciting versus inhibiting tyrosine hydroxylase-positive (TH+) neurons of the substantia nigra pars compacta while male mice produced at least a 3-second-long interval by depressing a lever for reward. Excitation of TH+ neurons shifted their timing behavior to the right, while inhibition led to a shift to the left. Our drift-diffusion-timing model-based analysis of the behavioral data clearly showed that TH+ neuron excitation and inhibition heightened and lowered the timing threshold, respectively, without affecting the rate of temporal integration (i.e., clock speed). Our work attributes a clear mechanistic role (i.e., threshold setting) to nigrostriatal dopaminergic function as part of the internal clock. Despite the ubiquity of time experience, how the brain perceives time is unresolved. Dopamine is a key neuromodulator system involved in subjective time experience. For instance, the time sense is disrupted in conditions characterized by dopaminergic dysfunction (e.g., Parkinson's disease, schizophrenia). However, the mechanistic role of dopamine in the operation of the internal clock is debated. We resolve this debate by optogenetically upregulating and downregulating the nigrostriatal dopamine in mice and evaluating the behavioral outcomes under a computational framework that assumes that the brain times by accumulating brain signals up to a threshold. Our results showed that modulating the nigrostriatal dopamine system alters the level to which the brain integrates clock signals (temporal caution) without altering the clock speed.

Being able to switch from established choices to new alternatives when conditions change - behavioral flexibility - is essential for survival. Cholinergic signaling in the striatum contributes to such flexible behavior, yet the timing and spatial organization of acetylcholine release during contingency changes remain unclear, limiting conceptual understanding of its role in behavioral flexibility. Using a genetically encoded acetylcholine sensor and 2-photon imaging in the dorsal striatum of behaving mice, we visualized acetylcholine dynamics during acquisition and reversal learning in a virtual reality Y-maze. Rewarded outcomes evoked phasic decreases in acetylcholine, whereas unexpected non-reward following reversal triggered widespread increases that predicted lose-shift behavior. Targeted inhibition of cholinergic interneurons reduced this adaptive response. Spatial analysis revealed heterogeneous, temporally distinct signals forming functionally diverse microdomains. These findings suggest that widespread and focal acetylcholine release during unexpected outcomes promotes adaptive response shifts, offering a mechanistic framework for understanding disorders such as addiction and obsessive-compulsive rituals.

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.

Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta. Axonal mitochondria in neurons reportedly differ in properties and morphologies from mitochondria in somata or dendrites. However, the function and morphology of axonal mitochondria in human dopaminergic neurons remain poorly understood. To define the function and morphology of axonal mitochondria in human dopaminergic neurons, we newly generated tyrosine hydroxylase (TH) reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines from one control and one PRKN-mutant patient iPSC lines and differentiated these iPSC lines into dopaminergic neurons in two-dimensional monolayer cultures or three-dimensional midbrain organoids. Immunostainings with antibodies against axonal and dendritic markers showed that axons could be better distinguished from dendrites of dopaminergic neurons in the peripheral area of three-dimensional midbrain organoids than in two-dimensional monolayers. Live-cell imaging and correlative light-electron microscopy in peripheral areas of midbrain organoids derived from control TH-GFP iPSCs demonstrated that axonal mitochondria in dopaminergic neurons had lower membrane potential and were shorter in length than those in non-dopaminergic neurons. Although the mitochondrial membrane potential did not significantly differ between dopaminergic and non-dopaminergic neurons derived from PRKN-mutant patient lines, these differences tended to be similar to those in control lines. These results were also largely consistent with those of our previous study on somatic mitochondria. The findings of the present study indicate that midbrain organoids are an effective tool to distinguish axonal from dendritic mitochondria in dopaminergic neurons. This may facilitate the analysis of axonal mitochondria to provide further insights into the mechanisms of dopaminergic neuron degeneration in patients with Parkinson's disease.

Being able to switch from established choices to new alternatives when conditions change - behavioral flexibility - is essential for survival. Cholinergic signaling in the striatum contributes to such flexible behavior, yet the timing and spatial organization of acetylcholine release during contingency changes remain unclear, limiting conceptual understanding of its role in behavioral flexibility. Using a genetically encoded acetylcholine sensor and 2-photon imaging in the dorsal striatum of behaving mice, we visualized acetylcholine dynamics during acquisition and reversal learning in a virtual reality Y-maze. Rewarded outcomes evoked phasic decreases in acetylcholine, whereas unexpected non-reward following reversal triggered widespread increases that predicted lose-shift behavior. Targeted inhibition of cholinergic interneurons reduced this adaptive response. Spatial analysis revealed heterogeneous, temporally distinct signals forming functionally diverse microdomains. These findings suggest that widespread and focal acetylcholine release during unexpected outcomes promotes adaptive response shifts, offering a mechanistic framework for understanding disorders such as addiction and obsessive-compulsive rituals.

Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson's disease.