Chronic pain frequently co-occurs with depression, forming a vicious cycle that mutually exacerbates both. Although the medial shell of nucleus accumbens (NAcMed) is known to modulate both pain and affective states, the distinct roles of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1- and D2-MSNs) within the NAcMed, as well as their respective circuits, in chronic pain and comorbid depression remain poorly defined. We observed decreased activity in both MSN subtypes during chronic pain and comorbid depression. Notably, activation of D1-MSNs alleviated depressive-like behaviors, whereas activation of D2-MSNs produced analgesic effects. Furthermore, we identified two parallel neural circuits: the NAcMed→mediodorsal thalamus pathway, which preferentially modulates depressive-like behaviors, and the NAcMed→lateral hypothalamus pathway, which selectively relieves pain. These findings delineate a circuit-specific dichotomy in which NAcMed and NAcMed govern distinct affective and sensory dimensions of chronic pain-depression comorbidity, providing circuit-specific targets for potential treatment.

The substantia nigra pars reticulata (SNr) is a primary output for basal ganglia signaling. It plays an important role in the control of movement, integrating inputs from upstream structures in the basal ganglia, before sending organized projections to a range of targets in the midbrain, brainstem, and thalamus. Here, we present a detailed in silico model of the mouse SNr, including its major afferent inputs. The electrophysiological and morphological properties of SNr neurons are characterized in acute brain slices via whole cell patch-clamp recordings and morphological reconstruction. Using reconstructed morphologies, multicompartmental models of single neurons are instantiated within the NEURON simulation environment and populated with relevant modeled ion channels. Model parameters are optimized via an evolutionary algorithm, such that simulated neurons faithfully reproduce recorded electrophysiological behavior. Using the simulation infrastructure software , single neuron models are incorporated into a circuit-level model, where the sparse connectivity within the SNr is recreated. We simulate the mouse SNr at scale, featuring realistic volumes and neuronal density. The unique synaptic properties and activity patterns of different afferent sources are captured in silico. Born out of ex vivo data, our model reproduces in vivo firing patterns. Our simulations suggest that paradoxical activity increases in response to experimental inhibition can be explained by lateral connectivity. In addition, our model predicts the functional implications of characteristic short-term synaptic plasticity in the indirect pathway of the basal ganglia. The model can be extended to include additional inputs and be connected with existing models of upstream basal ganglia nuclei to further explore circuit dynamics.

Striatal output is dynamically modulated by cholinergic interneurons (CINs), the primary source of acetylcholine in the striatum. CINs have been classically viewed as a random and homogeneous population, but recent evidence suggests heterogeneity in their anatomical and functional organization. Here, using systematic mapping and quantitative spatial analyses, we found that-contrary to current dogma-CINs exhibited striking enrichment and nonrandom clustering in the striosome compartment, particularly in the lateral striatum. Similar analyses carried out for parvalbumin- and somatostatin-expressing interneurons revealed that compartmental organization is interneuron specific. The strong "striosome preference" exhibited by CINs was confined within striosome borders, not extending to the surrounding matrix. We further found that striosome and matrix CINs differed in their expression levels of phospho-S6 ribosomal protein-Ser240/244 and choline acetyltransferase, suggesting functional differences, and clustered CINs differed from unclustered CINs in their intrinsic membrane properties. Finally, CINs expressing Lhx6, which defines a distinct γ-aminobutyric acid (GABA) coreleasing population, were notably absent from regions where highly clustered striosomal CINs appeared. Collectively, our findings uncover important dimensions of CIN organization, suggesting that modulation of regional and compartmental striatal output may depend upon the spatial-functional heterogeneity of CINs.

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.