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Villanueva, C.

Publications and source records attributed to Villanueva, C..

2 recordsLinked to original sources

Incentive valence differentially engages open- and closed-loop basal ganglia circuits during movement initiation

Incentives modulate voluntary movement, yet the circuitry channeling these signals into motor output remains unclear. Classical models emphasize a closed-loop circuit (CLC) linking dorsal putamen (PUTd) with motor cortex, but this pathway is anatomically segregated from affective processing regions. Anatomical and clinical evidence point to an alternative: an open-loop circuit (OLC) from ventral putamen (PUTv) that may route affective signals to motor cortex. Here, we conducted two experiments to test whether a functional OLC exists in humans and whether it is differentially engaged by incentive conditions. First, in 7 T resting-state fMRI (multi-echo), PUTv showed robust functional connectivity with both affective and motor regions, including the cingulate motor area (CMA), even after accounting for PUTd variance. This connectivity pattern supports the plausibility of an independent pathway linking affective basal ganglia regions to the motor cortex. Second, in 3 T task fMRI (incentivized reaching), jackpot (high-reward) and robber (high-loss avoidance) incentive conditions produced distinct behavioral and neural signatures. Jackpot produced a speed-accuracy trade-off, with faster movement initiation but more false starts. Neurally, this coincided with engagement (BOLD responses relevant for initiation speed) being reduced in CLC nodes but not in OLC. Robber, in contrast, eliminated engagement in both OLC and CLC nodes, instead recruiting stopping-related regions (e.g., STN), consistent with an avoidance phenomenology. Together, these findings support a versatile architecture for movement initiation that flexibly engages distinct cortico-subcortical circuits depending on incentive phenomenology, and offer a candidate mechanism through which affective salience and valence modulate voluntary movement. Significance StatementAffective signals profoundly influence movement, yet the mechanisms linking motivationally relevant contexts with motor behavior remain unclear. Combining ultra-high field (7 T) connectomics with task-based (3 T) neuroimaging, we provide the first systems-level evidence in humans for such a mechanism: a ventral putamen-centered open-loop circuit (OLC) connecting affective and motor areas, operating alongside the canonical dorsal putamen-centered closed-loop sensorimotor circuit (CLC). Critically, the phenomenological quality of incentive (how it is construed as reward versus threat) rather than magnitude alone, likely determines which circuit dominates during movement initiation. These findings help to explain paradoxical kinesia in Parkinsons disease, where affective contexts can bypass degraded sensorimotor circuits, and establish foundations for context-based therapeutic interventions.

neuroscience↗

Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source that partially compensates for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.

biochemistry↗