RZ5P Base Processor

Energy homeostasis and motivated behaviours are tightly interconnected processes coordinated by peripheral metabolic signals and central reward circuits. Among these signals, circulating triglycerides (TG) have emerged as neuromodulators of mesolimbic dopamine functions and reward processing. However, whether TG directly regulate the activity of defined neuronal populations within the nucleus accumbens (NAc) during appetitive behaviours remains unknown. Here, we investigated how central TG availability shapes the in vivo activity of NAc dopamine D2 receptor-expressing spiny projection neurons (D2R-SPNs) across distinct nutritional and metabolic states. Using in vivo fiber photometry in Drd2 -Cre mice, we monitored D2R-SPN Ca 2+ dynamics during appetitive Pavlovian conditioning and refeeding. D2R-SPNs progressively developed robust responses to a reward-predictive conditioned stimulus (CS + ) over the course of learning, while their activity during reward consumption remained stable. Acute elevation of central TG levels through carotid infusion did not alter D2R-SPN activity or behavioural performance in lean chow-fed mice, irrespective of whether they were fed or food-restricted. In contrast, in mice exposed to a high-fat diet (HFD), central TG delivery suppressed cue-evoked D2R-SPN activity in food-restricted animals without affecting reward consumption or behavioural outputs. Likewise, TG significantly reduced refeeding-evoked D2R-SPN activation in fasted HFD-mice, while leaving novelty-induced neuronal responses unchanged. Together, these findings demonstrate that obesogenic conditions reveal a metabolic state-dependent sensitivity of accumbal D2R-SPNs to circulating lipids. This work identifies TG as context-dependent modulators of D2R-SPN function and uncovers a mechanism through which dietary history interacts with current metabolic state to reshape the neural encoding of reward-predictive cues and food-directed behaviours.

Everyday decisions depend on associations between sensory stimuli, actions, and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine in the dorsomedial striatum partly through this cholinergic mechanism. Using anatomical and functional methods to identify the pathways involved, we found that visual and auditory cortices lack connectivity with CINs and were unable to drive cholinergic-dependent dopamine release. Frontal regions, which were activated by visual stimuli, strongly recruited CINs, producing robust dopamine release both ex vivo and in vivo. These findings reveal a fundamental distinction between sensory and frontal corticostriatal inputs, demonstrating that only the latter can evoke cholinergic-dependent dopamine signals. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

Hippocampus, a key hub of neural circuits for spatial learning and memory, has attracted tremendous studies. Neuronal information processing in the hippocampus can be regulated by many types of neuropeptides. Cholecystokinin ( Cck ), the most abundant neuropeptide in the central nervous system that is involved in modulating neuronal functions, such as cognition, memory, and neuroplasticity, is widely expressed in the hippocampus. However, whether local excitatory Cck neurons modulate hippocampal function is still unclear. In this study, we showed that CA1 pyramidal neurons receive projections from excitatory Cck neurons in area CA3 (CA3 Cck neurons) in adult mice. Subsequently, activation of the CA1-projecting CA3 Cck neurons triggers the release of Cck . Then, we found that the activity of CA3 Cck -CA1 neurons supports the hippocampal-dependent tasks. Furthermore, inhibition of CA3 Cck -CA1 projections or knockdown of CA3 Cck gene expression markedly impaired the behavioral tasks and neuroplasticity. Taken together, these results may add to a better understanding of how neuromodulators regulate the neural functions in the central nervous system.