@article{pmid42619977,

title = {The Cellular and Synaptic Actions of Dopamine During Behavior},

author = {Mélanie Druart and Yun C Yang and Nicolas X Tritsch and Tanya Sippy},

doi = {10.64898/2026.08.05.742858},

issn = {2692-8205},

year  = {2026},

date = {2026-08-01},

journal = {bioRxiv},

abstract = {Dopamine signaling in the striatum is essential for a wide range of functions, from reward learning to motor vigor and behavioral flexibility. Although dopamine signals fluctuate on sub-second timescales, how these signals are translated into lasting changes in striatal circuit function remains unknown. Resolving this requires cell-type-specific measurements of synaptic and intrinsic properties during behavior, a longstanding technical challenge. Here, we combined  whole-cell membrane potential recordings, simultaneous monitoring and bidirectional manipulation of dopamine signaling in awake, behaving mice to examine how dopamine shapes corticostriatal circuits. Acute manipulations of dopamine over seconds to minutes produced only modest effects on corticostriatal synaptic transmission and no detectable changes in membrane potential dynamics or intrinsic excitability. By contrast, associative learning robustly strengthened identified corticostriatal synapses onto both D1- and D2-expressing spiny projection neurons, yet only D1-SPN plasticity required dopamine signaling. These findings challenge models in which dopamine acts rapidly to tune striatal excitability and identify learning related plasticity as its principal mechanism for shaping striatal circuits .},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42539181,

title = {Distinct forms of dopamine transmission control locomotion and learning},

author = {Matthew M McGregor and Andrew G Yee and Selin Ekici and Saige K Power and Riccardo Melani and Joy Adler and Christina S Winborn and Matthew J Kennedy and Nicolas X Tritsch and Christopher P Ford},

doi = {10.64898/2026.07.24.740623},

issn = {2692-8205},

year  = {2026},

date = {2026-07-01},

journal = {bioRxiv},

abstract = {The neuromodulator dopamine is essential for voluntary movement and learning from experience. While these behaviors often occur simultaneously and rely on overlapping nigrostriatal dopamine circuits, they are also separable and can manifest independently. How a single neuromodulatory system controls such disparate aspects of behavior in parallel remains poorly understood. Here we show that striatal dopamine is released through two spatially and functionally distinct modes that are independently regulated and serve distinct behavioral roles. Eliminating dopamine release underlying bulk extracellular accumulation reveals a spatially restricted mode of transmission that maintains phasic dopamine receptor activation on striatal projection neurons. We find that selective loss of diffuse dopamine impairs striatal circuit excitability and reduces locomotion, while point-to-point transmission is sufficient to maintain striatal spine density and support motor and associative learning. We propose that the geometry of dopamine release determines its behavioral output, a principle that explains the breadth of dopamine's functions and more broadly elucidates how neurons multiplex different forms of information.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41214177,

title = {Subsecond dopamine fluctuations do not specify the vigor of ongoing actions},

author = {Haixin Liu and Riccardo Melani and Marta Maltese and James Taniguchi and Akhila Sankaramanchi and Ruoheng Zeng and Jenna R Martin and Nicolas X Tritsch},

doi = {10.1038/s41593-025-02102-1},

issn = {1546-1726},

year  = {2025},

date = {2025-12-01},

journal = {Nat Neurosci},

volume = {28},

number = {12},

pages = {2432--2438},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40766361,

title = {Ventral Striatal Dopamine Increases following Hippocampal Sharp-Wave Ripples},

author = {Miriam A Janssen and Hung-Tu Chen and Nicolas X Tritsch and Matthijs A A van der Meer},

doi = {10.1101/2025.07.24.666687},

issn = {2692-8205},

year  = {2025},

date = {2025-07-01},

journal = {bioRxiv},

abstract = {Leading theories suggest that hippocampal replay drives offline learning through coupling with an internal teaching signal such as ventral striatal dopamine (DA); however, the relationship between hippocampal replay and dopamine is unknown. Simultaneous recording of putative hippocampal replay events (dorsal CA1 sharp-wave ripples, SWRs) and fiber photometry of ventral striatal DA in mice revealed a significant increase in DA following SWRs, peaking ∼0.3 s after SWRs. This result establishes for the first time a core theoretical requirement of offline learning in the mammalian brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39570889,

title = {Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids},

author = {Emanuele Frattini and Gaia Faustini and Gianluca Lopez and Emma Veronica Carsana and Mattia Tosi and Ilaria Trezzi and Manuela Magni and Giulia Soldà and Letizia Straniero and Daniele Facchi and Maura Samarani and Mitchell Martá-Ariza and Chiara Maria Giulia De Luca and Elena Vezzoli and Alessandra Pittaro and Astghik Stepanyan and Rosamaria Silipigni and Isabel Rosety and Jens C Schwamborn and Sergio Pablo Sardi and Fabio Moda and Stefania Corti and Giacomo P Comi and Fabio Blandini and Nicolas X Tritsch and Mario Bortolozzi and Stefano Ferrero and Fulvia Milena Cribiù and Thomas Wisniewski and Rosanna Asselta and Massimo Aureli and Arianna Bellucci and Alessio Di Fonzo},

doi = {10.1093/brain/awae365},

issn = {1460-2156},

year  = {2025},

date = {2025-04-01},

journal = {Brain},

volume = {148},

number = {4},

pages = {1242--1257},

abstract = {Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson's disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson's disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered clarification of the link between mutant glucocerebrosidase and Parkinson's disease pathology. Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson's disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy pathology observed in human brains, including the generation of α-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Concurrently, we found that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate, glucosylceramide, are determinants of α-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated α-synuclein pathology by promoting fibrillary α-synuclein deposition. Finally, we demonstrated the efficacy of ambroxol and GZ667161 (two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson's disease) in reducing α-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39843745,

title = {Experience-dependent dopamine modulation of male aggression},

author = {Bing Dai and Bingqin Zheng and Xiuzhi Dai and Xiaoyang Cui and Luping Yin and Jing Cai and Yizhou Zhuo and Nicolas X Tritsch and Larry S Zweifel and Yulong Li and Dayu Lin},

doi = {10.1038/s41586-024-08459-w},

issn = {1476-4687},

year  = {2025},

date = {2025-03-01},

journal = {Nature},

volume = {639},

number = {8054},

pages = {430--437},

abstract = {Numerous studies support the role of dopamine in modulating aggression, but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors. Furthermore, eliminating dopamine synthesis in the VTA prevents the emergence of aggression in naive mice but leaves aggression intact in expert aggressors. VTA dopamine modulates aggression through the dorsal lateral septum (dLS), a region known for aggression control. Dopamine enables the flow of information from the hippocampus to the dLS by weakening local inhibition in novice aggressors. In expert aggressors, dLS local inhibition naturally weakens, and the ability of dopamine to modulate dLS cells diminishes. Overall, these results reveal a sophisticated role of dopamine in the rise of aggression in adult male mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39653807,

title = {Motivating interest in D3 dopamine receptors},

author = {Nicolas X Tritsch},

doi = {10.1038/s41593-024-01820-2},

issn = {1546-1726},

year  = {2025},

date = {2025-01-01},

journal = {Nat Neurosci},

volume = {28},

number = {1},

pages = {6--7},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39556753,

title = {A detailed look at striatal acetylcholine, dopamine, and their interactions},

author = {James Taniguchi and Nicolas X Tritsch},

doi = {10.1073/pnas.2419752121},

issn = {1091-6490},

year  = {2024},

date = {2024-11-01},

journal = {Proc Natl Acad Sci U S A},

volume = {121},

number = {48},

pages = {e2419752121},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38748470,

title = {Comment on 'Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation'},

author = {James Taniguchi and Riccardo Melani and Lynne Chantranupong and Michelle J Wen and Ali Mohebi and Joshua D Berke and Bernardo L Sabatini and Nicolas X Tritsch},

doi = {10.7554/eLife.95694},

issn = {2050-084X},

year  = {2024},

date = {2024-05-01},

journal = {Elife},

volume = {13},

abstract = {Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. Mohebi, Collins and Berke recently reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1 (Mohebi et al., 2023). Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38431842,

title = {GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABA receptors},

author = {Jyoti C Patel and Ang D Sherpa and Riccardo Melani and Paul Witkovsky and Madeline R Wiseman and Brian O'Neill and Chiye Aoki and Nicolas X Tritsch and Margaret E Rice},

doi = {10.1016/j.celrep.2024.113834},

issn = {2211-1247},

year  = {2024},

date = {2024-03-01},

journal = {Cell Rep},

volume = {43},

number = {3},

pages = {113834},

abstract = {Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37891198,

title = {Acetylcholine waves and dopamine release in the striatum},

author = {Lior Matityahu and Naomi Gilin and Gideon A Sarpong and Yara Atamna and Lior Tiroshi and Nicolas X Tritsch and Jeffery R Wickens and Joshua A Goldberg},

doi = {10.1038/s41467-023-42311-5},

issn = {2041-1723},

year  = {2023},

date = {2023-10-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {6852},

abstract = {Striatal dopamine encodes reward, with recent work showing that dopamine release occurs in spatiotemporal waves. However, the mechanism of dopamine waves is unknown. Here we report that acetylcholine release in mouse striatum also exhibits wave activity, and that the spatial scale of striatal dopamine release is extended by nicotinic acetylcholine receptors. Based on these findings, and on our demonstration that single cholinergic interneurons can induce dopamine release, we hypothesized that the local reciprocal interaction between cholinergic interneurons and dopamine axons suffices to drive endogenous traveling waves. We show that the morphological and physiological properties of cholinergic interneuron - dopamine axon interactions can be modeled as a reaction-diffusion system that gives rise to traveling waves. Analytically-tractable versions of the model show that the structure and the nature of propagation of acetylcholine and dopamine traveling waves depend on their coupling, and that traveling waves can give rise to empirically observed correlations between these signals. Thus, our study provides evidence for striatal acetylcholine waves in vivo, and proposes a testable theoretical framework that predicts that the observed dopamine and acetylcholine waves are strongly coupled phenomena.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37558873,

title = {Intrinsic dopamine and acetylcholine dynamics in the striatum of mice},

author = {Anne C Krok and Marta Maltese and Pratik Mistry and Xiaolei Miao and Yulong Li and Nicolas X Tritsch},

doi = {10.1038/s41586-023-05995-9},

issn = {1476-4687},

year  = {2023},

date = {2023-09-01},

journal = {Nature},

volume = {621},

number = {7979},

pages = {543--549},

abstract = {External rewards such as food and money are potent modifiers of behaviour. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA in the striatum at the same time that striatal cholinergic interneurons (CINs) produce a characteristic pause in firing. These phasic responses are thought to create unique, temporally limited conditions that motivate action and promote learning. However, the dynamics of DA and ACh outside explicitly rewarded situations remain poorly understood. Here we show that extracellular DA and ACh levels fluctuate spontaneously and periodically at a frequency of approximately 2 Hz in the dorsal striatum of mice and maintain the same temporal relationship relative to one another as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within the striatum. Instead, we provide evidence that periodic fluctuations in striatal DA are inherited from midbrain DANs, while striatal ACh transients are driven by glutamatergic inputs, which act to locally synchronize the spiking of CINs. Together, our findings show that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents. The dominance of intrinsic rhythms in DA and ACh offers new insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37505982,

title = {Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice},

author = {Francesco Longo and Sameer Aryal and Paul G Anastasiades and Marta Maltese and Corey Baimel and Federica Albanese and Joanna Tabor and Jeffrey D Zhu and Mauricio M Oliveira and Denise Gastaldo and Claudia Bagni and Emanuela Santini and Nicolas X Tritsch and Adam G Carter and Eric Klann},

doi = {10.1016/j.celrep.2023.112901},

issn = {2211-1247},

year  = {2023},

date = {2023-08-01},

journal = {Cell Rep},

volume = {42},

number = {8},

pages = {112901},

abstract = {Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36635111,

title = {Unraveling the dynamics of dopamine release and its actions on target cells},

author = {Tanya Sippy and Nicolas X Tritsch},

doi = {10.1016/j.tins.2022.12.005},

issn = {1878-108X},

year  = {2023},

date = {2023-03-01},

journal = {Trends Neurosci},

volume = {46},

number = {3},

pages = {228--239},

abstract = {The neuromodulator dopamine (DA) is essential for regulating learning, motivation, and movement. Despite its importance, however, the mechanisms by which DA influences the activity of target cells to alter behavior remain poorly understood. In this review, we describe recent methodological advances that are helping to overcome challenges that have historically hindered the field. We discuss how the employment of these methods is shedding light on the complex dynamics of extracellular DA in the brain, as well as how DA signaling alters the electrical, biochemical, and population activity of target neurons in vivo. These developments are generating novel hypotheses about the mechanisms through which DA release modifies behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36214545,

title = {G protein-coupled receptors cooperate to silence dopamine neurons},

author = {Haixin Liu and Nicolas X Tritsch},

doi = {10.1113/JP283842},

issn = {1469-7793},

year  = {2022},

date = {2022-11-01},

journal = {J Physiol},

volume = {600},

number = {22},

pages = {4773--4774},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35443174,

title = {Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake},

author = {Riccardo Melani and Nicolas X Tritsch},

doi = {10.1016/j.celrep.2022.110716},

issn = {2211-1247},

year  = {2022},

date = {2022-04-01},

journal = {Cell Rep},

volume = {39},

number = {3},

pages = {110716},

abstract = {Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNc) inhibit target cells in the striatum through postsynaptic activation of γ-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNc neurons lack enzymes typically required to produce GABA or package it into synaptic vesicles. Here, we show that aldehyde dehydrogenase 1a1 (Aldh1a1), an enzyme proposed to function as a GABA synthetic enzyme in SNc neurons, does not produce GABA for synaptic transmission. Instead, we demonstrate that SNc axons obtain GABA exclusively through presynaptic uptake using the membrane GABA transporter Gat1 (encoded by Slc6a1). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33983121,

title = {Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum},

author = {Marta Maltese and Jeffrey R March and Alexander G Bashaw and Nicolas X Tritsch},

doi = {10.7554/eLife.68041},

issn = {2050-084X},

year  = {2021},

date = {2021-05-01},

journal = {Elife},

volume = {10},

abstract = {Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity toward the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33758418,

title = {How alcohol affects motor control: not your usual suspects},

author = {Riccardo Melani and Nicolas X Tritsch},

doi = {10.1038/s42255-021-00355-1},

issn = {2522-5812},

year  = {2021},

date = {2021-03-01},

journal = {Nat Metab},

volume = {3},

number = {3},

pages = {293--294},

keywords = {},

pubstate = {published},

tppubtype = {article}

}