Biology subjects

Tritsch, N. X.

Publications and source records attributed to Tritsch, N. X..

9 recordsLinked to original sources

bioRxiv2026

The Cellular and Synaptic Actions of Dopamine During Behavior

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 in vivo 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 in vivo.

neuroscience↗

bioRxiv2025

Ventral Striatal Dopamine Increases following Hippocampal Sharp-Wave Ripples

The reactivation of task-related hippocampal activity during sharp-wave ripples (SWRs), often expressed as sequential "replay," is thought to contribute to behavior through both online and offline processes. Theories of replay-based learning and decision-making posit the need for replay events to be followed by an evaluative signal. Dopamine (DA) is a prime candidate for providing such a signal, particularly in the ventral striatum, where it reflects reward- and other prediction-error signals. Hippocampal activity influences mesolimbic dopamine signaling and neural activity in the ventral striatum, but it is unknown whether SWRs are coupled to ventral striatal DA release. To address this, we simultaneously recorded dorsal CA1 local field potentials to detect SWRs and measured ventral striatal DA concentration using fiber photometry in freely moving mice. We found a significant increase in DA following SWRs. This coupling was more prominent during offline rest than during periods of immobility during behavior, and was stronger following longer and higher-power SWRs. These results reveal coupling between hippocampal SWRs and striatal dopamine, providing a potential candidate mechanism through which internally generated hippocampal activity could engage evaluative signals during offline memory processing.

neuroscience↗

bioRxiv2024

Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking

Beyond the vast array of functional roles attributed to serotonin (5-HT) in the brain, changes in 5-HT levels have been shown to accompany changes in behavioral states, including WAKE, NREM and REM sleep. Whether 5-HT dynamics at shorter time scales can be seen to delineate substates within these larger brain states remains an open question. Here, we performed simultaneous recordings of extracellular 5-HT using a recently-developed G Protein-Coupled Receptor-Activation-Based 5-HT sensor (GRAB5-HT3.0) and local field potential (LFP) in the hippocampal CA1, which revealed the presence of prominent ultraslow (<0.05 Hz.) 5-HT oscillations both during NREM and WAKE states. Interestingly, the phase of these ultraslow 5-HT oscillations was found to distinguish substates both within and across larger behavioral states. Hippocampal ripples occurred preferentially on the falling phase of ultraslow 5-HT oscillations during both NREM and WAKE, with higher power ripples concentrating near the peak specifically during NREM. By contrast, hippocampal-cortical coherence was strongest and microarousals and intracranial EMG peaks were most prevalent during the rising phase in both wake and NREM. Overall, ultraslow 5-HT oscillations delineate substates within the larger behavioral states of NREM and WAKE, thus potentially temporally segregating internal memory consolidation processes from arousal-related functions.

neuroscience↗

bioRxiv2023

Comment on 'Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation'

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. A recent paper in eLife (Mohebi et al., 2023) 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. 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.

neuroscience↗

bioRxiv2022

Cell type-specific disruption of cortico-striatal circuitry drive repetitive patterns of behaviour in fragile X syndrome model mice

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviours (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 dissected the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. We found 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 revealed differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings represent the first evidence of a cell-type specific impact of the loss of FMRP on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS. HighlightsDysregulated striatal protein synthesis underlies altered synaptic plasticity and RRBs displayed by FXS model mice FXS model mice exhibit cell type-specific molecular, morphological, and synaptic changes in the dorsolateral striatum Selective deletion of Fmr1 from dSNPs in mice alters translation and causes repetitive behavior TRAP-Seq indicates that there is altered binding of >120 mRNAs to ribosomes in dSNPs of Fmr1 KO mice G-protein signaling (RGS) 4 translation is significantly reduced in dSPNs in FXS model mice Treatment of FXS model mice with VU0152100, a positive allosteric modulator of the M4 muscarinic receptor that is upstream of RGS4, can reverse RRBs

neuroscience↗

bioRxiv2022

A permissive role for dopamine in the production of vigorous movements

Dopamine is essential for the production of vigorous movements, but how dopamine modifies the gain of motor commands remains unclear. Here, we developed a dexterous motor task in which head-restrained mice self-initiate fast and large-amplitude lever pushes with their left forelimb to earn rewards. We show that this task is goal-directed and depends on cortico-striatal circuits in the hemisphere contralateral to the limb used to push the lever. We find that unilateral loss of midbrain dopamine neurons reduces the speed and amplitude of lever pushes, and that levodopa treatment rapidly restores motor vigor, consistent with parkinsonian bradykinesia. Photometry recordings of striatal dopamine levels indicate that the therapeutic efficacy of levodopa does not require phasic dopamine release. In dopamine-intact mice, optogenetic stimulation of midbrain dopamine neurons calibrated to mimic transients evoked by rewards is also insufficient to increase the speed and amplitude of forelimb movements. Together, our data show that phasic dopamine transients are unlikely to specify the vigor of forelimb movements online as they are being executed, and suggest instead that dopamine plays a permissive role in the selection and production of vigorous movements. Our findings have important implications for our understanding of how the basal ganglia contribute to motor control under physiological conditions and in Parkinsons disease.

neuroscience↗

bioRxiv2022

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

External rewards like food and money are potent modifiers of behavior1,2. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic cell-autonomous 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 levels in striatum3-5 at the same time as striatal cholinergic interneurons (CINs) produce a characteristic pause in firing6-8. These phasic responses are thought to create unique, temporally-limited conditions that motivate action and promote learning9-14. However, the dynamics of DA and ACh outside explicitly-rewarded situations remain poorly understood. Here we show that extracellular levels of DA and ACh fluctuate spontaneously in the striatum of mice and maintain the same temporal relationship as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within striatum. Periodic fluctuations in ACh are instead controlled by glutamatergic afferents, which act to locally synchronize spiking of striatal cholinergic interneurons. Together, our findings reveal that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents across behavioral contexts. The dominance of intrinsic reward-like rhythms in DA and ACh offers novel insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.

neuroscience↗

bioRxiv2021

Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake

Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNcDA) inhibit target cells in the striatum through postsynaptic activation of {gamma}-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNcDA 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 SNcDA neurons does not produce GABA for synaptic transmission. Instead, we demonstrate that SNcDA 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.

neuroscience↗

bioRxiv2019

Dopamine modulates the size of striatal projection neuron ensembles

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 Ca2+ 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 towards 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 Parkinsons disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinsons disease.

neuroscience↗