Biology subjects

Venance, L.

Publications and source records attributed to Venance, L..

14 recordsLinked to original sources

bioRxiv2025

The gut-brain vagal axis governs mesolimbic dopamine dynamics and reward events

Reward-related processes have traditionally been ascribed to neural circuits centered on the dopamine (DA) system. While exteroceptive stimuli, such as food and drugs of abuse, are well-established activators of DA-neuron activity, growing evidence indicates that interoceptive signals also play a critical role in modulating reward. Among these, the gut-brain vagal axis has emerged as a key pathway, yet its precise contribution to mesolimbic DA-dependent signaling, dynamics and behaviors remains poorly defined. Here, we combine complementary ex vivo and in vivo approaches across multiple scales to investigate how the gut-brain vagal axis regulates DA dynamics and reward-related behaviors. We show that gut-brain vagal tone is essential for gating mesolimbic DA system activity and functions, modulating DA-dependent molecular and cellular processes, and scaling both food- and drugs-induced reinforcement. These findings challenge the traditional brain-centric view of reward processing, supporting a more unified and integrated model in which gut-derived and vagus-mediated interoceptive signals are pivotal in intrinsically shaping motivation and reinforcement. By uncovering the influence of gut-brain vagal communication on mesolimbic DA functions, this work offers new insights into the neurobiological mechanisms underlying both adaptive and maladaptive reward processes, with broad implications for eating disorders and addiction.

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bioRxiv2024

Striatal endocannabinoid-long-term potentiation mediates one-shot learning

One-shot learning, the ability to form memories after a single, brief salient event, is essential to adapt ones behaviour in a dynamic world. However, how one-shot learning unfolds in the brain remains unknown. Challenges to elucidate its neural underpinnings stem experimentally from the scarcity of behavioral assays recapitulating one-shot learning in the laboratory, and conceptually from the limited number of neuronal plasticity mechanisms that could support learning after a small number of action potentials, as is common during a one-shot experience. Here, we overcome these challenges and identify a new mechanism for one-shot learning in dorsal striatum that relies on a non-classical form of plasticity, the endocannabinoid-mediated long-term potentiation (eCB-LTP). To do so, we develop a novel one-shot behavioral test, in which mice learn to avoid a sticky tape after a single, spontaneous and brief contact with the uncomfortable substrate, and maintain this memory for more than one month. We use the sticky tape avoidance test to demonstrate that striatal LTP emerges in vivo after one-shot learning; the observed patterns of activity in vivo suggest that eCB-LTP mediates one-shot learning, which we corroborate both ex vivo and through computational modeling. Consistent with this hypothesis, conditional knock-out mice abolishing eCB-LTP show impaired one-shot learning. These results highlight the importance of non-classical plasticity mechanisms in supporting memory formation after a single brief experience.

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bioRxiv2024

A novel critic signal in identified midbrain dopaminergic neurons of mice training inoperant tasks

Classically, midbrain dopaminergic neuron activity is triggered by unexpected rewards, then, upon learning, by reward-predictive conditioned stimuli. When expected rewards are withheld, firing is inhibited. This activity occurs too late to directly affect the neuronal circuitry underlying decision-making, inspiring the development of temporal difference (TD) reinforcement learning models. To test for more timely critical feedback during decision-making and learning, we recorded optogenetically identified dopaminergic, putative GABAergic and other neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta in mice training in visual and olfactory discrimination tasks. The mice often adhered to unrewarded and untrained task strategies (e.g., spatial alternation) rather than making random choices. In order to probe for reward/punishment predictive activity, a delay was imposed between nose-poke choices and signals for reward or punishment. As animals performed below criterion levels, dopaminergic and other neurons firing rates signaled correct versus incorrect choices immediately after choices, but prior to the onset of trial outcome signals. Thus, this activity signaled the rewarded rule even as the mice performed other unrewarded strategies. Putative GABAergic neurons fired during nose-poke choices, potentially reducing network activity prior to reward prediction signals. This reward predictive activity could serve as a critic signal expressed immediately after choices are made, priming the network for canonical DA reward/punishment activity, facilitating network functional modifications. This is consistent with a role for dopamine in arbitration between brain modules to choose among diverse strategies during goal-directed behavior. These findings suggest extensions of theoretical formulations interpreting dopaminergic neuronal activity. Significance statementModels of dopaminergic influence on circuit modifications during learning evoke mechanisms dealing with the delay between neural activity leading up to choices, and when the reinforcing outcome actually occurs. Here, as mice trained in sensory discrimination tasks with a delay between behavioral responses and reinforcement signals, they performed several unrewarded behavioral strategies. Simultaneously, dopaminergic nuclei neurons instead reflected the current task rule, predicting whether the choice was correct or not, providing an immediate "critic" signal prior to canonical trial outcome signals. This provides evidence for brain mechanisms to overcome innate or acquired habits to perform behaviors optimizing positive outcomes.

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bioRxiv2022

Rhythmic oscillations in the midbrain dopaminergic nuclei in mice

Dopamine release in the forebrain by midbrain ventral tegmental nucleus (VTA) and substantia nigra pars compacta (SNpc) neurons is implicated in reward processing, goal-directed learning, and decision-making. Rhythmic oscillations of neural excitability underlie coordination of network processing, and have been reported in these dopaminergic nuclei at several frequency bands. This paper provides a comparative characterization of several frequencies of oscillations of local field potential and single unit activity, highlighting some behavioral correlates. We recorded from optogenetically identified dopaminergic sites in mice training in operant olfactory and visual discrimination tasks. Rayleigh and Pairwise Phase Consistency (PPC) analyses revealed some VTA/SNc neurons phase-locked to each frequency range, with fast spiking interneurons (FSIs) prevalent at 1-2.5 Hz (slow) and 4 Hz bands, and dopaminergic neurons predominant in the theta band. More FSIs than dopaminergic neurons were phase-locked in the slow and 4 Hz bands during many task events. The highest incidence of phase-locking in neurons was in the slow and 4 Hz bands, and occurred during the delay between the operant choice and trial outcome (reward or punishment) signals. These data provide a basis for further examination of rhythmic coordination of activity of dopaminergic nuclei with other brain structures, and its impact for adaptive behavior.

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bioRxiv2022

Huntingtin-KIF1A-mediated axonal transport of synaptic vesicle precursors influences synaptic transmission and motor skill learning in mice

Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it is unclear whether axonal transport of SVPs modifies synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) causes it to recruit the kinesin motor KIF1A, which in turn increases axonal transport of SVPs and synaptic glutamate release. In mice, constitutive HTT phosphorylation leads to SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.

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bioRxiv2022

Video-based automated analysis of MDS-UPDRS III parameters in Parkinson disease

BackgroundAmong motor symptoms of Parkinsons disease (PD), including rigidity and resting tremor, bradykinesia is a mandatory feature to define the parkinsonian syndrome. MDS-UPDRS III is the worldwide reference scale to evaluate the parkinsonian motor impairment, especially bradykinesia. However, MDS-UPDRS III constitutes an agent-based score making reproducible measurements and follow-up challenging. ObjectivesUsing a deep learning approach, we developed a tool to compute an objective score of bradykinesia based on the gold-standard MDS-UPDRS III. MethodsIn the Movement Disorder unit of Avicenne University Hospital, we acquired a large database of videos of parkinsonian patients performing MDS-UPDRS III protocols. We applied two deep learning algorithms to detect a two-dimensional (2D) skeleton of the hand composed of 21 predefined points, and transposed it into a three-dimensional (3D) skeleton. ResultsWe developed a 2D and 3D automated analysis tool to study the evolution of several key parameters during the protocol repetitions of the MDS-UPDRS III. Scores from 2D automated analysis showed a significant correlation with gold-standard ratings of MDS-UPDRS III, measured with coefficients of determination for the tapping (0.609) and hand movements (0.701) protocols using decision tree algorithms. The individual correlations of the different parameters measured with MDS-UPDRS III scores carry meaningful information and are consistent with MDS-UPDRS III guidelines. ConclusionWe developed a deep learning-based tool to reliably score and analyze bradykinesia for parkinsonian patients.

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bioRxiv2022

Lactate supply overtakes glucose when neural computational and cognitive loads scale up

The neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high stimulation load activity patterns and high attentional load in cognitive tasks, and glucose being sufficient for less demanding neural computation and learning tasks. Overall, these results demonstrate that glucose and lactate metabolisms are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior. One sentence summaryNeuronal fueling by lactate versus glucose scales differently according to engram level and memory load.

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bioRxiv2021

Cerebellar stimulations prevent Levodopa-induced dyskinesia in mice and normalize brain activity

Chronic Levodopa therapy, the gold-standard treatment of Parkinsons Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulations have been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulations induce LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effect of cerebellar stimulations. Moreover, cerebellar stimulations reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide brain motor network, and may be valuable for LID treatment.

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bioRxiv2021

Extracellular and intracellular components of theimpedance of neural tissue

Electric phenomena in brain tissue can be measured using extracellular potentials, such as the local field potential, or the electro-encephalogram. The interpretation of these signals depend on the electric structure and properties of extracellular media, but the measurements of these electric properties are still debated. Some measurements point to a model where the extracellular medium is purely resistive, and thus parameters such as electric conductivity and permittivity should be independent of frequency. Other measurements point to a pronounced frequency dependence of these parameters, with scaling laws that are consistent with capacitive or diffusive effects. However, these experiments correspond to different preparations, and it is unclear how to correctly compare them. Here, we provide for the first time, impedance measurements (in the 1-10 KHz frequency range) using the same set-up in various preparations, from primary cell cultures to acute brain slices, with a comparison with similar measurements performed in artificial cerebrospinal fluid with no biological material. The measurements show that when the current flows across a cell membrane, the frequency dependence of the macroscopic impedance between intracellular and extracellular electrodes is significant, and cannot be captured by a model with resistive media. Fitting a mean-field model to the data shows that this frequency dependence could be explained by the ionic diffusion mainly associated to Debye layers surrounding the membranes. We conclude that neuronal membranes and their ionic environment induce strong deviations to resistivity, that should be taken into account to correctly interpret extracellular potentials generated by neurons. SignificanceThe electro-encephalogram recorded at the scalp surface and local-field potentials recorded within neural tissue are generated by electric currents in neurons, and thus depend on the impedance of neural tissue. Different measured values were proposed, and it is currently unclear what is the real impedance of neural tissue. Here, we show that the impedance depends on the measurement technique. If the measurement is exclusively extracellular, the system appears as equivalent to a simple resistor. However, if the measurement includes an intracellular electrode, a more complex impedance is observed, because the current has to flow through the membrane, as happening in the brain. Thus, we provide an explanation for apparent disagreements, and indicate in which cases each impedance should be used.

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bioRxiv2019

BDNF controls bidirectional endocannabinoid-plasticity at corticostriatal synapses

The dorsal striatum exhibits bidirectional corticostriatal synaptic plasticity, NMDAR- and endocannabinoids-(eCB)-mediated, necessary for the encoding of procedural learning. Therefore, characterizing factors controlling corticostriatal plasticity is of crucial importance. Brain-derived neurotrophic factor (BDNF) and its receptor, the tropomyosine receptor kinase-B (TrkB), shape striatal functions and their dysfunction deeply affect basal ganglia. BDNF/TrkB signaling controls NMDAR-plasticity in various brain structures including striatum. However, despite cross-talks between BDNF and eCBs, the role of BDNF in eCB-plasticity remains unknown. Here, we show that BDNF/TrkB signaling promotes eCB-plasticity (LTD and LTP) induced by rate-based (low-frequency stimulation) or spike-timing-based (spike-timing-dependent plasticity, STDP) paradigm in striatum. We show that TrkB activation is required for the expression and the scaling of both eCB-LTD and eCB-LTP. Using two-photon imaging of the dendritic spines combined with patch-clamp recordings, we show that TrkB activation induces an intracellular calcium boost, thus increasing eCB synthesis and release. We provide a mathematical model for the dynamics of the signaling pathways involved in corticostriatal plasticity. Finally, we show that TrkB activation allows an enlargement of the domain of expression of eCB-STDP. Our results reveal a novel role for BDNF/TrkB signaling in governing eCB-plasticity expression in striatum, and thus the engram of procedural learning.

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bioRxiv2018

Opto-activation of cortical somatostatin interneurons alleviates parkinsonian symptoms

Deep brain stimulation of the subthalamic nucleus is a symptomatic treatment of Parkinsons disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics and modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A mathematical model highlights how the decrease in pyramidal neurons activity can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.\n\nOne-sentence SummaryDeep brain stimulation recruits cortical somatostatin interneurons, and their opto-activation is beneficial in Parkinsons.

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bioRxiv2018

Actomyosin-mediated nanostructural remodeling of the presynaptic vesicle pool by cannabinoids induces long-term depression

Endo- and exocannabinoids, such as the psychoactive component of marijuana, exert their effects on brain function by inducing several forms of synaptic plasticity through the modulation of presynaptic vesicle release. However, the molecular mechanisms underlying the widely expressed endocannabinoid-mediated long-term depression (eCB-LTD), are poorly understood. Here, we reveal that eCB-LTD depends on the contractile properties of the pre-synaptic actomyosin cytoskeleton. Preventing this contractility, both directly by inhibiting non-muscle myosin II NMII ATPase and indirectly by inhibiting the upstream Rho-associated kinase ROCK, abolished long-term, but not short-term forms of cannabinoid-induced functional plasticity in both inhibitory hippocampal and excitatory cortico-striatal synapses. Furthermore, using 3D superresolution microscopy, we find an actomyosin contractility-dependent redistribution of synaptic vesicle pools within the presynaptic compartment following cannabinoid receptor activation, leading to vesicle clustering and depletion from the pre-synaptic active zone. These results suggest that cannabinoid-induced functional plasticity is mediated by a nanoscale structural reorganization of the presynaptic compartment produced by actomyosin contraction. By introducing the contractile NMII as an important actin binding/structuring protein in the dynamic regulation of synaptic function, our results open new perspectives in the understanding of mechanisms of synaptic and cognitive function, marijuana intoxication and psychiatric pathogenesis.

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bioRxiv2018

Encoding of odor fear memories in the mouse olfactory cortex

Odor memories are exceptionally robust and essential for animal survival. The olfactory (piriform) cortex has long been hypothesized to encode odor memories, yet the cellular substrates for olfactory learning and memory remain unknown. Here, using intersectional, cFos-based genetic manipulations (\"Fos-tagging\"), we show that olfactory fear conditioning activates sparse and distributed ensembles of neurons in mouse piriform cortex. We demonstrate that chemogenetic silencing of these Fos-tagged piriform ensembles selectively interferes with odor fear memory retrieval, but does not compromise basic odor detection and discrimination. Furthermore, chemogenetic reactivation of piriform neurons that were Fos-tagged during olfactory fear conditioning causes a decrease in exploratory behavior, mimicking odor-evoked fear memory recall. Together, our experiments identify odor-specific ensembles of piriform neurons as necessary and sufficient for odor fear memory recall.

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bioRxiv2018

Robustness of STDP to spike timing jitter

In Hebbian plasticity, neural circuits adjust their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebbs postulate that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. In recent years, STDP has attracted considerable attention in computational and experimental neurosciences. However, canonical STDP is assessed with deterministic (constant) spike timings and time intervals between successive pairings, thus exhibiting a regularity that strongly differs from the biological variability. Hence, the emergence of STDP from noisy neural activity patterns as expected in in vivo-like firing remains unresolved. Here, we used noisy STDP stimulations where the spike timing and/or the interval between successive pairings were jittered. We explored with a combination of experimental neurophysiology and mathematical modeling, the impact of jittering on three distinct forms of STDP at corticostriatal synapses: NMDAR-mediated tLTP, endocannabinoid-mediated tLTD and endocannabinoid-mediated tLTP. As the main result, we found a differential sensitivity to jittered spike timing: NMDAR-tLTP was highly fragile whereas endocannabinoid-plasticity (tLTD and tLTP) appeared more resistant. Moreover, when the frequency or the number of pairings was increased, NMDAR-tLTP became more robust and could be expressed despite strong jittering of the spike timing. Taken together, our results identify endocannabinoid-mediated plasticity as a robust form of STDP while the sensitivity to jitter of NMDAR-tLTP varies with activity frequency. This provides new insights into the mechanisms at play during the different phases of learning and memory and the emergence of Hebbian plasticity in in vivo-like firing.

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