Biology subjects

Roeper, J.

Publications and source records attributed to Roeper, J..

14 recordsLinked to original sources

bioRxiv2026

Slow Dynamics Differentially Determine the Robustness of Regular Pacemaking: Distinct Subpopulations of Midbrain Dopamine Neurons Illustrate the Principle

Pacemaking neurons, often found in mammalian nervous systems, integrate their inputs differently than quiescent neurons. Rhythmic single-spike pacemaking that is robust to noise can be achieved with a slow process that enforces a "resting potential" at each point along a ramp-like interspike interval (ISI) coupled with a fast restorative component. To demonstrate this phenomenon, we modeled previously identified distinct subpopulations of midbrain dopamine neurons that differed in projection target and in the regularity of their pacemaking. In the model of the more regularly-firing subpopulation projecting to the dorsomedial striatum, KV4 current was recruited by a deep after-hyperpolarizing potential (AHP) mediated by the SK channel. In the model of the less regularly-firing subpopulation projecting to the medial shell of the nucleus accumbens, the AHP was too shallow to recruit the KV4 current. In the more regularly firing population, the trajectory in the phase space of membrane potential and slow inactivation of KV4 was confined to move slowly through a narrow channel during the ramp-like portion of the ISI. Noisy perturbations from this channel were quickly damped by fast activation of KV4. In contrast, the smaller AHP in the model of the subpopulation projecting to the medial shell of the nucleus accumbens failed to recruit Kv4-mediated current, therefore the narrow channel was never entered, greatly decreasing the regularity in the presence of noise. This mechanism may be broadly applicable to single-spike pacemakers and explains how slow pacemaking with small net currents can be robust to fluctuations in single channel openings. Author SummaryPacemaking cells spike at regular intervals without the need for external input. There are numerous examples of pacemaking cells in the nervous system. We show that a process with slow dynamics relative to the individual spikes can make regular pacemaking robust to the noise that is always present in biological systems.

neuroscience↗

bioRxiv2026

Nullcline Analysis Provides Dynamic Mechanisms for the Differences in Electrical Activity of Distinct Subpopulations of Midbrain Dopamine Neurons

Previously, electrophysiological differences between subpopulations of midbrain dopamine (DA) neurons were identified based on projection targets, including distinct responses to hyperpolarization and in the regularity of pacemaking. Here we explored single-compartment models of three subpopulations of DA neurons, projecting to medial shell of the nucleus accumbens (VTA-mNAcc), dorsomedial striatum (SNc-DMS) or dorsolateral striatum (SNc-DLS). We reduced the dimensionality to a phase plane consisting of membrane potential and one slow variable, either total slow potassium conductance or Kv4 channel inactivation. Nullclines are curves on which the rate of change of each variable is zero, given the value of the other variable. The voltage nullclines had three branches: upper spiking, unstable middle, and lower quiescent branch. Recruitment of Kv4 channels by the more prominent after-hyperpolarizing potential (AHP) in the DA-DMS and DA-DLS models channels stabilized pacemaking by creating a restorative moving fixed point along the quiescent branch. The slow inactivation of KV4 channels dominated and regularized the dynamics during the interspike interval; a dominant slow process may be a general mechanisn for stable regular pacemaking in a frequency range between 1-10 Hz. In contrast, the smaller AHP in VTA-mNAcc models prevented recruitment of this Kv4-mediated moving fixed point, which increased the sensitivity to synaptic inputs. On rebound from hyperpolarization the ability to produce robust ramps reverses between the DA neurons: now VTA-mNAcc projecting DA models fully recruited Kv4 channels and produced stable ramp-like pauses, whereas SNc-DLS projecting cells recruited significant regenerative inward CaV3 channels that overwhelmed Kv4 channels and produced rebound bursts. Author SummaryMidbraim dopamine (DA) neurons in the mammalian midbrain are linked to motivation, control of voluntary movement initiation, and reward-based learning. Their dysfunction is implicated in major disorders like Parkinsons disease, schizophrenia or substance use disorders. Firing patters like bursts or pauses in most DA subpopulations are thought to signal better or worse than expected outcomes. Here we use dynamic systems analysis to capture how functional diversity of DA neurons of their intrinsic properties results in differences of synaptic input integration leading to the generation of burst and pause patterns of electrical activity.

neuroscience↗

bioRxiv2025

A fast and tiny current as common generator of slow regular pacemaking in brain and heart

Slow pacemaking is a key physiological process in specific excitable cells, yet its underlying mechanism remains debated. Here we identify a conserved, voltage-dependent pacemaker current that is essential for slow, regular firing in both midbrain dopaminergic neurons and sinoatrial node myocytes. Conductance-based models incorporating this current reproduce stable pacemaking, requiring a fast-activating, small-amplitude current. This is further confirmed by dynamic-clamp experiments in dopaminergic neurons. Replacing the pacemaker current in a model with a voltage-independent conductance such as the non-selective sodium leak channels fails to sustain slow rhythmicity, highlighting the necessity for an adequate voltage dependence. Our results suggest a novel and shared biophysical mechanism for slow pacemaking in neuronal and cardiac systems.

physiology↗

bioRxiv2021

Kv4.3 channel downregulation mediates chronic post-lesional pacemaker acceleration in surviving dopamine substantia nigra neurons

Dopamine (DA) neurons in the substantia nigra (SN) control several essential functions, including the voluntary movement, learning and motivated behavior. Healthy DA SN neurons show diverse firing patterns in vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient high frequency bursts (<100 Hz), interspersed with pauses that can last hundreds of milliseconds. Recent in vivo patch experiments have started to reveal the subthreshold mechanisms underlying this physiological diversity, but the impact of challenges like cell loss on the in vivo activity of adult DA SN neurons, and how these may relate to behavioral disturbances, are still largely unknown. We investigated the in vivo electrophysiological properties of surviving SN DA neurons after partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of neuronal cell loss. We show that mice subjected to this model have an initial motor impairment, measured by asymmetrical rotations in the open field test, which recovered over time. At 3 weeks post-lesion, when open field locomotion was strongly impaired, surviving DA SN neurons showed a compressed in vivo dynamic firing range, characterized by a 10-fold reduction of in vivo burst firing compared to controls. This in vivo phenotype was accompanied by pronounced in vitro pacemaker instability. In contrast, in the chronic post-lesion phase (>2 months), where turning symmetry in open field locomotion had recovered, surviving SN DA neurons displayed the full dynamic range of in vivo firing, including in vivo bursting, similar to controls. The normalized in vivo firing pattern was associated with a 2-fold acceleration of stable in vitro pacemaking, mediated by Kv4.3 potassium channel downregulation. Our findings demonstrate the existence of a homeostatic pacemaker plasticity mechanism in surviving DA SN neurons after pronounced cell loss.

neuroscience↗

bioRxiv2021

LACTATE IS A MAJOR ENERGY SUBSTRATE FOR CORTICAL NEURONS AND ENHANCES THEIR FIRING ACTIVITY

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with Kir6.2 and SUR1 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function. HighlightsO_LIMost cortical neurons subtypes express pancreatic beta-cell like KATP channels. C_LIO_LILactate enhances spiking activity via its uptake and closure of KATP channels. C_LIO_LICortical neurons take up and oxidize lactate. C_LIO_LICortical neurons produce ATP mainly by oxidative phosphorylation. C_LI

neuroscience↗

bioRxiv2021

Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN)-channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN-channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN-channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a novel role for HCN-channel subunits as a part of a general mechanism influencing cortical development in mammals. Significance StatementImpaired cell cycle regulation of neural stem and progenitor cells can affect cortical development and cause microcephaly. During cell cycle progression, the cellular membrane potential changes through the activity of ion channels and tends to be more depolarized in proliferating cells. HCN channels, which mediate a depolarizing current in neurons and cardiac cells, are linked to neurodevelopmental diseases, also contribute to the control of cell-cycle progression and proliferation of neuronal precursor cells. In this study, HCN-channel deficiency during embryonic and fetal brain development resulted in marked microcephaly of mice designed to be deficient in HCN-channel function in dorsal forebrain progenitors. The findings suggest that HCN-channel subunits are part of a general mechanism influencing cortical development in mammals.

neuroscience↗

bioRxiv2020

An unconventional conductance is required for pacemaking of nigral dopamine neurons

Although several ionic mechanisms are known to control rate and regularity of the pacemaker in dopamine (DA) neurons from the substantia nigra pars compacta (SNc), a conductance essential for pacing has yet to be defined. Here we provide pharmacological evidence that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidine (XG), an established blocker of gating pore currents in mutant voltage gated sodium channels, selectively stops pacemaking of DA SNc neurons and is without effect on the main pore of their voltage-gated channels. We isolated a voltage-dependent, non-inactivating XG-sensitive current of 20-25 pA which operates in the relevant subthreshold range and is carried by both Na+ and Cl- ions. While the molecular identity of this conductance remains to be determined, we show that this XG-sensitive current is crucial to sustain pacemaking in these neurons.

neuroscience↗

bioRxiv2020

Subthreshold repertoire and threshold dynamics of midbrain dopamine neuron firing in vivo.

The firing pattern of ventral midbrain dopamine neurons is controlled by afferent and intrinsic activity to generate prediction error signals that are essential for reward-based learning. Given the absence of intracellular in vivo recordings in the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. By establishing stable in vivo whole-cell recordings of >100 spontaneously active midbrain dopamine neurons in anaesthetized mice, we identified the repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. We demonstrate that dopamine neuron in vivo activity deviates from a single spike pacemaker pattern by eliciting transient increases in firing rate generated by at least two diametrically opposing biophysical mechanisms: a transient depolarization resulting in high frequency plateau bursts associated with a reactive, depolarizing shift in action potential threshold; and a prolonged hyperpolarization preceding slower rebound bursts characterized by a predictive, hyperpolarizing shift in action potential threshold. Our findings therefore illustrate a framework for the biophysical implementation of prediction error and sensory cue coding in dopamine neurons by tuning action potential threshold dynamics.

neuroscience↗

bioRxiv2019

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

No disease modifying therapy is currently available for Parkinsons disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant -synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility which is a common, very early symptom of prodromal PD. We show for the first time a causal chain of events from -synuclein via a biophysical dysfunction of specific neuronal populations to a clinically relevant prodromal symptom. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.

neuroscience↗

bioRxiv2019

Selective K-ATP channel-dependent loss of pacemaking in vulnerable nigrostriatal dopamine neurons by α-synuclein aggregates

Parkinson disease (PD), one of the most common neurodegenerative disorder, is believed to be driven by toxic -synuclein aggregates eventually resulting in selective loss of vulnerable neuron populations, prominent among them, nigrostriatal dopamine (DA) neurons in the lateral substantia nigra (l-SN). How -synuclein aggregates initiate a pathophysiological cascade selectively in vulnerable neurons is still unclear. Here, we show that the exposure to low nanomolar concentrations of -synuclein aggregates (i.e. fibrils) but not its monomeric forms acutely and selectively disrupted the electrical pacemaker function of the DA subpopulation most vulnerable in PD. This implies that only dorsolateral striatum projecting l-SN DA neurons were electrically silenced by -synuclein aggregates, while the activity of neither neighboring DA neurons in medial SN projecting to dorsomedial striatum nor mesolimbic DA neurons in the ventral tegmental area (VTA) were affected. Moreover, we demonstrate functional K-ATP channels comprised of Kir6.2 subunit in DA neurons to be necessary to mediate this acute pacemaker disruption by -synuclein aggregates. Our study thus identifies a molecularly defined target that quickly translates the presence of -synuclein aggregates into an immediate impairment of essential neuronal function. This constitutes a novel candidate process how a protein-aggregation-driven sequence in PD is initiated that might eventually lead to selective neurodegeneration.

neuroscience↗

bioRxiv2019

Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

neuroscience↗

bioRxiv2019

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

The functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.

neuroscience↗

bioRxiv2018

Alternative splicing of bicistronic MOCS1 defines a novel mitochondrial protein maturation mechanism

Molybdenum cofactor biosynthesis is a conserved multistep pathway. The first step, the conversion of GTP to cyclic pyranopterin monophosphate (cPMP), requires bicsistronic MOCS1. Alternative splicing of MOCS1 in exons 1 and 9 produces four different N-terminal and three different C-terminal products (type I-III). Type I splicing results in bicistronic transcripts with two open reading frames, of which only the first, MOCS1A, is translated, whereas type II/III splicing produces two-domain MOCS1AB proteins. Here, we report and characterize the mitochondrial translocation of alternatively spliced MOCS1 proteins. While MOCS1A requires exon 1a for mitochondrial translocation, MOCS1AB variants target to mitochondria via an internal motif overriding the N-terminal targeting signal. Within mitochondria, MOCS1AB undergoes proteolytic cleavage resulting in mitochondrial matrix localization of the MOCS1B domain. In conclusion we found that MOCS1 produces two functional proteins, MOCS1A and MOCS1B, which follow different translocation routes before mitochondrial matrix import, where both proteins collectively catalyze cPMP biosynthesis. MOCS1 protein maturation provides a novel mechanism of alternative splicing ensuring the coordinated targeting of two functionally related mitochondrial proteins encoded by a single gene.

biochemistry↗

bioRxiv2018

Deletion of the alternative splice variant KChIP4a in midbrain dopamine neurons selectively enhances extinction learning

Midbrain dopamine neurons are essential for flexible control of adaptive behaviors. DA neurons that project to different target regions have unique biophysical properties, and it is thought that this diversity reflects functional specialization. This assumption implies the presence of specific genetic determinants with precise impacts on behavior. We tested this general hypothesis by homing in on one particular biophysical mechanism, Kv4 channel inactivation, using a combination of molecular, proteomic, electrophysiological, computational, and behavioral approaches. We demonstrate that KChIP4a, a singular Kv4 {beta}-subunit splice variant, prolongs hyperpolarization-rebound delays selectively in dopamine neurons projecting to the nucleus accumbens core, shifts the integration of inhibitory inputs and, in turn, selectively regulates learning from negative prediction-errors. Our results reveal a highly specialized, gene-to-behavior mechanistic chain that is only operative in a particular dopaminergic subsystem, illuminating how molecularly defined biophysical switches are employed for neuron subtype-specific information processing in the brain. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/344499v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@167984borg.highwire.dtl.DTLVardef@3f8fbborg.highwire.dtl.DTLVardef@f5402aorg.highwire.dtl.DTLVardef@147bb3b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗