Biology subjects

Stojanovic, S.

Publications and source records attributed to Stojanovic, S..

4 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↗

bioRxiv2022

Free-Standing Multilayer Films as Growth Factor Reservoirs for Future Wound Dressing Applications

Chronic skin wounds place a high burden on patients and health care systems. The use of angiogenic and mitogenic growth factors (GF) can facilitate the healing but GF are quickly inactivated by the wound environment if added exogenously. Here, free-standing multilayer films (FSF) are fabricated from chitosan (CHI) and alginate (ALG) as opposing polyelectrolytes in an alternating manner using layer-by-layer technique (LbL). One hundred bilayers form an about 450 {micro}m thick, detachable free-standing film (N-FSF) that is subsequently crosslinked by either ethyl (dimethylaminopropyl) carbodiimide (EDC) combined with N-hydroxysuccinimide (NHS) (E-FSF) or genipin (G-FSF). The characterization of swelling, oxygen permeability and crosslinking density shows reduced swelling and oxygen permeability for both crosslinked films compared to N-FSF. Loading of fibroblast growth factor 2 (FGF2) into the films results in a sustained release of GF from crosslinked in comparison to N-FSF. Biocompatibility studies in vitro with human dermal fibroblasts (HDF) cultured underneath the films demonstrate increased cell growth and cell migration for all films with and without FGF2. Especially G-FSF loaded with FGF2 greatly increases cell proliferation and migration. In vivo biocompatibility studies by subcutaneous implantation in mice show that E-FSF causes a strong inflammatory response while G-FSF is of high biocompatibility. N-FSF also represents a biocompatible film but shows early degradation. All FSF possess antibacterial properties against gram+ and gram-bacteria demonstrated by an agar diffusion disc assay. In summary, FSF made of ALG and CHI crosslinked with genipin can act as a reservoir for the sustained release of FGF2, possessing high biocompatibility in vitro and in vivo. Moreover, G-FSF promotes growth and migration of HDF and has antibacterial properties which makes it an interesting candidate for bioactive wound dressings.

bioengineering↗

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↗