Biology subjects

Selcho, M.

Publications and source records attributed to Selcho, M..

10 recordsLinked to original sources

bioRxiv2025

Selective octopaminergic tuning of mushroom body circuits during memory formation

The catecholamines octopamine and tyramine undoubtedly have a major impact on the life of an insect. A wide range of physiological processes and behaviours are regulated by these neurotransmitters/hormones. Octopamine and tyramine act homologous to the adrenergic system of vertebrates, primarily adapting the organism to the given situation, by switching between the states of alertness and rest. Interestingly, higher brain functions like learning and memory are also regulated by octopamine and tyramine. About 30 years ago, initial work in Drosophila has demonstrated that dopaminergic neurons signal punishment, while octopaminergic neurons signal reward during olfactory associative learning and memory. In the meantime, however, it has become clear that distinct types of dopaminergic neurons convey both reward and punishment signals to the mushroom bodies, a central brain region responsible for the formation and storage of associative memories. Although some conflicting data remain, these findings challenge the previously established model of functional segregation and may limit the proposed role of octopamine neurons as teaching neurons during memory formation. We have therefore re-examined the role of octopamine in learning and memory in Drosophila larvae. Through a combination of Ca2+ imaging, anatomical studies and gain-of-function and loss-of-function behavioural approaches, we demonstrate that octopamine signalling plays a crucial role in larval learning by modulating dopaminergic neurons across distinct cell clusters to orchestrate memory processes.

neuroscience↗

bioRxiv2024

Neuropathic pain and distinct CASPR2 autoantibody IgG subclasses drive neuronal hyperexcitability

Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain, in some patients even as the only symptom. CASPR2 is an adhesion protein of the neurexin IV family and part of the voltage-gated potassium channel complex (VGKC) in neurons of dorsal root ganglia (DRG). The subsequent pathological mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass. Previous studies have neglected subclass-dependent effects. Here we investigated 49 subclassified patient serum samples positive for CASPR2 aAbs. To unravel underlying molecular mechanisms, we used a combination of super-resolution lattice structural illumination microscopy (SIM2) and functional readouts by calcium imaging and electrophysiological recordings. CASPR2-positive patient sera subclassified in IgG4 together with at least one other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain group. Patient subclassification shed further light on the pathological mechanisms of CASPR2 aAbs. A decrease of CASPR2 expression after long-term exposure to CASPR2 aAbs was only observed for the patient group without pain. Upon withdrawal of the CASPR2 aAbs, CASPR2 expression returned to normal level. Structural alterations were obtained by increased distances between CASPR2 and associated potassium channels along DRG axons using high-resolution lattice SIM2 microscopy but only following binding of CASPR2 aAbs from patients with pain. Similarly, CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all four CASPR2 aAbs subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs. Notably, a patient serum sample lacking IgG4 did not alter Kv channel function. Withdrawal of aAbs rescued Kv channel function to normal levels suggesting that the affected potassium channel function is rather due to a functional block of the VGKC rather than altered structural integrity of the VGKC. Taken together, we found IgG4 aAbs to be a major modifier of potassium channel function. The increase in DRG excitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAbs binding but additional and so far unidentified signal pathways contribute to this process in patients with neuropathic pain.

neuroscience↗

bioRxiv2023

Rab3 mediates cyclic AMP-dependent presynaptic plasticity and olfactory learning

Presynaptic forms of plasticity occur throughout the nervous system and play an important role in learning and memory but the underlying molecular mechanisms are insufficiently understood. Here we show that the small GTPase Rab3 is a key mediator of cyclic AMP (cAMP)-induced presynaptic plasticity in Drosophila. Pharmacological and optogenetic cAMP production triggered concentration-dependent alterations of synaptic transmission, including potentiation and depression of evoked neurotransmitter release, as well as strongly facilitated spontaneous release. These changes correlated with a nanoscopic rearrangement of the active zone protein Unc13A and required Rab3. To link these results to animal behaviour, we turned to the established role of cAMP signalling in memory formation and demonstrate that Rab3 is necessary for olfactory learning. As Rab3 is dispensable for basal synaptic transmission, these findings highlight a molecular pathway specifically dedicated to tuning neuronal communication and adaptive behaviour.

neuroscience↗

bioRxiv2023

Neuronal correlates of time integration into memories

The circadian clock affects a wide range of physiological processes. Of particular interest is the influence of the clock on memory performance, as circadian dysfunction is associated with age- and disease-related decline in memory. In various species it has been shown that memory performance is regulated by the circadian clock. However, the anatomical and functional connection of the circadian clock and memory neurons has not been described in detail so far. This study now identifies that Diuretic hormone 31 (DH31)-positive clock neurons of the DN1p cluster regulate memory performance. DH31, a functional homolog of the mammalian calcitonin gene-related peptide, plays a crucial role in this process as a clock communication signal. DH31 facilitates memory performance during the night via indirect signalling, while DH31 signals directly to the mushroom bodies restricting memory performance specifically in the evening. This pleiotropic action of DH31 suggests that the circadian clock confines memory performance to a physiological dynamic range.

neuroscience↗

bioRxiv2023

Immediate effects of light on circadian eclosion and locomotor activity depend on distinct sensory input pathways

Animals need to be able to sharpen circadian behavioural output in the adaptation to the variable environment. Light is the main entraining signal of the circadian clock, but can also directly increase alertness, locomotor activity, body temperature and heart rate in diurnal animals including humans. Thus, immediate effects of light can enhance or even overwrite circadian output and thereby mask circadian behaviour. In Drosophila melanogaster, immediate light effects are most evident as a lights-on response in two well described behavioural rhythms of the fly - the emergence rhythm of the adult insect from the pupa, called eclosion, and the diurnal rhythm of locomotor activity. Here, we show that the immediate effect of light on rhythmic eclosion depends on the R8 photoreceptor cells of the compound eyes, while the light response of locomotor activity is triggered by different light detecting cells and organs, that seem to compensate for the loss of each other.

neuroscience↗

bioRxiv2020

Dopamine signaling in wake promoting clock neurons is not required for the normal regulation of sleep in Drosophila

Dopamine is a wakefulness promoting neuromodulator in mammals and fruit flies. In D. melanogaster, the network of clock neurons that drives sleep/activity cycles comprises both wake and sleep promoting cell types, indicating that the sleep-wake circuitry is intimately linked to the circadian clock. The large and small ventrolateral neurons (l-LNvs and s-LNvs) have been identified as wake-promoting neurons within the clock neuron network. The l-LNvs are innervated by dopaminergic neurons, and earlier work proposed that dopamine signaling raises cAMP levels in the l-LNvs and thus induces excitatory electrical activity (action potential firing), which results in wakefulness and inhibits sleep. Here, we test this hypothesis by combining cAMP imaging and patch-clamp recordings in isolated brains. We find that dopamine application indeed increases cAMP levels and depolarizes the l-LNvs, but surprisingly, it does not result in increased firing rates. Down-regulation of the excitatory dopamine receptor, Dop1R1 in the l-and s-LNvs, but not of Dop1R2, abolished the depolarization of l-LNvs in response to dopamine. This indicates that dopamine signals via Dop1R1 to the l-LNvs. Down-regulation of Dop1R1 or Dop1R2 receptors in the l- and s-LNvs does not affect sleep. Unexpectedly, we find a moderate decrease of daytime sleep with down-regulation of Dop1R1 and of nighttime sleep with down-regulation of Dop1R2. Since the l-LNvs do not utilize Dop1R2 receptors and the s-LNvs respond also to dopamine, we conclude that the s-LNvs are responsible for the observed decrease in nighttime sleep. In summary, dopamine signaling in the wake-promoting LNvs is not required for daytime arousal, but likely promotes nighttime sleep via the s-LNvs. Significance statementIn insect and mammalian brains, sleep promoting networks are intimately linked to the circadian clock, and the mechanisms underlying sleep and circadian timekeeping are evolutionarily ancient and highly conserved. Here we show that dopamine, one important sleep modulator in flies and mammals, plays surprisingly complex roles in the regulation of sleep by clock containing neurons. Dopamine inhibits neurons in a central brain sleep center to promote sleep and excites wake-promoting circadian clock neurons. It is therefore predicted to promote wakefulness through both of these networks. Nevertheless, our results reveal that dopamine acting on wake promoting clock neurons promotes sleep, revealing a previously unappreciated complexity in the dopaminergic control of sleep.

neuroscience↗

bioRxiv2020

Antinociceptive modulation by the adhesion-GPCR CIRL promotes mechanosensory signal discrimination

Adhesion-type G protein-coupled receptors (aGPCRs) participate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family. CIRL (ADGRL/Latrophilin, LPHN), one of the oldest members of the aGPCR family, sensitizes sensory responses of larval Drosophila to gentle touch and sound by amplifying mechanosensory signal transduction in low-threshold mechanoreceptors (Scholz et al., 2015; 2017). In the present study, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathophysiological conditions. Optogenetic in vivo experiments indicate that CIRL quenches cAMP levels in both mechanosensory submodalities. However, contrasting its effect in touch sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display a drop in Cirl1 expression during allodynia. Taken together, these results demonstrate that CIRL exerts opposing modulatory functions in low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action likely facilitates the separation of mechanosensory signals carrying different physiological information.

physiology↗

bioRxiv2020

Endocrine fine-tuning of daily locomotor activity patterns under non-starving conditions in Drosophila

1.Animals need to balance competitive behaviours to maintain internal homeostasis. The underlying mechanisms are complex, but typically involve neuroendocrine signalling. Using Drosophila, we systematically manipulated signalling between energy-mobilising endocrine cells producing adipokinetic hormone (AKH), octopaminergic neurons and the energy-storing fat body to assess whether this neuroendocrine axis involved in starvation-induced hyperactivity also balances activity levels under ad libitum access to food. Our results suggest that AKH signals via two divergent pathways that are mutually competitive in terms of activity and rest. AKH increases activity via the octopaminergic system during the day, while it prevents high activity levels during the night by signalling to the fat body. This regulation involves feedback signalling from octopaminergic neurons to AKH-producing cells (APCs). APCs are known to integrate a multitude of metabolic and endocrine signals. Our results add a new facet to the versatile regulatory functions of APCs by showing that their output contributes to shape the daily activity pattern under ad libitum access to food.

neuroscience↗

bioRxiv2018

A comprehensive anatomical map of the peripheral octopaminergic/tyraminergic system of Drosophila melanogaster

The modulation of an animals behavior through external sensory stimuli, previous experience and its internal state is crucial to survive in a constantly changing environment. In most insects, octopamine (OA) and its precursor tyramine (TA) modulate a variety of physiological processes and behaviors by shifting the organism from a relaxed or dormant condition to a responsive, excited and alerted state. Even though OA/TA neurons of the central brain are described on single cell level in Drosophila melanogaster, the periphery was largely omitted from anatomical studies. Given that OA/TA is involved in behaviors like feeding, flying and locomotion, which highly depend on a variety of peripheral organs, it is necessary to study the peripheral connections of these neurons to get a complete picture of the OA/TA circuitry. We here describe the anatomy of this aminergic system in relation to peripheral tissues of the entire fly. OA/TA neurons arborize onto skeletal muscles all over the body and innervate reproductive organs, the heart, the corpora allata, and sensory neurons in the antenna, wings and halteres underlining their relevance in modulating complex behaviors.

neuroscience↗

bioRxiv2018

Reward signaling in a recurrent circuit of dopaminergic neurons and Kenyon cells

1.Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that a functional recurrent signaling loop exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. An optogenetic activation of Kenyon cells paired with an odor is sufficient to induce appetitive memory, while a simultaneous impairment of the dopaminergic pPAM neurons abolishes memory expression. Thus, dopaminergic pPAM neurons mediate reward information to the Kenyon cells, but in turn receive feedback from Kenyon cells. We further show that the activation of recurrent signaling routes within mushroom body circuitry increases the persistence of an odor-sugar memory. Our results suggest that sustained activity in a neuronal circuitry is a conserved mechanism in insects and vertebrates to consolidate memories.

neuroscience↗