Biology subjects

Hotz, A. L.

Publications and source records attributed to Hotz, A. L..

4 recordsLinked to original sources

bioRxiv2024

Guardian of Excitability: Multifaceted Role of Galanin in Whole Brain Excitability

Galanin is a neuropeptide, which is critically involved in homeostatic processes like controlling arousal, sleep, and regulation of stress. This extensive range of functions aligns with implications of galanin in diverse pathologies, including anxiety disorders, depression, and epilepsy. Here we investigated the regulatory function of galanin on whole-brain activity in larval zebrafish using wide-field Ca2+ imaging. Combining this with genetic perturbations of galanin signaling and pharmacologically increasing neuronal activity, we are able to probe actions of galanin across the entire brain. Our findings demonstrate that under unperturbed conditions and during epileptic seizures, galanin exerts a sedative influence on the brain, primarily through the galanin receptor 1a (galr1a). However, exposure to acute stressors like pentylenetetrazole (PTZ) compromises galanins sedative effects, leading to overactivation of the brain and increased seizure occurrence. Interestingly, galanins impact on seizures appears to be bidirectional, as it can both decrease seizure severity and increase seizure occurrence, potentially through different galanin receptor subtypes. This nuanced interplay between galanin and various physiological processes underscores its significance in modulating stress-related pathways and suggests its potential implications for neurological disorders such as epilepsy. Taken together, our data sheds light on a multifaceted role of galanin, where galanin regulates whole-brain activity but also shapes acute responses to stress.

neuroscience↗

bioRxiv2022

Reflective multi-immersion microscope objectives inspired by the Schmidt telescope

Rapid advances in tissue clearing protocols have begun to outpace the capabilities of existing microscope objectives: High-resolution imaging inside cm-sized cleared samples is often not possible as it requires multi-immersion objectives with high numerical aperture (NA > 0.7), long working distance (WD > 10 mm) and a large field-of-view (FOV > 1 mm). Here, we introduce a novel mirror-based optical design, the "Schmidt objective", which meets all these criteria despite containing only two optical elements. It consists of a spherical mirror in contact with the immersion medium and an aspherical correction plate. We showcase a multi-photon variant of a Schmidt objective that reaches NA 1.08 at an refractive index of 1.56 and demonstrate its versatility by imaging fixed samples in a wide range of immersion media ranging from air and water to BABB, DBE, and ECI. In addition, we demonstrate in vivo imaging by recording neuronal activity in larval zebrafish.

neuroscience↗

bioRxiv2022

Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks

The switch between non-seizure and seizure states involves profound alterations in network excitability and synchrony. Both increased and decreased excitability may underlie the state transitions, as shown in epilepsy patients and animal models. Inspired by video-electroencephalography recordings in patients, we developed a framework to study spontaneous and photic-evoked neural and locomotor activity in zebrafish larvae. We combined high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging to perform side-by-side comparison of multiple zebrafish seizure and epilepsy models. Our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that locomotor and neural activity during interictal and spontaneous ictal periods exhibit great diversity across models. Yet, during photic stimulation, hyperexcitability and rapid response dynamics was well conserved across multiple models, highlighting the reliability of photic-evoked seizure activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by fast decay of neural activity and a prominent depressed state. We argue that such depressed states are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies. KEY POINTSO_LIFeatures of spontaneous locomotor and neural activity varies across zebrafish epilepsy and seizure models. C_LIO_LIWe propose photic stimulation as a reliable tool to investigate behavioral and physiological phenotypes in zebrafish epilepsy and seizure models. C_LIO_LIWe observed elevated activity with faster dynamics in response to photic stimulation in all tested zebrafish models. C_LIO_LIPhotic-evoked neural responses were often followed by depressed state in seizure-prone networks C_LI

neuroscience↗

bioRxiv2021

Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish

Astroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Hence, an impairment in EAAT2 function could lead to an imbalanced neural network excitability. Here, we investigated the functional alterations of neuronal and astroglial networks associated with the loss of function in the astroglia predominant eaat2a gene in zebrafish. We observed that eaat2a-/- mutant zebrafish larvae display recurrent spontaneous and light-induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal neuronal and astroglial activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased overall locomotion. Our results reveal an essential and mechanistic contribution of EAAT2a in balancing brain excitability, and its direct link to epileptic seizures.

neuroscience↗