Abstract
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. Furthermore, excitability of the brain is tightly controlled by balancing excitatory and inhibitory inputs. A key role in this process falls to excitatory amino acid transporter 2 (EAAT2) that removes the main excitatory neurotransmitter glutamate from the synaptic cleft after a synaptic event. Failure to do so may result in hyperexcitation and epileptic seizures. Knockout of eaat2a in zebrafish leads to behavioral and functional impairments in homozygous larvae. While eaat2a-/- zebrafish suffer from epileptic seizures, interictally, they show reduced neuronal activity and reduced locomotion. Here, in Chapter 2, 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 were able to probe the actions of galanin across the entire brain. Furthermore, in Chapter 3, I set out to elucidate possible adaptive mechanisms in eaat2a mutants by looking at transcriptomic changes in their brain. Additionally, I tried to investigate more aspects of how galanin affects the zebrafish brain, by implementing different heat shock regiments to upregulate galanin under the hsp70l heat shock promoter. Our findings demonstrate that under normal 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 galanin's sedative effects, leading to overactivation of the brain and increased seizure occurrence. Interestingly, galanin's 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.
Rieser, Nicolas