Biology subjects

Weiglein, A.

Publications and source records attributed to Weiglein, A..

6 recordsLinked to original sources

bioRxiv2025

Individual dopaminergic neurons induce unique, yet overlapping combinations of behavioural modulations including safety learning, memory retrieval and acute locomotion

Two evolutionary highly conserved functions of dopamine are to carry "teaching" signals during associative learning and to control movement. In mammals and humans, these functions are generally thought to be produced by different populations of neurons. Here, we investigated in the larva of Drosophila melanogaster whether both these functions can be induced by the same individual dopaminergic neurons in the central brain. Focusing on the dopaminergic neurons of the DL1-cluster, we asked whether the optogenetic activation of individual neurons established associative punishment and/or safety memories, controlled the retrieval of the established memories, and acutely modulated locomotion. We found that each neuron had a unique, yet overlapping set of behavioural effects. Several individual neurons both established a memory and modulated acute locomotion by increasing the animals bending and decreasing its velocity. Our results demonstrate that individual dopaminergic neurons can fulfil a surprisingly broad range of functions in different behavioural contexts. Given the highly conserved roles of the dopaminergic system across the animal kingdom, this study raises the question whether a similarly diverse functionality can be found also in other animals, including humans.

neuroscience↗

bioRxiv2022

Rewarding capacity of optogenetically activating a giant GABAergic central-brain interneuron in larval Drosophila

Larvae of the fruit fly Drosophila melanogaster are a powerful study case for understanding the neural circuits underlying behavior. Indeed, the numerical simplicity of the larval brain has permitted the reconstruction of its synaptic connectome, and genetic tools for manipulating single, identified neurons allow neural circuit function to be investigated with relative ease and precision. We focus on one of the most complex neurons in the brain of the larva (of either sex), the GABAergic anterior paired lateral neuron (APL). Using behavioral and connectomic analyses, optogenetics, Ca2+ imaging and pharmacology, we study how APL affects associative olfactory memory. We first provide a detailed account of the structure, regional polarity, connectivity, and metamorphic development of APL, and further confirm that optogenetic activation of APL has an inhibiting effect on its main targets, the mushroom body Kenyon cells. All these findings are consistent with the previously identified function of APL in the sparsening of sensory representations. To our surprise, however, we found that optogenetically activating APL can also have a strong rewarding effect. Specifically, APL activation together with odor presentation establishes an odor-specific, appetitive, associative short-term memory, whereas naive olfactory behavior remains unaffected. An acute, systemic inhibition of dopamine synthesis as well as an ablation of the dopaminergic pPAM neurons impair reward learning through APL activation. Our findings provide a study case of complex circuit function in a numerically simple brain, and suggest a previously unrecognized capacity of central-brain GABAergic neurons to engage in dopaminergic reinforcement. Significance statementThe single, identified giant anterior paired lateral (APL) neuron is one of the most complex neurons in the insect brain. It is GABAergic and contributes to the sparsening of neuronal activity in the mushroom body, the memory center of insects. We provide the most detailed account yet of the structure of APL in larval Drosophila as a neurogenetically accessible study case. We further reveal that, contrary to expectations, the experimental activation of APL can exert a rewarding effect, likely via dopaminergic reward pathways. The present study both provides an example of unexpected circuit complexity in a numerically simple brain, and reports an unexpected effect of activity in central-brain GABAergic circuits.

neuroscience↗

bioRxiv2022

Optogenetically induced reward and 'frustration' memory in larval Drosophila

Humans and animals alike form oppositely valenced memories for stimuli that predict the occurrence versus the termination of a reward: appetitive reward memory for stimuli associated with the occurrence of a reward and aversive frustration memory for stimuli that are associated with its termination. We characterize these memories in larval Drosophila using a combination of Pavlovian conditioning, optogenetic activation of the dopaminergic central-brain DAN-i1864 neuron, and high-resolution video-tracking. This reveals their dependency on the number of training trials and the duration of DAN-i1864 activation, their temporal stability, and the parameters of locomotion that are modulated during memory expression. Together with previous results on punishment versus relief learning by DAN-f1 neuron activation, this reveals a 2x2 matrix of timing-dependent memory valence for the occurrence/ termination of reward/ punishment. These findings should aid the understanding and modelling of how brains decipher the predictive, causal structure of events around a target reinforcing occurrence.

neuroscience↗

bioRxiv2022

Choosing memory retrieval strategies: a critical role for inhibition in the dentate gyrus

Remembering the location of food is essential for survival. Rodents and humans employ mainly hippocampus-dependent spatial strategies, but when being stressed they shift to striatum-mediated stimulus-based strategies. To investigate underlying brain circuits, we tested mice with a heightened stress susceptibility due to a lack of the GABA-synthetizing enzyme GAD65 (GAD65-/- mice) in a dual solution task. Here, GAD65-/- mice preferred to locate a food reward in an open field via a proximal cue, while their wildtype littermates preferred a spatial strategy. The analysis of cFos co-activation across brain regions and of stress-induced mRNA expression changes of GAD65 pointed towards the hippocampal dorsal dentate gyrus (dDG) as a central structure for mediating stress effects on strategy choices via GAD65. Reducing the GAD65 expression locally in the dDG by a shRNA mediated knock down was sufficient to replicate the phenotype of the global GAD65 knock out and to increase dDG excitability. Using DREADD vectors to specifically interfere with dDG circuit activity during dual solution retrieval but not learning confirmed that the dDG modulates strategy choices and that a balanced excitability of this structure is necessary to establish spatial strategy preference. These data highlight the dDG as a critical hub for choosing between spatial and non-spatial foraging strategies.

neuroscience↗

bioRxiv2021

A quick and versatile protocol for the 3D visualization of transgene expression across the whole body of larval Drosophila

Larval Drosophila are used as a genetically accessible study case in many areas of biological research. Here we report a fast, robust and user-friendly procedure for the whole-body multifluorescence imaging of Drosophila larvae; the protocol has been optimized specifically for larvae by systematically tackling the pitfalls associated with clearing this small but cuticularized organism. Tests on various fluorescent proteins reveal that the recently introduced monomeric infrared fluorescent protein (mIFP) is particularly suitable for our approach. This approach comprises an effective, low-cost clearing protocol with minimal handling time and reduced toxicity in the reagents employed. It combines a success rate high enough to allow for small-scale screening approaches and a resolution sufficient for cellular-resolution analyses with light sheet and confocal microscopy. Given that publications and database documentations typically specify expression patterns of transgenic driver lines only within a given organ system of interest, the present procedure should be versatile enough to extend such documentation systematically to the whole body. As examples, the expression patterns of transgenic driver lines covering the majority of neurons, or subsets of chemosensory, central brain or motor neurons, are documented in the context of whole larval body volumes (using nsyb-Gal4, IR76b-Gal4, APL-Gal4 and mushroom body Kenyon cells, or OK371-Gal4, respectively). Notably, the presented protocol allows for triple-color fluorescence imaging with near-infrared, red and yellow fluorescent proteins.

neuroscience↗

bioRxiv2020

Associative learning in larval and adult Drosophila is impaired by the dopamine-synthesis inhibitor 3-Iodo-L-tyrosine

Across the animal kingdom, dopamine plays a crucial role in conferring reinforcement signals that teach animals about the causal structure of the world. In the fruit fly Drosophila melanogaster, the dopamine system has largely been studied using a rich genetic toolbox. Here, we suggest a complementary pharmacological approach applying the dopamine-synthesis inhibitor 3-Iodo-L-tyrosine (3IY), which causes acute systemic inhibition of dopamine signaling. Using Pavlovian conditioning, across developmental stages (3rd instar larva versus adult), valence domains (reward versus punishment), and types of reinforcement (natural versus optogenetically induced), we find that 3IY feeding specifically impairs associative learning, whereas additional feeding of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of dopamine, rescues this impairment. This study establishes a simple, quick, and comparably low-cost approach that can be combined with the available genetic tools to manipulate and clarify the functions of the dopaminergic system - in D. melanogaster and other animals.

neuroscience↗