Biology subjects

Grunwald Kadow, I. C.

Publications and source records attributed to Grunwald Kadow, I. C..

10 recordsLinked to original sources

bioRxiv2026

Reduced dopaminergic reinforcement, not learning capacity, limits operant learning in aging Drosophila

Aging is associated with a progressive decline in cognitive function, including the ability to adapt behavior based on its consequences. While classical conditioning in Drosophila melanogaster has provided key insights into reinforcement learning, how aging impacts operant learning and adjusting behavior based on action outcomes remains unclear. Here, we used a closed-loop optogenetic paradigm to test how aging affects operant learning and the role of dopaminergic neurons (DANs; PPL1 and PAM) in this process. Activation of distinct DAN subsets revealed that both young and aged flies retain PPL1-dependent avoidance learning, indicating preserved action-outcome learning with age. However, learning in aged flies depended on prolonged reinforcement: unlike young flies, they failed to learn under shorter optogenetic stimulation durations, suggesting an aging-associated reduced dopaminergic reinforcement rather than a loss of learning capacity. Moreover, reducing mitochondrial antioxidant capacity via SOD2 knockdown in PPL1 neurons phenocopied the aging-related deficit, implicating oxidative stress in impaired reinforcement signaling. In contrast, broad PAM neuron activation drove robust learning across ages and stimulation regimes. Nevertheless, functional dissection of PAM subpopulations revealed subtype-specific aging-associated vulnerability within dopaminergic circuits. In line with the behavioral data, PPL1 but not PAM neurons exhibited age-dependent reductions in cell size. Together, our findings suggest that aging selectively reduces dopaminergic reinforcement in a DAN subtype-dependent manner while preserving the capacity for operant learning. Increasing reinforcement length rescues this deficit, indicating that altered dopaminergic signaling, rather than impaired learning capacity, is a key driver of age-related cognitive decline.

neuroscience↗

bioRxiv2026

Deep Representation Learning on Whole-Brain Population Dynamics Uncovers Geometrically Separable Neural Codes

Learning interpretable low-dimensional representations of whole-brain neuronal dynamics remains a major computational challenge in systems neuroscience. We present a wiring-agnostic deep-learning framework that couples a convolutional encoder with a temporal transformer to learn compact representations directly from volumetric calcium imaging of the entire Drosophila melanogaster brain. Trained to classify 16 experimental conditions that factorially combine metabolic state (fed, starved), sensory modality (olfaction, gustation, or combined), and stimulus valence (appetitive, aversive, or conflicting), the model organizes pan-neuronal whole-brain population activity into geometrically distinct, condition-specific clusters. Analysis of the models latent space reveals that state, modality, and valence are encoded along three near-orthogonal axes: a separable structure that emerges from the classification objective without explicit disentanglement constraints. Spatial attribution and regional importance analyses link modality decoding to distinct anatomical circuits, whereas metabolic state and valence related information show weaker regional specificity and broader distribution across the brain. Our approach does not require anatomical annotation, neuronal identification, or connectivity information, and thus provides a scalable foundation for comparative whole-brain imaging and representation learning of brain wide dynamics.

neuroscience↗

bioRxiv2025

Avoidance engages dopaminergic punishment in Drosophila

It was classically suggested that behaviour can cause emotions (Darwin 1872). For example, smiling can make us feel happier, and in rodents the induced patterns of cardiac activity and breathing that are indicative of fear can in turn evoke it (Coles et al. 2022, Hsueh et al. 2023, Jhang et al. 2024). However, the adaptive significance of such feedback is unclear. We show that inducing backward movement, an element of avoidance behaviour in Drosophila, engages negative valence signals in these animals, and reveal the neuronal mechanisms and adaptive significance of this effect. We develop a paradigm with odours as conditioned stimuli paired with optogenetically induced backward movement instead of a punishing unconditioned stimulus, and combined these experiments with pharmacology, high-resolution video tracking, functional imaging, connectome analyses, and modelling. Our results show that backward movement engages dopaminergic punishment neurons and supports aversive memories. Such avoidance-to-punishment feedback counterbalances extinction learning and maintains learned avoidance, reducing the risk of further punishment. This can explain the long-standing "avoidance paradox", the observation that avoidance adaptively persists even when it is successful and no punishment is received (Bolles 1972). Our results provide a neurobiologically grounded argument for an integrated view of behaviour organization and valence processing.

neuroscience↗

bioRxiv2024

A Bidirectional Brain-Fat Body Axis for Pathogen Avoidance

Ingesting pathogens through spoiled food can cause serious harm, including infections, tissue damage, and even death. To prevent these outcomes, many animals have evolved behaviors to avoid consuming harmful pathogens. While pathogen avoidance behavior is conserved across species, the mechanisms linking immune responses of the body with neuron-controlled behavior remain unclear. Building on our previous findings, we here present a new bidirectional body-brain communication between the fat body and the nervous system that drives immune receptor-induced avoidance behavior. We show that immune receptor signaling and a specific antimicrobial peptide (AMP) are essential in both octopaminergic neuromodulatory neurons and the fat body for rapidly reducing pathogen intake after initial ingestion. Mechanistically, the octopaminergic neurons innervate the flys fat body where they trigger a calcium response through a specific octopamine receptor. This octopaminergic signal prompts the fat body to release dopamine. In turn, Dop1R1 signaling in output neurons of the mushroom body, the insect higher brain center, drives pathogen avoidance. Together, our data suggest that ingested pathogens are detected by immune receptors in neurons, which, through synaptic connections, trigger the release of dopamine and AMPs from fat cells. While AMPs combat the pathogens, dopamine reduces further ingestion by inducing behavioral changes. This mechanism demonstrates efficient communication between the body and brain, coordinating survival behaviors through systemic dopamine signaling from the fat body to the brain.

neuroscience↗

bioRxiv2024

Adenosine signaling in glia modulates metabolic state-dependent behavior in Drosophila

An animals metabolic state strongly influences its behavior. Hungry animals prioritize food seeking and feeding behaviors, while sated animals suppress these behaviors to engage in other activities. Additionally, neuronal activity and synaptic transmission are among the most energy expensive processes. Yet neurons do not uptake nutrients from the circulation. Instead, glia fulfill this highly evolutionary conserved function. Recent studies have shown that glia can modulate neuronal activity and behavior. However, how different glia subtypes sense metabolic state and modulate neurons and behavior is incompletely understood. Here, we unravel two types of glia-mediated modulation of metabolic state-dependent behavior. In food-deprived flies, astrocyte-like and perineurial glia promote foraging and feeding, respectively, while cortex glia suppress these behaviors. We further show that adenosine and adenosine receptor modulate intracellular calcium levels in these glia subtypes, which ultimately controls behavior. This study reveals a new mechanism how different glia subtypes sense the metabolic state of the animal and modulate its behavior accordingly.

neuroscience↗

bioRxiv2023

Optimized design and in vivo application of optogenetically functionalized Drosophila dopamine receptors

Neuromodulatory signaling via G protein-coupled receptor (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. Recent efforts have led to the development of optogenetic tools to induce G protein-mediated signaling, with the promise of acute and cell type-specific manipulation of neuromodulatory signals. However, designing and deploying optogenetically functionalized GPCRs (optoXRs) with accurate specificity and activity to mimic endogenous signaling in vivo remains challenging. Here we optimized the design of optoXRs by considering evolutionary conserved GPCR-G protein interactions and demonstrate the feasibility of this approach using two Drosophila Dopamine receptors (optoDopRs). We validated these optoDopRs showing that they exhibit high signaling specificity and light sensitivity in vitro. In vivo we detected receptor and cell type-specific effects of dopaminergic signaling in various behaviors including the ability of optoDopRs to rescue loss of the endogenous receptors. This work demonstrates that OptoXRs can enable optical control of neuromodulatory receptor specific signaling in functional and behavioral studies.

neuroscience↗

bioRxiv2023

The Preoptic Area and Dorsal Habenula Jointly Support Homeostatic Navigation in Larval Zebrafish

Animals must maintain physiological processes within an optimal temperature range despite changes in their environment. While the preoptic area of the hypothalamus (PoA) acts as a thermostat in mammals through autonomic and behavioral adaptations, its role in temperature regulation of animals lacking internal homeostatic mechanisms is not known. Through novel behavioral assays, wholebrain functional imaging and neural ablations, we show that larval zebrafish achieve thermoregulation through movement and a neural network connecting the PoA to brain areas enabling spatial navigation. PoA drives reorientation when thermal conditions are worsening and conveys this information for instructing future motor actions to the navigation-controlling habenula (Hb) - interpeduncular nucleus (IPN) circuit. These results suggest a conserved function of the PoA in thermoregulation acting through species- specific neural networks. We propose that homeostatic navigation arose from an ancient chemotaxis navigation circuit that was subsequently extended to serve in other sensory modalities.

neuroscience↗

bioRxiv2022

Walking elicits global brain activity in Drosophila

Movement-correlated brain activity has been found across species and brain regions. Here, we used fast whole-brain lightfield imaging in adult Drosophila to investigate the relationship between walk and neuronal activity. We observed brainwide activity that tightly correlated with spontaneous bouts of walk. While imaging specific sets of excitatory, inhibitory, and neuromodulatory neurons highlighted their joint contribution, spatial heterogeneity in forward walk- and turning-induced activity allowed parsing unique responses from subregions and sometimes individual neurons. For example, previously uncharacterized serotonergic neurons were inhibited during walk. While activity onset in some areas preceded walk onset exclusively in spontaneously walking animals, spontaneous and forced walk elicited highly similar activity in most brain regions. These data suggest a major contribution of walk and walk-related sensory or proprioceptive information to brain state. We conclude that walk-related signals induce global but heterogeneous patterns of activity, allowing for local and brain-wide integration of behavioral state into other processes in the brain.

neuroscience↗

bioRxiv2021

A distributed dopamine-gated circuit underpins reproductive state-dependent behavior in Drosophila females

Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in most female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the flys learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female flys ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the {beta}1 compartment are sufficient to replace mating experience in virgin females inducing the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the {beta}1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the {beta}2 compartment enables expression of high polyamine attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.

neuroscience↗

bioRxiv2019

Valence and state-dependent population coding in dopaminergic neurons in the fly mushroom body

Neuromodulation permits flexibility of synapses, neural circuits and ultimately behavior. One neuromodulator, dopamine, has been studied extensively in its role as reward signal during learning and memory across animal species. Newer evidence suggests that dopaminergic neurons (DANs) can modulate sensory perception acutely, thereby allowing an animal to adapt its behavior and decision-making to its internal and behavioral state. In addition, some data indicate that DANs are heterogeneous and convey different types of information as a population. We have investigated DAN population activity and how it could encode relevant information about sensory stimuli and state by taking advantage of the confined anatomy of DANs innervating the mushroom body (MB) of the fly Drosophila melanogaster. Using in vivo calcium imaging and a custom 3D image registration method, we find that the activity of the population of MB DANs is predictive of the innate valence of an odor as well as the metabolic and mating state of the animal. Furthermore, DAN population activity is strongly correlated with walking or running, consistent with a role of dopamine in conveying behavioral state to the MB. Together our data and analysis suggest that distinct DAN population activities encode innate odor valence, movement and physiological state in a MB-compartment specific manner. We propose that dopamine shapes innate odor perception through combinatorial population coding of sensory valence, physiological and behavioral context.

neuroscience↗