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Neural processing of context-dependent innate behavior

Periodic Reporting for period 3 - FlyContext (Neural processing of context-dependent innate behavior)

Reporting period: 2018-07-01 to 2019-12-31

Perceptions and decisions depend on sensory impressions, but also on past experiences and the internal state of an animal. Behavior is therefore very adaptive and flexible. For instance, a hungry animal perceives the smell and taste of food as much more positive than a fed animal. At the same time, the hungry animal is willing to take a high risk in order to find food. Which signals and neural networks allow the communication between brain and body? And how do they modulate behavior?
In this project, we are studying these questions on the example of the senses of smell and taste, the most important modalities in food-related decisions and preferences. Specifically, we want to understand how chemosensory information is processed by the brain to guide decision-making and how physiology and metabolic needs such as hunger influence neuronal processes and cognitive function. To this aim, we are using an interdisciplinary approach combining molecular biology, genetics and genomics in the model organisms Drosophila melanogaster, electrophysiology, in vivo multiphoton functional imaging and state-of-the-art behavioral analysis.
Ultimately, we strive to contribute with our findings in model organisms to the understanding of human health and behaviour and to decipher how brain and body interact to maintain long-term health and well-being.
"The project had three major aims. In the following I will summarize our finding up to now for the first two aims. As work regarding the third aim has only recently started, it will be described in the final report.

Internal state as well as available environmental information shape our sensory perception. Most of our sensory perceptions are complex. For example, a smell usually appears in combination with many other odours - including pleasant and unpleasant ones. For the fruit fly Drosophila, the smell of carbon dioxide (CO2) is repulsive in most scenarios. The gas is released by stressed flies to warn other members of the species. When the insects smell CO2 an innate flight response is triggered. However, CO2 is also produced by overripe fruit - a coveted source of food for many insects. Foraging flies must therefore be able to ignore their innate aversion to CO2 in instances where the gas is present in combination with food odours. How does the brain deal with such conflicting information in a context-dependent manner? We have used the opposing significance of CO2 for fruit flies to explore how the brain correctly evaluates individual sensory impressions depending on the situation. We found that CO2 activates neurons in the neural network that includes the mushroom body of the insect, a brain region highly important for the formation of olfactory memories. These aversive odor responsive neurons trigger the flies' flight behaviour. However, if CO2 occurs along with food odours such as vinegar, the food odour stimulates neurons within the mushroom body network that release the neurotransmitter dopamine. Dopamine occurs in many species, including humans, in connection with positive values. When food smells are present along with CO2, these dopaminergic neurons in fruit flies transmit this information to the mushroom body, where they suppress the innate CO2 response by inhibiting the ""avoidance neurons"". Interestingly, the experience that CO2 frequently occurs together with food odours does not cause the insects to lose their aversion to CO2 in the long run. Instead the mushroom body appears to be required for an immediate change of behaviour. We speculate that the absence of a permanent change in behaviour could be vital in many situations. The smell of predators, for example, triggers an instinctive fear in humans. We do not lose this fear, even after experiencing caged predators and their smell at a zoo. The human brain therefore also appears to compare and draw different conclusions depending on the circumstances.

Hunger is a more general state where the body needs primarily calories. Do specific nutritional needs also guide odor and taste preferences? We have analysed this question on the example of polyamines. Polyamines are small organic compounds that play a role in such fundamental cellular processes like cell division and growth. Consequently, polyamine deficiency can have negative impacts on health, cognition, fertility, reproduction and life expectancy. Since excessive polyamine concentrations can also be harmful, the supply of polyamines to the body should match its current requirements. Polyamines are particularly demanded during growth, injury or periods of increased physical demands, such as pregnancy. The body is able to produce some of the required polyamines by itself, and also with the help of intestinal bacteria. Still, a considerable amount of polyamines is obtained from food.
We observed that flies are strongly attracted by the smell of polyamines. Female flies preferred to lay their eggs on older, polyamine-rich fruit rather than on fresher fruit. We discovered that the animals not only perceive the odour but also use their sense of taste to find and examine polyamine-rich sources of food. Initially, flies find a polyamine-rich food source by its odour, using the chemosensory receptors IR76b and IR41a. The taste neurons then evaluate the quality of the identified polyamines with the help of the IR76b receptor and a bitter taste receptor. As is the case in humans, an excessively high polyamine concentration appears to deter the flies. They only ate or laid their eggs on polyamine-rich food if the bitter taste of the polyamines was concealed by other food components, for example sugar. Interestingly, the three receptors that enable the recognition of polyamines belong to a class of proteins that is very old, in evolutionary terms. They are related to receptors that control synaptic activities of for instance human neurons. It is therefore possible that the recognition of polyamines through these receptors improved the chances of survival of animals at an early stage in evolutionary history.

Specific metabolic states but also life stages demand more or less of a specific nutrient. A pregnancy represents a huge challenge for the mother's body. To provide optimal nutrition for the developing offspring, her nutrition must be adapted to the altered requirements. Given the important role of polyamines in embryonic development, we asked whether gravid fly females adapted their behaviour to polyamines upon mating. In fact, after mating, female fruit flies show a preference for food with a high polyamine content. A combination of behavioural studies and physiological tests revealed that the change in the appeal of polyamines to flies before and after mating is triggered by a neuropeptide receptor known as the sex peptide receptor (SPR) and its neuropeptide binding partner. SPR initiates egg production in mated flies among other functions. Surprisingly, egg laying itself was not required to change the female's preference, instead mating appeared to be the signal. We found that about 10 times more SPR receptors are integrated into the surfaces of the peripheral chemosensory neurons including the olfactory sensory neurons in mated females. This increase in neuropeptide signalling modifies the reaction of the sensory neurons to the odour and taste. The thereby modulated odour and taste perception thus occurs at a very early stage in the nervous system. Remarkably, an increase in SPR exclusively in chemosensory neurons was sufficient to enable the neurons of virgin flies to react more strongly to polyamines, which ultimately resulted in a change of their preference. Like their mated species counterparts, virgins now preferred the polyamine-rich food sources.
The study demonstrated the existence of a mechanism through which pregnancy modifies specific chemosensory neurons and alters the perception of important nutrients and behaviour towards them. ""Because smell and taste are processed in a similar way in insects and mammals, a corresponding mechanism in humans could also ensure an optimal nutritional supply for the developing life.

Taken together, our current progress is well in line with our hopes for the project. We have already published some of our results, submitted others, and are working on additional interesting data. Regarding the general implications and the bigger picture that is emerging from all these projects, the mushroom body has crystallized as a central brain structure involved in context-dependent behavior, in particular state-dependent adaptive behavior. Our data emphasizes that plasticity of synapses and plasticity of neural circuits is required not only for future behavior, but also for present behavior and immediate adaptation to internal and environmental context through integration of internal and external information. Furthermore, our data allows the hypothesis that neuromodulation in early sensory processing impacts higher order processing and thereby strongly influences the sensory experience and ultimately the information available for decision making.

For the remainder of the project, we want to dive deeper into the signals and neurons that connect the body to the brain to ultimately modulate behavior and decision making. To this end, we are evaluating the impact of beneficial and pathogenic bacteria on the behavior, its neural underpinnings, and of the genes that are involved. Furthermore, we have investigated how neural circuits allow prioritizing behavioural perseverance over withdrawal based on the animal's need. Through the development of a single fly spherical treadmill, we show that hungry flies display increasing perseverance to track a food odor in the repeated absence of the predicted food reward. While this reward prediction error is mediated by a group of dopaminergic neurons, a subset of neurons expressing octopamine, the invertebrate noradrenaline, provide reward feedback and counteract dopamine-motivated food seeking. Our data suggest that two important neuromodulators tally internal and external signals to ultimately coordinate motivation-dependent antagonistic behavioral drives: perseverance vs. change of behavior. Finally, we have greatly improved our abilities to image neuronal responses in vivo from larger populations of neurons. Through collaborations, we have developed methods allowing us to compare different datasets from different animals and analyze them in an unbiased manner. We are using this method to unravel how value and valence are represented in the brain in a state-dependent manner.