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 Molecular Systems Biology of Learning

 Research

Traumatic events leave traces in our memory. Understanding how such memories are formed and kept would help understanding the behavioural consequences of trauma, including the related psychiatric conditions. We aim at contributing to this using the fruit fly as a model, because flies’ behaviour is complex enough to be compared to higher animals, while their brains are sufficiently simple and experimentally accessible to be studied in detail.

Flies, when they are given pulses of electric shock, form two opposite kinds of associative memory: Odours that precede shock are learned as signals for punishment and are later on avoided. Odours that follow shock on the other hand are later on approached by the flies, likely because they become signals for the feeling of relief upon shock-cessation. Strikingly, these opposing kinds of memory about a painful shock are paralleled in rodents and man. We study them in the fruit fly comparatively in terms of genetic effectors, molecular mechanisms and neuronal circuits.

An experience with electric shock leaves two opponent memories. Odours that closely precede shock during training are later on avoided; whereas odours that closely follow shock are subsequently approached. Different colours indicate various datasets acquired through the last ~ 10 years. Grey line represents an average across all data sets.

 

Genetic effectors of punishment versus relief learning

Any given behaviour relies on the coordinated functionality of a huge number of genes. In order to comparatively map out the genetic effectors of punishment versus relief learning and in addition innate escape from electric shock, we completed a genome-wide association study, which yielded pools of candidate genes for all three kinds of behaviour. With respect to innate escape, we validated initial candidate genes using specific mutants; whereas bioinformatic gene-network analyses suggested a previously unknown role for mechanosensory bristles in shock-sensation. Similar follow-up is now underway with respect to punishment and relief learning. Given the evolutionary conservation of genes and their effects on behaviour, we hope that our analyses provide interesting hypotheses on the molecular bases of pain and trauma-related behaviour in humans, too.

About 40 inbred fruit fly strains were characterized for their performance in punishment and relief learning as well as innate escape from shock. Association analyses between these behavioural data and the available transcriptomic and genomic data pointed to candidate genes.

 

Neuronal circuit for punishment versus relief learning

Converging evidence points to a specific fly-brain region, the mushroom bodies, as the site of the critical synaptic plasticity underlying olfactory punishment and reward learning. Distinct dopaminergic neurons carry the respective reinforcement signals to the mushroom bodies, whereas partially overlapping output neurons seem to “read out” the respective memory traces. Our initial experiments point to a requirement for mushroom body-function for relief learning, too. Following up on this, we now ask: Which neurons carry a relief-related reinforcement signal to the mushroom bodies? Which neurons are responsible for retrieving relief memories from the mushroom bodies? We tackle these questions using a novel and refined set of transgenic tools, which enable us to block or induce the activity of nearly all mushroom body-associated neurons almost one-at-a-time, screening for effects on relief learning. This shall yield candidate neurons, which we will then study in further anatomical and functional detail. A comprehensive neural circuit account of relief versus punishment learning can in the future be implemented in computational models and perhaps even robotic devices.

Mushroom body function is commonly necessary for punishment, food-reward and relief learning. Following up on what is already known about punishment and reward learning, we now ask how relief reinforcement is signalled to the mushroom bodies and how relief memories are “read out” from the mushroom bodies. Apple photograph from FreeFoodPhotos

 

The long term memory proteome

Behaviour is often affected by memories of events long past. We use the fruit fly as a model to study the ‘where’ and ‘what’ of such long term memory. An evolutionarily conserved feature of long term memory is the requirement for de novo protein synthesis. We use in vivo, cell-specific metabolic protein labeling to localize a long-term associative engram by visualizing this protein synthesis à ‘where’; and to characterize this engram’s molecular content by identifying the newly synthesized proteins à ‘what’. Finally, we will validate the emerging candidate proteins in terms of their causal role in long term memory using specific mutants and RNAi-knockdown. Given that the molecular mechanisms of learning and memory are well-conserved across phyla, we can reasonably hope for translational value of our results.

 

The “content” of olfactory memory

The adaptive value of learned avoidance depends upon the extent to which it is applied to cues different than the trained one: Over-generalization may lead to unnecessary avoidance of irrelevant cues; over-specificity may preclude necessary avoidance of a predictive cue that varies, due to noise, from the original. Fly olfactory memories are partially specific along the odour-identity and -intensity dimensions. The specificity of memory for the trained odour can be explained by the combinatorial coding all along the olfactory pathway. It is however so far unknown how the intensity-specificity of olfactory memory comes about. In a modelling approach, we designed a minimal circuit motif that solves this problem by combining excitation, inhibition and homeostatic plasticity. The key features of our model were consistent with the known architecture and physiology of the fly olfactory system, enabling us to make clear circuit-hypotheses on intensity learning, which we intend to test in the following years.

 

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