Anti-memories through compartmentalised activity in a single neuron in a Drosophila memory centre

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Most neurons communicate through self-regenerating signals. They take in and sum up signals in the input part of the neuron, and if these inputs surpass a certain threshold, they send a self-regenerating electrical impulse to the output part of the neuron, which releases chemicals to signal to other neurons. But in many neurons, activity is 'compartmentalised': activating the neuron in one part makes it release output signals only in that one part, not other parts, because electrical activity does not spread readily to other parts of the neuron. Why do they do this? In most cases, we don't know: there are few examples where the behavioural function of compartmentalised neuronal activity is clearly understood.We address this gap by studying olfactory memory in fruit flies. Flies learn to avoid punished odours and approach rewarded odours. These memories are suppressed by a neuron in the fly brain called 'APL', which inhibits memory-storing neurons called Kenyon cells (KCs). The explanation isn't as simple as 'APL inhibits memories because APL inhibits KCs.' Rather, we propose that APL suppresses learning because its activity is compartmentalised.This is because behavioural responses to odours are controlled by the balance between two opposing types of neurons, which make the fly either approach or avoid the odour. These 'approach' and 'avoidance' neurons, called 'mushroom body output neurons' (MBONs), are activated by KCs, which are activated by odours. Odour+punishment training weakens connections from KCs onto approach (but not avoidance) MBONs, so that avoidance dominates and flies avoid the punished odour. Similarly, odour+reward weakens KC->avoidance connections. Thus, learned behaviour is determined by the balance in MBON signalling, not the total output of KCs.Therefore, APL can only suppress memory if it lessens the imbalance between odour-evoked activity in approach and avoidance MBONs. To do this, it must inhibit some KC->MBON connections more strongly than others: e.g., suppress punishment memories by inhibiting KC->avoidance connections more than KC->approach connections. To achieve this:(1) APL activity (and thus its inhibitory output) must be compartmentalised. This would allow the single neuron APL to differentially inhibit KC->approach and KC->avoidance connections because they are in different spatial 'zones'.(2) APL must have different activity in approach vs. avoidance zones. APL's activity is controlled by KCs, so this would occur if KC->APL connections are modified by learning in the same way as KC->MBON connections in the same zone: e.g., odour+punishment selectively weakens KC->APL connections in the 'approach' zone. In this scenario, because APL inhibits KCs locally, after learning APL would inhibit KCs (and thereby MBONs) more strongly in the avoidance zone than in the approach zone. This would lessen the imbalance in MBON activity induced by odour+punishment (avoidance greater than approach).Thus, if APL activity is compartmentalised, learning could simultaneously induce synaptic modifications that support memory (KC->MBON connections) and modifications that oppose memory (local KC->APL connections). We call the latter 'anti-memories' because they are an active change that acts as a 'mirror opposite' to memory, rather than passive decay. Such anti-memories might gate memory formation or expression, and would provide the first clear cognitive function for compartmentalised activity. Our preliminary data has already confirmed some of the predictions above. We will test the rest using brain imaging: we will take an engineered protein that lights up when neurons are active, put the protein in KCs, APL or MBONs, and image the whole volume of the neurons of interest while the fly smells odours. We will do this before and after training, or while manipulating activity in small areas of the neural circuit, and we will analyse how activity differs in different parts of APL.