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

大多数神经元通过自我再生信号进行交流。它们接收并汇总神经元输入部分的信号，如果这些输入超过一定的阈值，它们就会向神经元的输出部分发送一个自我再生的电脉冲，神经元的输出部分会释放化学物质，向其他神经元发出信号。但在许多神经元中，活动是“区室化的”：激活一个部分的神经元使其仅在该部分释放输出信号，而不是其他部分，因为电活动不容易传播到神经元的其他部分。他们为什么要这样做？在大多数情况下，我们不知道：有几个例子，在划分的神经元活动的行为功能被清楚地理解。我们通过研究果蝇的嗅觉记忆来解决这个差距。苍蝇学会避开惩罚性气味，接近奖励性气味。这些记忆被果蝇大脑中一种名为“APL”的神经元抑制，这种神经元抑制称为凯尼恩细胞（KC）的记忆储存神经元。对此的解释并不像“APL抑制记忆是因为APL抑制了KC”那么简单。“相反，我们认为APL抑制学习是因为它的活动是区域化的。这是因为对气味的行为反应是由两种相反类型的神经元之间的平衡控制的，这使得苍蝇要么接近要么避开气味。”这些“接近”和“回避”神经元被称为“蘑菇体输出神经元”（MBON），被KC激活，KC被气味激活。气味+惩罚训练削弱了从KC到接近（但不是回避）MBON的连接，因此回避占主导地位，苍蝇避开了惩罚的气味。同样地，气味+奖励削弱了KC->回避连接。因此，学习行为是由MBON信号的平衡决定的，而不是KCs的总输出。因此，APL只能抑制记忆，如果它减少了接近和回避MBON的气味诱发的活动之间的不平衡。为此，它必须比其他连接更强烈地抑制某些KC->MBON连接：例如，通过抑制KC->回避连接而不是KC->接近连接来抑制惩罚记忆。为了实现这一点：（1）APL活性（因此其抑制输出）必须被区室化。这将允许单个神经元APL差异地抑制KC->接近和KC->回避连接，因为它们处于不同的空间“区”中。(2)杀伤人员地雷在进近区和避碰区必须有不同的活动。APL的活动由KC控制，因此如果KC->APL连接通过以与相同区域中的KC->MBON连接相同的方式学习而被修改，则会发生这种情况：例如，气味+惩罚选择性地削弱“接近”区的KC->APL连接。在这种情况下，因为APL局部抑制KC，所以在学习之后，APL将在回避区中比在接近区中更强烈地抑制KC（并且从而抑制MBON）。这将减少气味+惩罚诱导的MBON活动的不平衡（回避大于接近）。因此，如果APL活动被区室化，学习可以同时诱导支持记忆的突触修饰（KC->MBON连接）和反对记忆的修饰（局部KC->APL连接）。我们称后者为“反记忆”，因为它们是一种主动的变化，充当记忆的“镜子对立面”，而不是被动的衰退。这种反记忆可能会门记忆的形成或表达，并将提供第一个明确的认知功能的区隔活动。我们的初步数据已经证实了上述一些预测。我们将使用大脑成像来测试其余部分：我们将采用一种在神经元活跃时会发光的工程蛋白质，将蛋白质放入KC，APL或MBON中，并在苍蝇闻到气味时对感兴趣的神经元的整个体积进行成像。我们将在训练前后或在操纵神经回路的小区域活动时进行这项工作，我们将分析APL不同部分的活动如何不同。

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.