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的信号进行交流。它们吸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，后者会释放化学物质，向其他神经元发送信号。但在许多神经元中，活动是“分区的”：激活一个部分的神经元，使其只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。他们为什么要这么做？在大多数情况下，我们不知道：很少有例子清楚地了解隔区神经元活动的行为功能。我们通过研究果蝇的嗅觉记忆来解决这一差距。苍蝇学会避免被惩罚的气味，并接近奖励的气味。这些记忆被苍蝇大脑中一种名为APL的神经元抑制，这种神经元抑制被称为Kenyon细胞(KCs)的记忆存储神经元。这一解释并不像“APL抑制记忆，因为APL抑制KC”那么简单。相反，我们认为APL抑制学习是因为它的活动是分开的。这是因为对气味的行为反应由两种相反类型的神经元之间的平衡控制，这两种神经元要么让苍蝇接近，要么让它避开气味。这些“接近”和“回避”神经元被称为“蘑菇体输出神经元”(MBON)，由KCs激活，KCs被气味激活。气味+惩罚训练削弱了KCs与接近(但不是回避)MBON的联系，因此回避占主导地位，苍蝇避免受到惩罚的气味。同样，气味+奖励会削弱KC-&gt；的回避联系。因此，习得行为是由MBON信号的平衡决定的，而不是KC的总输出。因此，APL只有在减少接近和回避MBON中气味诱发活动之间的失衡时，才能抑制记忆。要做到这一点，它必须比其他连接更强地抑制某些KC->MBON连接：例如，通过抑制KC->避免连接而不是KC->；接近连接来抑制惩罚记忆。要做到这一点：(1)APL活性(以及它的抑制输出)必须被划分。这将允许单个神经元APL不同地抑制KC->接近和KC->回避连接，因为它们位于不同的空间‘区’。(2)APL在接近区和回避区必须有不同的活动。APL的活动是由KCs控制的，因此，如果KC-APL连接通过学习以与同一区域中的KC-MBON连接相同的方式进行修改，则会发生这种情况：例如，气味+惩罚选择性地削弱了‘接近’区域中的KC-APL连接。在这种情况下，由于APL在局部抑制KCs，在学习后，APL将在回避区比在接近区更强地抑制KCs(从而抑制MBON)。这将减轻气味+惩罚(回避大于接近)引起的MBON活动的失衡。因此，如果APL活动被区分开来，学习可以同时诱导支持记忆的突触修改(KC-和GT；MBON连接)和反对记忆的修改(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，起着与记忆相反的‘镜子’的作用，而不是被动的衰退。这种反记忆可能会阻止记忆的形成或表达，并将为分区活动提供第一个明确的认知功能。我们的初步数据已经证实了上面的一些预测。我们将使用脑成像来测试其余的部分：我们将提取一种当神经元活跃时会发光的工程蛋白质，将该蛋白质放入KCs、APL或MBON中，并在苍蝇闻到气味时对感兴趣神经元的整个体积进行成像。我们将在训练前和训练后，或在操纵神经回路小区域的活动时这样做，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.