Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.
Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.
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作者：
Lawrenson C;Paci E;Pickford J;Drake RAR;Lumb BM;Apps R
中脑导水管周围灰质（PAG）在恐惧学习中的关键作用是通过识别雄性大鼠腹外侧PAG（vlPAG）中的神经元来加强的，所述神经元通过在检索期间呈现未加强的条件音（CS+）期间发出信号来编码恐惧记忆。有些单位只显示CS+起始或偏移响应，两种信号的消光灵敏度不同，表明它们是相互独立的。此外，通过以下发现推进了对小脑对生存回路的贡献的理解：（i）在恐惧巩固期间小脑内侧核（MCN）的可逆失活导致随后的检索（a）vlPAG偏移的时间精确性的破坏，但不是对CS+的起始响应，以及（B）冻结行为的持续时间的增加。和（ii）在恐惧获得过程中MCN-vlPAG投射的化学发生操纵（a）减少了恐惧相关的超声发声的发生，和（B）在随后的检索过程中，减缓了恐惧相关的冻结的消退速率。这些研究结果表明，小脑是生存网络的一部分，它以多种方式在多个时间尺度上调节恐惧记忆过程，从而提高了小脑生存网络中功能失调的相互作用可能是恐惧相关疾病和合并症的基础的可能性。焦虑症是一组心理健康状况，其特征是持续和过度的恐惧和担忧。它们影响着全世界数百万人，但治疗有时可能无效，并产生不必要的副作用。了解哪些大脑区域与恐惧和焦虑相关的行为有关，以及这些区域是如何连接的，是设计更有效治疗方法的第一步。一个被称为中脑导水管周围灰质（PAG）的区域位于大脑恐惧和焦虑网络的中心，调节疼痛，编码恐惧记忆并对威胁和压力源做出反应。它还控制生存行为，如动物受到惊吓时的“冻结”反应。位于大脑底部的小脑是最近加入恐惧和焦虑网络的。这个区域和PAG之间的双向联系已经得到了很好的描述，但是小脑如何影响恐惧和焦虑相关的行为仍然不清楚。为了探索这一作用，Lawrenson，Paci等人研究了小脑是否调节PAG内的大脑活动，如果是，这与恐惧行为有何关系。老鼠的大脑中植入了电极，以记录PAG内神经细胞的活动。然后，一个常见的恐惧条件反射任务被用来引发“冻结”反应：一个声音与轻微的足部电击配对，直到动物学会害怕听觉信号。在大鼠中，PAG内的一部分神经元对音调做出反应，这与编码恐惧记忆的细胞一致。但是，当一种药物在恐惧条件反射过程中阻断小脑的输出时，PAG反应的时间就不那么精确了，老鼠的冻结反应持续的时间也更长了。Lawrenson，Paci等人得出结论，小脑通过与大脑的恐惧和焦虑网络的相互作用，可能负责协调对恐惧的最适当的行为反应，以及“冻结”持续多久。总之，这些发现表明小脑是大脑生存网络的一部分，它调节恐惧记忆过程。它提出了一种可能性，即小脑的破坏可能是焦虑和其他恐惧相关疾病的基础，从而为未来的治疗提供了一个新的目标。
The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities. Anxiety disorders are a cluster of mental health conditions characterised by persistent and excessive amounts of fear and worry. They affect millions of people worldwide, but treatments can sometimes be ineffective and have unwanted side effects. Understanding which brain regions are involved in fear and anxiety-related behaviours, and how those areas are connected, is the first step towards designing more effective treatments. A region known as the periaqueductal grey (or PAG) sits at the centre of the brain’s fear and anxiety network, regulating pain, encoding fear memories and responding to threats and stressors. It also controls survival behaviours such as the ‘freeze’ response, when an animal is frightened. A more recent addition to the fear and anxiety network is the cerebellum, which sits at the base of the brain. Two-way connections between this region and the PAG have been well described, but how the cerebellum might influence fear and anxiety-related behaviours remains unclear. To explore this role, Lawrenson, Paci et al. investigated whether the cerebellum modulates brain activity within the PAG and if so, how this relates to fear behaviours. Rats had electrodes implanted in their brains to record the activity of nerve cells within the PAG. A common fear-conditioning task was then used to elicit ‘freeze’ responses: a sound was paired with mild foot shocks until the animals learned to fear the auditory signal. In the rats, a subset of neurons within the PAG responded to the tone, consistent with those cells encoding a fear memory. But when a drug blocked the cerebellum’s output during fear conditioning, the timing of the PAG response was less precise and the rats’ freeze response lasted longer. Lawrenson, Paci et al. concluded that the cerebellum, through its interactions with the brain’s fear and anxiety network, might be responsible for coordinating the most appropriate behavioural response to fear, and how long ‘freezing’ lasts. In summary, these findings show that the cerebellum is a part of the brain’s survival network which regulates fear-memory processes. It raises the possibility that disruption of the cerebellum might underlie anxiety and other fear-related disorders, thereby providing a new target for future therapies.
影响因子：
3.7
作者：
Fujita E;Tanabe Y;Imhof BA;Momoi MY;Momoi T
通讯作者：
Momoi T