Nature:两项研究揭示光遗传学颠覆性发现
生物通 · 2015/01/21
最近Nature杂志上同时发表了两项光遗传学研究,颠覆了人们对恐惧记忆的认识。研究显示,当恐惧记忆产生之后,检索恐惧记忆的大脑回路会随着时间推移发生改变。也就是说,回忆旧记忆的大脑通路与回忆新鲜恐惧记忆不同。


科学家们一直在尝试理解人类的记忆,光遗传学技术为他们提供了前所未有的便利工具,让他们能够特异性控制大脑回路的开和关。

最近Nature杂志上同时发表了两项光遗传学研究,颠覆了人们对恐惧记忆的认识。研究显示,当恐惧记忆产生之后,检索恐惧记忆的大脑回路会随着时间推移发生改变。也就是说,回忆旧记忆的大脑通路与回忆新鲜恐惧记忆不同。

波多黎各大学的Gregory Quirk和Fabricio Do-Monte用温和电击训练大鼠对一种声音产生恐惧。一段时间之后,大鼠的恐惧行为并没有变化,但大鼠回忆这一创伤事件的神经通路发生了改变。研究人员认为,这种改变可能是为了强化这段记忆。

研究显示,在条件性恐惧发生之后,立刻就会有一条从前额皮质(执行中枢)到杏仁核(恐惧中枢)的神经回路被激活。但几天之后,检索这段记忆的回路发生了改变:从前额皮质到丘脑的PVT(paraventricular)区域,然后从PVT到杏仁核的另一个部分。杏仁核的这个部分主要是协调恐惧的学习和表达。研究人员指出,PVT能将恐惧与其他适应性应答(比如压力应答)整合起来,对恐惧记忆进行强化。

患有焦虑症(比如创伤后应激障碍PTSD)的人,往往会经历长时间的高度恐惧,这类疾病可能与恐惧记忆的检索回路被破坏有关。

“尽管我们的记忆是持续性的,但支持它们的神经通路实际上慢慢发生了改变,”Quirk解释道。“这一发现将改变人们对PTSD的认识,PTSD患者通常在恐惧性事件发生几个月甚至几年之后才发病。”

冷泉港的Bo Li和Mario Penzo在小鼠中也发现了同样的神经通路转变,并对这一机制进行了深入分析。他们发现,PVT的神经元能对中央杏仁核区域储存恐惧记忆的神经元起作用,调控恐惧记忆的加工。

研究显示,PVT的这种活性来自于大脑的神经营养因子(BDNF)。BDNF被认为涉及了情绪障碍和焦虑症,举例来说,BDNF表达水平的改变与PTSD有关。

研究人员发现,PVT的BDNF作用于一个特殊的受体,激活储存记忆的杏仁核神经元。将BDNF注入小鼠的中央杏仁核区域,会使小鼠吓呆。这说明BDNF不仅促使恐惧记忆形成,还参与了恐惧反应的表达。

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  • A temporal shift in the circuits mediating retrieval of fear memory

    Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning1, 2, but little is known about how retrieval circuits change with time3, 4. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval5, 6, 7, sends dense projections to the PVT8. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

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  • The paraventricular thalamus controls a central amygdala fear circuit

    Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors1, 2, 3. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression4, 5. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory6. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression5, 6. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.

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