2017/12/27 榎本

Bo Liらの仕事を中心に、いま現在の扁桃体……特に中心核（CeA）をとりまく嫌悪学習／可塑性に関わる神経回路の理解と、そこに至るまでの歴史をご紹介いたします。役者もいろいろ、論文も沢山ありますが、大事なところを見極めていきましょう。

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The amygdala.

Joseph LeDoux
Curr Biol. 2007 Oct 23;17(20):R868-74.

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Encoding of fear learning and memory in distributed neuronal circuits.

Cyril Herry & Joshua P Johansen
Nat Neurosci. 2014 Dec;17(12):1644-54.

Abstract

How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.

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Experience-dependent modification of a central amygdala fear circuit.

Haohong Li, Mario A Penzo, Hiroki Taniguchi, Charles D Kopec, Z Josh Huang & Bo Li
Nat Neurosci. 2013 Mar;16(3):332-9. doi: 10.1038/nn.3322. Epub 2013 Jan 27.

Abstract

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, the mechanism by which CeA contributes to the learning and expression of fear is unclear. We found that fear conditioning in mice induced robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of the CeA (CeL). This experience-dependent plasticity was cell specific, bidirectional and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impaired fear memory formation. Furthermore, activation of these neurons was necessary for fear memory recall and was sufficient to drive fear responses. Our findings support a model in which fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output, thereby disinhibiting the medial subdivision of CeA and releasing fear expression.

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Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala.

Mario A. Penzo, Vincent Robert and Bo Li
J Neurosci. 2014 Feb 12;34(7):2432-7. doi: 10.1523/JNEUROSCI.4166-13.2014.

Abstract

Recent studies indicate that the lateral subdivision of the central amygdala (CeL) is essential for fear learning. Specifically, fear conditioning induces cell-type-specific synaptic plasticity in CeL neurons that is required for the storage of fear memories. The CeL also controls fear expression by gating the activity of the medial subdivision of the central amygdala (CeM), the canonical amygdala output to areas that mediate defensive responses. In addition to the connection with CeM, the CeL sends long-range projections to innervate extra-amygdala areas. However, the long-range projection CeL neurons have not been well characterized, and their role in fear regulation is unknown. Here we show in mice that a subset of CeL neurons directly project to the midbrain periaqueductal gray (PAG) and the paraventricular nucleus of the thalamus, two brain areas implicated in defensive behavior. These long-range projection CeL neurons are predominantly somatostatin-positive (SOM(+)) neurons, which can directly inhibit PAG neurons, and some of which innervate both the PAG and paraventricular nucleus of the thalamus. Notably, fear conditioning potentiates excitatory synaptic transmission onto these long-range projection CeL neurons. Thus, our study identifies a subpopulation of SOM(+) CeL neurons that may contribute to fear learning and regulate fear expression independent of CeM.

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The paraventricular thalamus controls a central amygdala fear circuit.

Penzo MA, Robert V, Tucciarone J, De Bundel D, Wang M, Van Aelst L, Darvas M, Parada LF, Palmiter RD, He M, Huang ZJ, Li B.
Nature. 2015 Mar 26;519(7544):455-9. doi: 10.1038/nature13978. Epub 2015 Jan 19.

Abstract

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 stressors. 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 expression. 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 memory. 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 expression. 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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Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors.

Kai Yu, Pedro Garcia da Silva, Dinu F. Albeanu and Bo Li
J Neurosci. 2016 Jun 15;36(24):6488-96. doi: 10.1523/JNEUROSCI.4419-15.2016.

Abstract

The central amygdala (CeA) has a key role in learning and expression of defensive responses. Recent studies indicate that somatostatin-expressing (SOM(+)) neurons in the lateral division of the CeA (CeL) are essential for the acquisition and recall of conditioned freezing behavior, which has been used as an index of defensive response in laboratory animals during Pavlovian fear conditioning. However, how exactly these neurons participate in fear conditioning and whether they contribute to the generation of defensive responses other than freezing remain unknown. Here, using fiber-optic photometry combined with optogenetic and molecular techniques in behaving mice, we show that SOM(+) CeL neurons are activated by threat-predicting sensory cues after fear conditioning and that activation of these neurons suppresses ongoing actions and converts an active defensive behavior to a passive response. Furthermore, inhibition of these neurons using optogenetic or molecular methods promotes active defensive behaviors. Our results provide the first in vivo evidence that SOM(+) neurons represent a CeL population that acquires learning-dependent sensory responsiveness during fear conditioning and furthermore reveal an important role of these neurons in gating passive versus active defensive behaviors in animals confronted with threat.

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The central amygdala controls learning in the lateral amygdala.

Kai Yu, Sandra Ahrens, Xian Zhang, Hillary Schiff, Charu Ramakrishnan, Lief Fenno, Karl Deisseroth, Fei Zhao, Min-Hua Luo, Ling Gong, Miao He, Pengcheng Zhou, Liam Paninski & Bo Li

Nat Neurosci. 2017 Dec;20(12):1680-1685.

Abstract

Experience-driven synaptic plasticity in the lateral amygdala is thought to underlie the formation of associations between sensory stimuli and an ensuing threat. However, how the central amygdala participates in such a learning process remains unclear. Here we show that PKC-δ-expressing central amygdala neurons are essential for the synaptic plasticity underlying learning in the lateral amygdala, as they convey information about the unconditioned stimulus to lateral amygdala neurons during fear conditioning.

PDF | Supplementary information


阻害薬なんかの薬物注入やLesion実験から最新のオプトジェネティクス、カルシウムイメージングにいたるまで手法も進化していますし、実験系も単純なFoot shockでフリージングを見るだけのものから、頭部固定して報酬へのApproachingなども測定するようになっています。古典的な嫌悪反応だけではなく、報酬系についても知りたいのでしょうね。てことで扁桃体や室傍核などだけでなく、ここに線条体やドパミン系などがどのように関わって学習が起こっているのか興味深いところ。

ともあれ、これでやっと現在に追いついた！　と思ったら年が変わって、もう新しいのが出てますね……おそろしい……。

An insula-central amygdala circuit for guiding tastant-reinforced choice behavior

Hillary Schiff, Anna Lien Bouhuis, Kai Yu, Mario A. Penzo, Haohong Li, Miao He and Bo Li
Journal of Neuroscience 5 January 2018, 1773-17; DOI: https://doi.org/10.1523/JNEUROSCI.1773-17.2017

Abstract

Predicting which substances are suitable for consumption during foraging is critical for animals to survive. Despite extensive study, the neural circuit mechanisms underlying such adaptive behavior remain poorly understood. Here we examined the anatomical and functional connectivity of the insular cortex (IC) to central amygdala (CeA) circuit and the role of this circuit in the establishment of appropriate behavioral responses in a tastant (sucrose/quinine)-reinforced “go/no-go” task in male and female mice. Using anatomic tracing approaches combined with optogenetics-assisted circuit mapping, we found that the gustatory region of the IC sends direct excitatory projections to the lateral division of the CeA (CeL), making monosynaptic excitatory connections with distinct populations of CeL neurons. Specific inhibition of neurotransmitter release from the CeL-projecting IC neurons prevented mice from acquiring the “no-go” response, and also impaired the “go” responses in the go/no-go task. Furthermore, selective activation of the IC-CeL pathway with optogenetics drove unconditioned lick suppression in thirsty animals, induced aversive responses, and was sufficient to instruct conditioned action suppression in response to a cue predicting the optogenetic activation. These results indicate that activities in the IC-CeL circuit are critical for establishing taste-reinforced behavioral responses, including avoidance responses to an aversive tastant, and are sufficient to drive learning of anticipatory avoidance. Our findings suggest that the IC-CeL circuit plays an important role in guiding appropriate choices during foraging.

今年もやっていきましょう。