2018/04/12 榎本

Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions

Justin M. Moscarello and Joseph E. LeDoux
J Neurosci. 2013 Feb 27;33(9):3815-23.

Abstract

Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.

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レビューがいくつか出ています。

Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour.
Joseph LeDoux & Nathaniel D. Daw
Nat Rev Neurosci. 2018 Mar 29. doi: 10.1038/nrn.2018.22.
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New perspectives on central amygdala function.
Jonathan P Fadok, Milica Markovic, Philip Tovote, Andreas Luthi
Curr Opin Neurobiol. 2018 Apr;49:141-147. doi: 10.1016/j.conb.2018.02.009.
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Basolateral amygdala circuitry in positive and negative valence.
Pia-Kelsey O’Neill, Felicity Gore, C Daniel Salzman
Curr Opin Neurobiol. 2018 Apr;49:175-183. doi: 10.1016/j.conb.2018.02.012.
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2018/03/23 春野

Gating of Fear in Prelimbic Cortex by Hippocampal and Amygdala Inputs

Francisco Sotres-Bayon, Demetrio Sierra-Mercado, Enmanuelle Pardilla-Delgado, Gregory J. Quirk
Neuron. 2012 Nov 21;76(4):804-12. doi: 10.1016/j.neuron.2012.09.028.

Highlights

• In behaving rats, BLA excites projection cells and vHPC excites interneurons in PL
• BLA promotes fear-signaling in PL, whereas vHPC inhibits it
• vHPC inhibits fear expression after, but not before, extinction
• vHPC gates fear expression via the PL after, but not before, extinction

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2018/03/09 榎本

Amygdala and Ventral Striatum Make Distinct Contributions to Reinforcement Learning

Vincent D. Costa, Olga Dal Monte, Daniel R. Lucas, Elisabeth A. Murray, Bruno B. Averbeck
Neuron. 2016 Oct 19;92(2):505-517. doi: 10.1016/j.neuron.2016.09.025.

Highlights

• The amygdala is necessary for deterministic and stochastic reinforcement learning
• The ventral striatum is only necessary for learning stochastic reward associations
• Amygdala and ventral striatum lesions decrease choice consistency
• Ventral striatum lesions hasten choice reaction times leading to more errors

これまでいろいろと見てきましたが、扁桃体を含んだ神経回路にどのような計算モデルが実装されているか、というのはまだ判然としませんし、そこに挑んでいる仕事もまだ多くありません。今回の論文は扁桃体と腹側線条体を損傷させたサルに確率的な行動選択課題を行わせ、強化学習モデルなどの計算モデルを当てはめることで、その問題にアプローチしています。

両側で扁桃体（イボテン酸使用）もしくは側坐核（キノリン酸使用）を損傷させ、一般的なTwo-arms bandit taskをやらせます。動物の行動は正と負のフィードバックそれぞれに別の学習率をおく強化学習モデルで（ベイズモデルやPearce-Hallモデルよりも）よりよく推定できました。扁桃体損傷動物ではタスク全体的に学習率が落ちますが、線条体損傷動物では確率的な課題条件でのみ学習率が下がっていました。また選択行動はどちらも雑になります（行動の一貫性……逆温度が低くなる）が、線条体損傷動物でのみ反応時間が短く（衝動的に）なりました。

今回の結果からでは神経回路についてはもちろん、BLAやCeA、NAc shellとNAc coreの違いなどについては何も分かりませんが、このような計算論的アプローチと最新の手法とを組み合わせることで、重要な問題解決につながるのでは、という示唆を得られました。

最近の報告

Reversal Learning and Dopamine: A Bayesian Perspective
Vincent D. Costa, Valery L. Tran, Janita Turchi and Bruno B. Averbeck
J Neurosci. 2015 Feb 11;35(6):2407-16. doi: 10.1523/JNEUROSCI.1989-14.2015.
同じタスクでドパミンをコントロールしてベイズ／強化学習で行動モデルに当てはめています。ベイズは今回ぜんぜんダメでしたけど……。


おまけです。
Long time-scales in primate amygdala neurons support aversive learning
Aryeh H. Taub, Tamar Stolero, Uri Livneh, Yosef Shohat, Rony Paz

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2018/02/23 春野

Shared neural coding for social hierarchy and reward value in primate amygdala

Jérôme Munuera, Mattia Rigotti & C. Daniel Salzman
Nat Neurosci. 2018 Mar;21(3):415-423. doi: 10.1038/s41593-018-0082-8.

Abstract

The social brain hypothesis posits that dedicated neural systems process social information. In support of this, neurophysiological data have shown that some brain regions are specialized for representing faces. It remains unknown, however, whether distinct anatomical substrates also represent more complex social variables, such as the hierarchical rank of individuals within a social group. Here we show that the primate amygdala encodes the hierarchical rank of individuals in the same neuronal ensembles that encode the rewards associated with nonsocial stimuli. By contrast, orbitofrontal and anterior cingulate cortices lack strong representations of hierarchical rank while still representing reward values. These results challenge the conventional view that dedicated neural systems process social information. Instead, information about hierarchical rank—which contributes to the assessment of the social value of individuals within a group—is linked in the amygdala to representations of rewards associated with nonsocial stimuli.

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2018/2/14 木村

Multiple systems for emotion-based action selection in the amygdala

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Htr2a-Expressing Cells in the Central Amygdala Control the Hierarchy between Innate and Learned Fear

Tomoko Isosaka, Tomohiko Matsuo, Takashi Yamaguchi, Kazuo Funabiki, Shigetada Nakanishi, Reiko Kobayakawa, Ko Kobayakawa
Cell. 2015 Nov 19;163(5):1153-1164. doi: 10.1016/j.cell.2015.10.047.

Highlights

• A hierarchical relationship exists between innate- and learned-fear responses 
• Innate but not learned-fear stimuli suppress the activity of CeA Htr2a+ cells 
• CeA Htr2a+ cell inhibition up/downregulates innate/learned freezing, respectively 
• CeA Htr2a+ cells act as a hierarchy generator prioritizing innate over learned fear

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A competitive inhibitory circuit for selection of active and passive fear responses

Jonathan P. Fadok, Sabine Krabbe, Milica Markovic, Julien Courtin, Chun Xu, Lema Massi, Paolo Botta, Kristine Bylund, Christian Müller, Aleksandar Kovacevic, Philip Tovote & Andreas Lüthi
Nature. 2017 Feb 2;542(7639):96-100. doi: 10.1038/nature21047.

Abstract

When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses. Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents. However, rodents also exhibit active responses such as flight under natural conditions. The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established. Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF+) mediate conditioned flight, and activation of somatostatin-positive (SOM+) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF+ and SOM+ neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.

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2018/2/14 榎本

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment

Burgos-Robles A, Kimchi EY, IzadmehrEM, PorzenheimMJ, Ramos-GuaspWA, NiehEH, Felix-Ortiz AC, NamburiP, LepplaCA, PresbreyKN, AnandalingamKK, Pagan-Rivera PA, AnahtarM, BeyelerA, TyeKM.
Nat Neurosci. 2017 Jun;20(6):824-835. doi: 10.1038/nn.4553.

報酬＋嫌悪条件下において扁桃体BLAと内側前頭前野PL（前辺縁皮質）領域との相互神経連絡がもつ行動情報。砂糖水も貰えるけれどもフットショックもくるアンビバレントな課題。ラットで電気生理実験と相互相関解析、オプトジェネティクスやDREADDなんかも用いて、BLA→PL投射がショックを予告する刺激に対してフリージングを引き起こすに必要十分であることを示しています。機械学習で（いちおう）行動予測もできる。

PLはIL（下辺縁皮質）とも相互連絡があり、どちらも腹側海馬から入力を受けて扁桃体や側坐核に投射しています。かねてより恐怖学習・消去、薬物依存などのパラダイムで役割の違いなどについて調べられており、ここ数年でその神経回路メカニズムが明らかになりつつあります。PL・ILはヒトやサルにおける帯状皮質の一部ですので、そのへんの対応関係にも注意してまとめてみたいと思います。つづく。

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参考文献

Prefrontal control of fear: more than just extinction.
Sotres-Bayon F, Quirk GJ.
Curr Opin Neurobiol. 2010 Apr;20(2):231-5. doi: 10.1016/j.conb.2010.02.005.

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Long-range connectivity defines behavioral specificity of amygdala neurons.
Senn V, Wolff SB, Herry C, Grenier F, Ehrlich I, Gründemann J, Fadok JP, Müller C, Letzkus JJ, Lüthi A.
Neuron. 2014 Jan 22;81(2):428-37. doi: 10.1016/j.neuron.2013.11.006.

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Functional Connectivity between Amygdala and Cingulate Cortex for Adaptive Aversive Learning

Oded Klavir, Rotem Genud-Gabai, Rony Paz
Neuron. 2013 Dec 4;80(5):1290-300. doi: 10.1016/j.neuron.2013.09.035.

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Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells.
Lu J, Tucciarone J, Padilla-Coreano N, He M, Gordon JA, Huang ZJ.
Nat Neurosci. 2017 Oct;20(10):1377-1383. doi: 10.1038/nn.4624.

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Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex.
Murugan M, Jang HJ, Park M, Miller EM, Cox J, Taliaferro JP, Parker NF, Bhave V, Hur H, Liang Y, Nectow AR, Pillow JW, Witten IB.
Cell. 2017 Dec 14;171(7):1663-1677.e16. doi: 10.1016/j.cell.2017.11.002.

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2018/1/31 木村

扁桃体の行動学習と記憶：神経回路と情報（１）

SLIDE

Amygdala microcircuits controlling learned fear.

Sevil Duvarci, Denis Pare

Neuron. 2014 Jun 4;82(5):966-80. doi: 10.1016/j.neuron.2014.04.042.

Molecular Mechanisms of Fear Learning and Memory

Joshua P. Johansen, Christopher K. Cain, Linnaea E. Ostroff, Joseph E. LeDoux
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Hebbian and neuromodulatory mechanisms interact to trigger associative memory formation

Joshua P. Johansen, Lorenzo Diaz-Mataix, Hiroki Hamanaka, Takaaki Ozawa, Edgar Ycu, Jenny Koivumaa, Ashwani Kumar, Mian Hou, Karl Deisseroth, Edward S. Boyden and Joseph E. LeDoux
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5584-92. doi: 10.1073/pnas.1421304111.

Modular organization of the brainstem noradrenaline system coordinates opposing learning states

Akira Uematsu, Bao Zhen Tan, Edgar A Ycu, Jessica Sulkes Cuevas, Jenny Koivumaa, Felix Junyent, Eric J Kremer, Ilana B Witten, Karl Deisseroth & Joshua P Johansen
Nat Neurosci. 2017 Nov;20(11):1602-1611. doi: 10.1038/nn.4642.

Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits

Li Jiang, Srikanya Kundu, James D. Lederman, Gretchen Y. López-Hernández, Elizabeth C. Ballinger, Shaohua Wang, David A. Talmage, Lorna W. Role

Neuron. 2016 Jun 1;90(5):1057-70. doi: 10.1016/j.neuron.2016.04.028.