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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2018/2/14 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）

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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
Neuron. 2004 Sep 30;44(1):75-91.

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.

2018/01/17 春野

Aversive Prediction Errorはどこにありどう学習に使われるのか?

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Dysregulation of aversive signaling pathways: a novel circuit endophenotype for pain and anxiety disorders.

Li-Feng Yeh, Mayumi Watanabe, Jessica Sulkes-Cuevas, Joshua P Johansen
Curr Opin Neurobiol. 2017 Sep 28;48:37-44.

abstract

Aversive experiences activate dedicated neural instructive pathways which trigger memory formation and change behavior. The strength of these aversive memories and the degree to which they alter behavior is proportional to the intensity of the aversive experience. Dysregulation of aversive learning circuits can lead to psychiatric pathology. Here we review recent findings elucidating aversive instructive signaling circuits for fear conditioning. We then examine how chronic pain as well as stress and anxiety disrupt these circuits and the implications this has for understanding and treating psychiatric disease. Together this review synthesizes current work on aversive instructive signaling circuits in health and disease and suggests a novel circuit based framework for understanding pain and anxiety syndromes.

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

Fabricio H. Do-Monte, Kelvin Quiñones-Laracuente & Gregory J. Quirk
Nature. 2015 Mar 26;519(7544):460-3.

abstract

Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. 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 retrieval, sends dense projections to the PVT. 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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Placing prediction into the fear circuit.

Gavan P. McNally, Gavan P. McNally, Joshua P. Johansen, Hugh T. Blair
Trends Neurosci. 2011 Jun;34(6):283-92.

Abstract

Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals.

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Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray.

Joshua P Johansen, Jason W Tarpley, Joseph E LeDoux & Hugh T Blair
Nat Neurosci. 2010 Aug;13(8):979-86. doi: 10.1038/nn.2594.

Abstract

A form of aversively motivated learning called fear conditioning occurs when a neutral conditioned stimulus is paired with an aversive unconditioned stimulus (UCS). UCS-evoked depolarization of amygdala neurons may instruct Hebbian plasticity that stores memories of the conditioned stimulus-unconditioned stimulus association, but the origin of UCS inputs to the amygdala is unknown. Theory and evidence suggest that instructive UCS inputs to the amygdala will be inhibited when the UCS is expected, but this has not been found during fear conditioning. We investigated neural pathways that relay information about the UCS to the amygdala by recording neurons in the amygdala and periaqueductal gray (PAG) of rats during fear conditioning. UCS-evoked responses in both amygdala and PAG were inhibited by expectation. Pharmacological inactivation of the PAG attenuated UCS-evoked responses in the amygdala and impaired acquisition of fear conditioning, indicating that PAG may be an important part of the pathway that relays instructive signals to the amygdala.

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A feedback neural circuit for calibrating aversive memory strength.

Takaaki Ozawa, Edgar A Ycu, Ashwani Kumar, Li-Feng Yeh, Touqeer Ahmed, Jenny Koivumaa & Joshua P Johansen
Nat Neurosci. 2017 Jan;20(1):90-97. doi: 10.1038/nn.4439.

Abstract

Aversive experiences powerfully regulate memory formation, and memory strength is proportional to the intensity of these experiences. Inhibition of the neural circuits that convey aversive signals when they are predicted by other sensory stimuli is hypothesized to set associative memory strength. However, the neural circuit mechanisms that produce this predictive inhibition to regulate memory formation are unknown. Here we show that predictive sensory cues recruit a descending feedback circuit from the central amygdala that activates a specific population of midbrain periaqueductal gray pain-modulatory neurons to control aversive memory strength. Optogenetic inhibition of this pathway disinhibited predicted aversive responses in lateral amygdala neurons, which store fear memories, resulting in the resetting of fear learning levels. These results reveal a control mechanism for calibrating learning signals to adaptively regulate the strength of behavioral learning. Dysregulation of this circuit could contribute to psychiatric disorders associated with heightened fear responsiveness.

恐怖記憶の強さを制御するフィードバック機構 : ライフサイエンス 新着論文レビュー
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Hypothalamic corticotropin-releasing factor is centrally involved in learning under moderate stress.

Morgan Lucas, Alon Chen & Gal Richter-Levin
Neuropsychopharmacology. 2013 Aug;38(9):1825-32. doi: 10.1038/npp.2013.82.

Abstract

The corticotropin-releasing factor (CRF) neuropeptide is found to have a pivotal role in the regulation of the behavioral and neuroendocrine responses to stressful challenges. Here, we studied the involvement of the hypothalamic CRF in learning under stressful conditions. We have used a site-specific viral approach to knockdown (KD) CRF expression in the paraventricular nucleus of the hypothalamus (PVN). The two-way shuttle avoidance (TWSA) task was chosen to assess learning and memory under stressful conditions. Control animals learned to shuttle from one side to the other to avoid electrical foot shock by responding to a tone. Novel object and social recognition tasks were used to assess memory under less stressful conditions. KD of PVN-CRF expression decreased the number of avoidance responses in a TWSA session under moderate (0.8 mA), but not strong (1.5 mA), stimulus intensity compared to control rats. On the other hand, KD of PVN-CRF had no effect on memory performance in the less stressful novel object or social recognition tasks. Interestingly, basal or stress-induced corticosterone levels in CRF KD rats were not significantly different from controls. Taken together, the data suggest that the observed impairment was not a result of alteration in HPA axis activity, but rather due to reduced PVN-CRF activity on other brain areas. We propose that hypothalamic CRF is centrally involved in learning under moderate stressful challenge. Under 'basal' (less stressful) conditions or when the intensity of the stress is more demanding, central CRF ceases to be the determinant factor, as was indicated by performances in the TWSA with higher stimulus intensity or in the less stressful tasks of object and social recognition.

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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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2017/12/13 榎本

Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala Activity at Discrete Time Points during Risky Decision Making
Orsini CA, Hernandez CM, Singhal S, Kelly KB, Frazier CJ, Bizon JL, Setlow B
J Neurosci. 2017 Nov 29;37(48):11537-11548. doi: 10.1523/JNEUROSCI.2344-17.2017. Epub 2017 Oct 27

ラットにSmall & Safe rawardかLarge & Risky rewardかを選ばせる課題を用い、扁桃体BLAを光刺激で抑制したときに、光刺激のタイミングによって真逆の効果が見られることを報告しています。

Abstract

Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (risky decision-making task) in which rats choose between a small, “safe” reward and a large reward accompanied by varying probabilities of footshock punishment. Male Long–Evans rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the risky decision-making task. Laser delivery during the task occurred during intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did laser delivery affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.

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参考に、ここ数年の扁桃体関連論文リストです。

2014/10/21 春野

Aversive prediction error signals in the amygdala
McHugh SB, Barkus C, Huber A, Capitão L, Lima J, Lowry JP, Bannerman DM.
J Neurosci. 2014 Jul 2;34(27):9024-33. doi: 10.1523/JNEUROSCI.4465-13.2014.

マウスのBLAから取ったhemodynamic responseがかなり高い精度で
aversive prediction errorを表しそうだというJNSの論文を紹介します。

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2014/06/10 山中

Amygdala interneuron subtypes control fear learning through disinhibition
Wolff SB, Gründemann J, Tovote P, Krabbe S, Jacobson GA, Müller C, Herry C, Ehrlich I, Friedrich RW, Letzkus JJ, Lüthi A.
Nature. 2014 May 22;509(7501):453-8. doi: 10.1038/nature13258. Epub 2014 May 11.

basolateral amygdala(BLA)のマイクロサーキットの機能についての論文を紹介します。
amygdalaの入力部であるBLAのシナプス可塑性が恐怖学習の神経基盤として重要であることは知られていますが、その中の抑制性介在細胞が投射細胞を介してそのような学習をコントロールする神経回路メカニズムをオプトジェネティクスとユニットレコーディングを組み合わせて明らかにしようとしている論文です。

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2014/06/10 春野

Separate amygdala subregions signal surprise and predictiveness during associative fear learning in humans
Boll S, Gamer M, Gluth S, Finsterbusch J, Büchel C.
Eur J Neurosci. 2013 Mar;37(5):758-67. doi: 10.1111/ejn.12094. Epub 2012 Dec 21.

Rescola-WagnerとPearce-Hallのハイブリッドモデルでヒトの恐怖条件付けのfMRデータを解析して扁桃体CMとBLAの差について議論する論文です。

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2014/02/21 田中

Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior
Felix-Ortiz AC1, Tye KM.
J Neurosci. 2014 Jan 8;34(2):586-95. doi: 10.1523/JNEUROSCI.4257-13.2014.

mouse のoptogeneticsを用い、
Amygdala(BLA)→ventral Hippocampusへの 入力(Glu) をコントロールする事でsocial behavior (他者への興味）が変化する事を示した論文です。

同じグループのNature2011,Neuron2013は同じ系を用いて、Anxietyの発現に
Amygdala(BLA)→ventral Hippocampus、
Amygdala(BLA)→CeA
が逆の効果をもたらす事をこれまでに示しています。

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2014/02/14 野々村

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.

Highlights
► Fear conditioning and extinction activate distinct populations of BA neurons
► Behavioral specificity of optogenetically identified IL- and PL-projecting neurons
► Balance of activity between IL- and PL-projecting BA cells regulates fear extinction
► Fear conditioning and extinction induce pathway-specific intrinsic plasticity

Andreas Luthiのラボから出た論文を紹介したいと思います．

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2013/12/13 渡邊

Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety
Ekaterina Likhtik, Joseph M Stujenske, Mihir A Topiwala, Alexander Z
Harris & Joshua A Gordon
Nature Neuroscience Published online 17 November 2013

BLA-mPFCのコネクションはFear extinctionに重要であることが知られており、また最近ではBLA-mPFCのLocal field potentialのTheta oscillationの同期の関与が注目されております。
この論文ではFear discrimination (あるCueまたは状況が危険か危険ではないか)という弁別にもこのBLA-mPFCのTheta oscilattionが関与していることを報告しています。
また、単にTheta bandの同期があるということのみではなく、OscillationがmPFCとBLAでどちらが優位か(先導しているか)という点で様々な解析を行っております。結果としましては、安全なCueが提示された場合には同期のリズムがmPFC⇒BLAとなり、つまりmPFC優位になります。一方で危険なCueに対してはBLAの神経発火が上昇し、Theta oscillation同期はBLAとmPFCどちらかが先行することはなくなります。
外界から喚起される情動がどのようにコントロールされ、また反対にコントロールから解放されて強い情動を喚起するのか、示唆を与えてくれる内容です。

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2013/05/10 木村

Distinct extended amygdala circuits for divergent motivational states.
Jennings JH, Sparta DR, Stamatakis AM, Ung RL, Pleil KE, Kash TL, Stuber GD.
Nature. 2013 Apr 11;496(7444):224-8.

Diverging neural pathways assemble a behavioural state from separable features in anxiety.
Kim SY, Adhikari A, Lee SY, Marshel JH, Kim CK, Mallory CS, Lo M, Pak S, Mattis J, Lim BK, Malenka RC, Warden MR, Neve R, Tye KM, Deisseroth K.
Nature. 2013 Apr 11;496(7444):219-23.

Bed nucleus of stria terminalis (BNST) 分界条床核は「偏桃体の伸びた部分」"Extended amygdala"とも呼ばれ、情動の統合と表出に関わる神経核です。最近注目されているところで、mouse optogeneticsを使って調べた研究がnatureに掲載されました。

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