面對威脅性或有害的刺激時，產生恐懼表現、自我防衛行為及適時地消除恐懼，將有利於個體的生存。帕弗洛夫恐懼制約與恐懼消滅 (Pavlovian fear conditioning and extinction) 為科學研究中最為廣泛使用的行為模型，儘管近年來對於恐懼記憶的習得已有很大的進展，然而，對於個體是如何學習恐懼記憶的消滅，仍有許多待解之處。另一方面，近年來對於外側眼窩前額葉皮質 (lateral orbitofrontal cortex) 的研究指出其在連結型學習 (associative learning) 及情緒調控中扮演重要角色，外側眼窩前額葉皮質的正常活性，更與精神疾病的發生息息相關。在這一系列的實驗中，我們利用此恐懼制約與恐懼消滅行為模型，並結合藥理學的方式，來探討外側眼窩前額葉皮質的活性對於習得恐懼消滅的影響。動物在恐懼制約訓練後的隔天進行恐懼消滅的學習，並在此隔天，進行學習表現的測試，我們在恐懼消滅學習前透過雙側微注射 N-甲基-D-天門冬氨酸 (N-Methyl-D-aspartic acid, NMDA) 來達到活化動物的外側眼窩前額葉皮質的目的，透過此一實驗，我們發現在動物學習恐懼消滅前活化外側眼窩前額葉皮質，會使動物在即便沒有恐懼制約刺激的出現下，都展現出一開始低、並隨時間逐漸升高的恐懼反應，同時也會使動物在學習測試時展現顯著高於控制組的恐懼表現，顯示這樣的操弄將會使恐懼消滅的學習受損。接著，為了探討外側眼窩前額葉皮質產生前述作用的效力，我們透過單側活化的方式來予以檢視，我們在動物進行恐懼消滅學習前單側或雙側活化此腦區，結果顯示在只有右側外側眼窩前額葉皮質活化的情況下，動物的恐懼表現並不會如左側或雙側活化般受到影響，然而，即便右側活化的動物在恐懼記憶的提取上展現出和控制組相同的表現，在第三天學習測試時，先前有受到操弄的動物，都可以觀察出恐懼消滅學習受損的狀況。我們的實驗證實了外側眼窩前額葉皮質的活性確實在恐懼消滅的習得過程中扮演著重要的角色，提供了臨床研究對於精神疾病的共病性及暴露治療法重要的參考，另外，我們也意外的觀察到外側眼窩前額葉皮質可能存在著的功能側化現象，而這相當值得未來研究的關注。

Fear extinction is a pertinent ability for individuals to adapt to the ever-changing environment. In our study, we demonstrated that the active involvement of the lateral orbitofrontal cortex (lOFC) affected conditioned fear expression and impaired fear extinction. Animals were trained and tested for fear extinction with the Pavlovian fear conditioning and extinction paradigm. Immediately before fear extinction training, N-Methyl-D-aspartic acid (NMDA) was injected directly into the lOFC of the animals to engage the lOFC in the learning process. We found that this manipulation would lead to an initially low then gradually increased freezing behavior and impaired fear extinction acquisition in that the experimental groups could not perform as well as the control groups during extinction retrieval. We further explored the efficacy of this manipulation with unilateral lOFC activation. This led to a surprising reveal of a functional lateralization in that during extinction, the right lOFC activation did not affect fear expression, but the left and bilateral lOFC activation did. However, regardless of the side being activated earlier, all animals showed impaired extinction acquisition. This result is of great translational value, since the abnormal activity in the OFC has been reliably found in patients with anxiety disorder, especially the obsessive-compulsive disorder (OCD). In conclusion, our data suggested that the abnormal activation of the lOFC could act to disturb fear extinction acquisition.

Abramowitz JS, Taylor S, McKay D (2009). Obsessive-compulsive disorder. The Lancet 374(9688): 491-499.

Agustin-Pavon C, Braesicke K, Shiba Y, Santangelo AM, Mikheenko Y, Cockroft G, et al (2012). Lesions of ventrolateral prefrontal or anterior orbitofrontal cortex in primates heighten negative emotion. Biological psychiatry 72(4): 266-272.

Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K, et al (2012). Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior. Science 340(6137): 1234-1239.

Amano T, Duvarci S, Popa D, Pare D (2011). The fear circuit revisited: contributions of the basal amygdala nuclei to conditioned fear. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(43): 15481-15489.

Anglada-Figueroa D, Quirk GJ (2005). Lesions of the basal amygdala block expression of conditioned fear but not extinction. The Journal of neuroscience : the official journal of the Society for Neuroscience 25(42): 9680-9685.

Balooch SB, Neumann DL, Boschen MJ (2012). Extinction treatment in multiple contexts attenuates ABC renewal in humans. Behav Res Ther 50(10): 604-609.

Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL (2007). Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci 2(4): 303-312.

Bechara A, Damasio H, Damasio AR (2000). Emotion, Decision Making and the Orbitofrontal Cortex. Cerebral Cortex 10(3): 295–307.

Berlin HA, Rolls ET, Kischka U (2004). Impulsivity, time perception, emotion and reinforcement sensitivity in patients with orbitofrontal cortex lesions. Brain 127(Pt 5): 1108-1126.

Berretta S, Pantazopoulos H, Caldera M, Pantazopoulos P, Pare D (2005). Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala. Neuroscience 132(4): 943-953.

Beucke JC, Sepulcre J, Talukdar T, Linnman C, Zschenderlein K, Endrass T, et al (2013). Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder. JAMA Psychiatry 70(6): 619-629.

Bishop S, Duncan J, Brett M, Lawrence AD (2004). Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat Neurosci 7(2): 184-188.

Blair HT, Schafe GE, Bauer EP, Rodrigues SM, LeDoux JE (2001). Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn Mem 8(5): 229-242.

Bouton ME (2004). Context and Behavioral Processes in Extinction. Learn Mem 11: 485–494.

Burguière E, Monteiro P, Feng G, Graybiel AM (2013). Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors. Science 340(6137): 1243-1246.

Campbell EJ, Marchant NJ (2018). The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. Br J Pharmacol 175(7): 994-1003.

Carmichael ST, Price JL (1995a). Limbic Connections of the Orbital and Medial Prefrontal Cortex in Macaque Monkeys. J Comp Neurol 363: 615-641.

Carmichael ST, Price JL (1995b). Sensory and Premotor Connections of the Orbital and Medial Prefrontal Cortex of Macaque Monkeys. J Comp Neurol 363(4): 642-664.

Cassell MD, Freedman LJ, Shi C (1999). The intrinsic organization of the central extended amygdala. Annals of the New York Academy of Sciences 877: 217-241.

Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N, et al (2008). Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 321(5887): 421-422.

Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M (1993). Psychobiologic Mechanisms of Posttraumatic Stress Disorder. Arch Gen Psychiatry 50(4): 294-305.

Cheng W, Rolls ET, Qiu J, Xie X, Wei D, Huang C-C, et al (2018). Increased functional connectivity of the posterior cingulate cortex with the lateral orbitofrontal cortex in depression. Translational Psychiatry 8(1).

Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, et al (2010). Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468(7321): 277-282.

Clark L, Manes F, Antoun N, Sahakian BJ, Robbins TW (2003). The contributions of lesion laterality and lesion volume to decision-making impairment following frontal lobe damage. Neuropsychologia 41(11): 1474-1483.

Corcoran KA, Quirk GJ (2007). Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. The Journal of neuroscience : the official journal of the Society for Neuroscience 27(4): 840-844.

Cromer KR, Schmidt NB, Murphy DL (2007). An investigation of traumatic life events and obsessive-compulsive disorder. Behav Res Ther 45(7): 1683-1691.

Dalley JW, Cardinal RN, Robbins TW (2004). Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28(7): 771-784.

Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR (1994). The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science 264(5162): 1102-1105.

Debiec J, Bush DE, LeDoux JE (2011). Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats--a possible mechanism for the persistence of traumatic memories in PTSD. Depress Anxiety 28(3): 186-193.

Do-Monte FH, Manzano-Nieves G, Quinones-Laracuente K, Ramos-Medina L, Quirk GJ (2015). Revisiting the role of infralimbic cortex in fear extinction with optogenetics. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(8): 3607-3615.

Duvarci S, Pare D (2014). Amygdala microcircuits controlling learned fear. Neuron 82(5): 966-980.

Duvarci S, Popa D, Pare D (2011). Central amygdala activity during fear conditioning. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(1): 289-294.

Ehrlich I, Humeau Y, Grenier F, Ciocchi S, Herry C, Luthi A (2009). Amygdala inhibitory circuits and the control of fear memory. Neuron 62(6): 757-771.

Elliott R, Dolan RJ, Frith CD (2000). Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb Cortex 10(3): 308-317.

Fellows LK, Farah MJ (2005). Different underlying impairments in decision-making following ventromedial and dorsolateral frontal lobe damage in humans. Cereb Cortex 15(1): 58-63.

Fenno L, Yizhar O, Deisseroth K (2011). The development and application of optogenetics. Annu Rev Neurosci 34: 389-412.

Fenster RJ, Lebois LAM, Ressler KJ, Suh J (2018). Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nature reviews Neuroscience 19(9): 535-551.

Fettes P, Schulze L, Downar J (2017). Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness. Front Syst Neurosci 11: 25.

Floresco SB, Todd CL, Grace AA (2001). Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 21(13): 4915-4922.

Foa EB (2000). Psychosocial Treatment of Posttraumatic Stress Disorder. J Clin Psychiatry 61(suppl 5): 43-48.

Fontenelle LF, Cocchi L, Harrison BJ, Shavitt RG, do Rosario MC, Ferrao YA, et al (2012). Towards a post-traumatic subtype of obsessive-compulsive disorder. J Anxiety Disord 26(2): 377-383.

Forster GL, Simons RM, Baugh LA (2017). Revisiting the Role of the Amygdala in Posttraumatic Stress Disorder.

Fox KCR, Yih J, Raccah O, Pendekanti SL, Limbach LE, Maydan DD, et al (2018). Changes in subjective experience elicited by direct stimulation of the human orbitofrontal cortex. Neurology 91(16): e1519-e1527.

Gallagher M, McMahan RW, Schoenbaum G (1999). Orbitofrontal cortex and representation of incentive value in associative learning. The Journal of neuroscience : the official journal of the Society for Neuroscience 19(15): 6610-6614.

Gershuny BS, Baer L, Jenike MA (2002). Comorbid posttraumatic stress disorder impact on treatment outcome for obsessive-compulsive disorder. Am J Psychiatry 159(5): 852-854.

Ghashghaei HT, Barbas H (2002). Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience 115(4): 1261-1279.

Giustino TF, Maren S (2015). The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear. Frontiers in behavioral neuroscience 9: 298.

Golkar A, Lonsdorf TB, Olsson A, Lindstrom KM, Berrebi J, Fransson P, et al (2012). Distinct contributions of the dorsolateral prefrontal and orbitofrontal cortex during emotion regulation. PLoS One 7(11): e48107.

Goosens KA, Maren S (2001). Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learn Mem 8(3): 148-155.

Gourley SL, Taylor JR (2016). Going and stopping: Dichotomies in behavioral control by the prefrontal cortex. Nat Neurosci 19(6): 656-664.

Graham BM, Milad MR (2011). Translational Research in the Neuroscience of Fear Extinction: Implications for Anxiety Disorders. Am J Psychiatry 168(12): 1255-1265.

Gruner P, Pittenger C (2017). Cognitive inflexibility in Obsessive-Compulsive Disorder. Neuroscience 345: 243-255.

Herry C, Ciocchi S, Senn V, Demmou L, Muller C, Luthi A (2008). Switching on and off fear by distinct neuronal circuits. Nature 454(7204): 600-606.

Hooker CI, Knight RT (2006). The role of lateral orbitofrontal cortex in the inhibitory control of emotion. In: Zald D, Rauch S (eds). The Orbitofrontal Cortex. Oxford University Press.

Hornak J, Bramham J, Rolls ET, Morris RG, O'Doherty J, Bullock PR, et al (2003). Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 126(Pt 7): 1691-1712.

Izquierdo A (2017). Functional Heterogeneity within Rat Orbitofrontal Cortex in Reward Learning and Decision Making. The Journal of neuroscience : the official journal of the Society for Neuroscience 37(44): 10529-10540.

Izquierdo A, Brigman JL, Radke AK, Rudebeck PH, Holmes A (2017). The neural basis of reversal learning: An updated perspective. Neuroscience 345: 12-26.

Izquierdo A, Murray EA (2004). Combined unilateral lesions of the amygdala and orbital prefrontal cortex impair affective processing in rhesus monkeys. J Neurophysiol 91(5): 2023-2039.

Jackowski AP, de Araújo Filho GM, de Almeida AG, de Araújo CM, Reis M, Nery F, et al (2012). The involvement of the orbitofrontal cortex in psychiatric disorders: an update of neuroimaging findings. Revista Brasileira de Psiquiatria 34(2): 207-212.

Janak PH, Tye KM (2015). From circuits to behaviour in the amygdala. Nature 517(7534): 284-292.

Jin J, Maren S (2015). Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats. Sci Rep 5: 8388.

Jin J, Narayanan A, Perlman G, Luking K, DeLorenzo C, Hajcak G, et al (2017). Orbitofrontal cortex activity and connectivity predict future depression symptoms in adolescence. Biol Psychiatry Cogn Neurosci Neuroimaging 2(7): 610-618.

Johansen JP, Hamanaka H, Monfils MH, Behnia R, Deisseroth K, Blair HT, et al (2010). Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc Natl Acad Sci U S A 107(28): 12692-12697.

Jollant F, Lawrence NS, Olie E, O'Daly O, Malafosse A, Courtet P, et al (2010). Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior. NeuroImage 51(3): 1275-1281.

Kim CK, Adhikari A, Deisseroth K (2017). Integration of optogenetics with complementary methodologies in systems neuroscience. Nature reviews Neuroscience 18(4): 222-235.

Klavir O, Prigge M, Sarel A, Paz R, Yizhar O (2017). Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex. Nat Neurosci 20(6): 836-844.

Knapska E, Maren S (2009). Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learn Mem 16(8): 486-493.

Krabbe S, Grundemann J, Luthi A (2018). Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning. Biological psychiatry 83(10): 800-809.

Krettek JE, Price JL (1977). Projections from the amygdaloid complex to the cerebral cortex and thalamus in the rat and cat. J Comp Neurol 172(4): 687-722.

Kringelbach ML, Rolls ET (2004). The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol 72(5): 341-372.

Kuerbitz J, Arnett M, Ehrman S, Williams MT, Vorhees CV, Fisher SE, et al (2018). Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes. The Journal of neuroscience : the official journal of the Society for Neuroscience 38(5): 1160-1177.

LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA (1998). Human Amygdala Activation during Conditioned Fear Acquisition and Extinction: a Mixed-Trial fMRI Study. Neuron 20(5): 937-945.

LeDoux J (2007). The amygdala. Curr Biol 17(20): R868-874.

LeDoux JE (2000). Emotion circuits in the brain. Annu Rev Neurosci 23: 155-184.

LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM (1990). The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. Journal of Neuroscience 10(4): 1062-1069.

LeDoux JE, Iwata J, Cicchetti P, Reis DJ (1988). Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. The Journal of neuroscience : the official journal of the Society for Neuroscience 8(7): 2517-2529.

Legault M, Rompré PP, Wise RA (2000). Chemical Stimulation of the Ventral Hippocampus Elevates Nucleus Accumbens Dopamine by Activating Dopaminergic Neurons of the Ventral Tegmental Area. The Journal of neuroscience : the official journal of the Society for Neuroscience 20(4): 1635-1642.

Liberzon I, Sripada CS (2007). The functional neuroanatomy of PTSD: a critical review. 167: 151-169.

Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Pare D (2008). Amygdala intercalated neurons are required for expression of fear extinction. Nature 454(7204): 642-645.

Manes F, Sahakian B, Clark L, Rogers R, Antoun N, Aitken M, et al (2002). Decision-making processes following damage to
the prefrontal cortex. Brain 125(Pt3): 624-639.

Marek R, Jin J, Goode TD, Giustino TF, Wang Q, Acca GM, et al (2018a). Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat Neurosci 21(3): 384-392.

Marek R, Strobel C, Bredy TW, Sah P (2013). The amygdala and medial prefrontal cortex: partners in the fear circuit. J Physiol 591(10): 2381-2391.

Marek R, Xu L, Sullivan RKP, Sah P (2018b). Excitatory connections between the prelimbic and infralimbic medial prefrontal cortex show a role for the prelimbic cortex in fear extinction. Nature Neuroscience 21(5): 654-658.

Maren S (1999). Neurotoxic Basolateral Amygdala Lesions Impair Learning and Memory But Not the Performance of Conditional Fear in Rats. The Journal of neuroscience : the official journal of the Society for Neuroscience 19(19): 8696-8703.

Maren S, Phan KL, Liberzon I (2013). The contextual brain: implications for fear conditioning, extinction and psychopathology. Nature reviews Neuroscience 14(6): 417-428.

Maren S, Quirk GJ (2004). Neuronal signalling of fear memory. Nature reviews Neuroscience 5(11): 844-852.

McCracken CB, Grace AA (2007). High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbitofrontal cortex in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 27(46): 12601-12610.

McDonald AJ, Augustine JR (1993). Localization of GABA-like immunoreactivity in the monkey amygdala. Neuroscience 52(2): 281-294.

McDonald AJ, Mascagni F, Guo L (1996). Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71(1): 55-75.

Milad MR, Quinn BT, Pitman RK, Orr SP, Fischl B, Rauch SL (2005). Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc Natl Acad Sci U S A 102(30): 10706-10711.

Milad MR, Quirk GJ (2002). Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420(6911): 70-74.

Milad MR, Rauch SL (2007). The role of the orbitofrontal cortex in anxiety disorders. Annals of the New York Academy of Sciences 1121: 546-561.

Milad MR, Rauch SL (2012). Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 16(1): 43-51.

Monteiro P, Feng G (2016). Learning From Animal Models of Obsessive-Compulsive Disorder. Biological psychiatry 79(1): 7-16.

Morris JS, Dolan RJ (2004). Dissociable amygdala and orbitofrontal responses during reversal fear conditioning. NeuroImage 22(1): 372-380.

Muller J, Corodimas KP, Fridel Z, LeDoux JE (1997). Functional Inactivation of the Lateral and Basal Nuclei of theAmygdala by Muscimol Infusion Prevents Fear Conditioningto an Explicit Conditioned Stimulus and to Contextual Stimuli. Behavioral Neuroscience 111(4): 683-691.

Myers KM, Davis M (2007). Mechanisms of fear extinction. Mol Psychiatry 12(2): 120-150.

Nacasch N, Fostick L, Zohar J (2011). High prevalence of obsessive-compulsive disorder among posttraumatic stress disorder patients. Eur Neuropsychopharmacol 21(12): 876-879.

Nader K, Majidishad PA, P., LeDoux JE (2001). Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learn Mem 8(3): 156-163.

Neumann DL, Kitlertsirivatana E (2010). Exposure to a novel context after extinction causes a renewal of extinguished conditioned responses: implications for the treatment of fear. Behav Res Ther 48(6): 565-570.

Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, et al (2004). For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. NeuroImage 23(2): 483-499.

Öngür D, Price JL (2000). The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex 10(3): 206–219.

Orsini CA, Kim JH, Knapska E, Maren S (2011). Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(47): 17269-17277.

Orsini CA, Trotta RT, Bizon JL, Setlow B (2015). Dissociable roles for the basolateral amygdala and orbitofrontal cortex in decision-making under risk of punishment. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(4): 1368-1379.

Ostlund SB, Balleine BW (2007). Orbitofrontal cortex mediates outcome encoding in Pavlovian but not instrumental conditioning. The Journal of neuroscience : the official journal of the Society for Neuroscience 27(18): 4819-4825.

Padoa-Schioppa C, Assad JA (2006). Neurons in the orbitofrontal cortex encode economic value. Nature 441(7090): 223-226.

Padoa-Schioppa C, Conen KE (2017). Orbitofrontal Cortex: A Neural Circuit for Economic Decisions. Neuron 96(4): 736-754.

Paré D, Smith Y (1993). The intercalated cell masses project to the central and medial nuclei of the amygdala in cats. Neuroscience 57(4): 1077-1090.

Pauls DL, Abramovitch A, Rauch SL, Geller DA (2014). Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nature reviews Neuroscience 15(6): 410-424.

Paxinos G, Watson C (2007). The Rat Brain in Stereotaxic Coordinates, 6th edn. Elsevier Inc., xxxii-xxxvpp.

Phan KL, Fitzgerald DA, Nathan PJ, Moore GJ, Uhde TW, Tancer ME (2005). Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biological psychiatry 57(3): 210-219.

Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004). Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43(6): 897-905.

Pickens CL, Saddoris MP, Setlow B, Gallagher M, Holland PC, Schoenbaum G (2003). Different Roles for Orbitofrontal Cortex and Basolateral Amygdala in a Reinforcer Devaluation Task. The Journal of neuroscience : the official journal of the Society for Neuroscience 23(35): 11078-11084.

Posner J, Marsh R, Maia TV, Peterson BS, Gruber A, Simpson HB (2014). Reduced functional connectivity within the limbic cortico-striato-thalamo-cortical loop in unmedicated adults with obsessive-compulsive disorder. Hum Brain Mapp 35(6): 2852-2860.

Premkumar P, Fannon D, Sapara A, Peters ER, Anilkumar AP, Simmons A, et al (2015). Orbitofrontal cortex, emotional decision-making and response to cognitive behavioural therapy for psychosis. Psychiatry Res 231(3): 298-307.

Price JL (2007). Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. Annals of the New York Academy of Sciences 1121: 54-71.

Quirk GJ, Beer JS (2006). Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Current opinion in neurobiology 16(6): 723-727.

Quirk GJ, Mueller D (2008). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33(1): 56-72.

Quirk GJ, Russo GK, Barron JL, Lebron K (2000). The Role of Ventromedial Prefrontal Cortex in the Recovery of Extinguished Fear. The Journal of neuroscience : the official journal of the Society for Neuroscience 20(16): 6225-6231.

Rao VR, Sellers KK, Wallace DL, Lee MB, Bijanzadeh M, Sani OG, et al (2018). Direct Electrical Stimulation of Lateral Orbitofrontal Cortex Acutely Improves Mood in Individuals with Symptoms of Depression. Curr Biol 28(24): 3893-3902 e3894.

Rauch SL, Milad MR, Orr SP, Quinn BT, Fischl B, Pitman RK (2005). Orbitofrontal thickness, retention of fear extinction, and extraversion. Neuroreport 16(17): 1909-1912.

Rauch SL, Shin LM, Phelps EA (2006). Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biological psychiatry 60(4): 376-382.

Ray JP, Price JL (1992). The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain–prefrontal cortex topography. J Comp Neurol 323: 167–197.

Reep RLC, J. V.; King, V. (1996). Neuronal connections of orbital cortex in rats: topography of cortical and thalamic afferents. Exp Brain Res 111(2): 215–232.

Remijnse PL, Nielen MM, van Balkom AJ, Cath DC, van Oppen P, Uylings HB, et al (2006). Reduced Orbitofrontal-Striatal Activity on a Reversal Learning Task in Obsessive-Compulsive Disorder. Arch Gen Psychiatry 63(11): 1225-1236.

Rempel-Clower NL (2007). Role of orbitofrontal cortex connections in emotion. Annals of the New York Academy of Sciences 1121: 72-86.

Reppucci CJ, Petrovich GD (2015). Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats. Brain Struct Funct 221(6): 2937-2962.

Ressler KJ (2010). Amygdala activity, fear, and anxiety: modulation by stress. Biological psychiatry 67(12): 1117-1119.

Roberts NA, Beer JS, Werner KH, Scabini D, Levens SM, Knight RT, et al (2004). The impact of orbital prefrontal cortex damage on emotional activation to unanticipated and anticipated acoustic startle stimuli. 4(3): 307-316.

Rodriguez-Romaguera J, Do-Monte FH, Quirk GJ (2012). Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear. Proc Natl Acad Sci U S A 109(22): 8764-8769.

Rodriguez-Romaguera J, Do-Monte FH, Tanimura Y, Quirk GJ, Haber SN (2015). Enhancement of fear extinction with deep brain stimulation: evidence for medial orbitofrontal involvement. Neuropsychopharmacology 40(7): 1726-1733.

Rolls ET (2004). Convergence of sensory systems in the orbitofrontal cortex in primates and brain design for emotion. Anat Rec A Discov Mol Cell Evol Biol 281(1): 1212-1225.

Rolls ET, Hornak J, Wade D, McGrath J (1994). Emotion-related learning in patients with social and emotional changes associated with frontal lobe damage. J Neurol Neurosurg Psychiatry 57(12): 1518-1524.

Romanski LM, Clugnet MC, Bordi F, LeDoux JE (1993). Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav Neurosci 107(3): 444-450.

Rotge JY, Langbour N, Jaafari N, Guehl D, Bioulac B, Aouizerate B, et al (2010). Anatomical alterations and symptom-related functional activity in obsessive-compulsive disorder are correlated in the lateral orbitofrontal cortex. Biological psychiatry 67(7): e37-38.

Roth BL (2016). DREADDs for Neuroscientists. Neuron 89(4): 683-694.

Royer S, Martina M, Paré D (1999). An Inhibitory Interface Gates Impulse Traffic between the Input and Output Stations of the Amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience 19(23): 10575-10583.

Royer S, Paré D (2002). Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience 115(2): 455-462.

Rudebeck PH, Saunders RC, Prescott AT, Chau LS, Murray EA (2013). Prefrontal mechanisms of behavioral flexibility, emotion regulation and value updating. Nat Neurosci 16(8): 1140-1145.

Rule RR, Shimamura AP, Knight RT (2002). Orbitofrontal cortex and dynamic filtering of emotional stimuli. Cognitive, affective & behavioral neuroscience 2(3): 264-270.

Ruscio AM, Stein DJ, Chiu WT, Kessler RC (2010). The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 15(1): 53-63.

Sah P, Faber ESL, Lopez de Armentia M, Power J (2003). The Amygdaloid Complex: Anatomy and Physiology. Physiological Reviews 83(3): 803-834.

Sarlitto MC, Foilb AR, Christianson JP (2018). Inactivation of the Ventrolateral Orbitofrontal Cortex Impairs Flexible Use of Safety Signals. Neuroscience 379: 350-358.

Saxena S, Rauch SL (2000). Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am 23(3): 563-586.

Schneider B, Koenigs M (2017). Human lesion studies of ventromedial prefrontal cortex. Neuropsychologia 107: 84-93.

Schoenbaum G, Setlow B, Nugent SL, Saddoris MP, Gallagher M (2003). Lesions of orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-guided discriminations and reversals. Learn Mem 10(2): 129-140.

Schoenbaum G, Takahashi Y, Liu TL, McDannald MA (2011). Does the orbitofrontal cortex signal value? Annals of the New York Academy of Sciences 1239: 87-99.

Sengupta A, Winters B, Bagley EE, McNally GP (2016). Disrupted Prediction Error Links Excessive Amygdala Activation to Excessive Fear. The Journal of neuroscience : the official journal of the Society for Neuroscience 36(2): 385-395.

Shin LM, Liberzon I (2010). The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35(1): 169-191.

Sierra-Mercado D, Jr., Corcoran KA, Lebron-Milad K, Quirk GJ (2006). Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur J Neurosci 24(6): 1751-1758.

Sierra-Mercado D, Padilla-Coreano N, Quirk GJ (2010). Dissociable Roles of Prelimbic and Infralimbic Cortices, Ventral Hippocampus, and Basolateral Amygdala in the Expression and Extinction of Conditioned Fear. Neuropsychopharmacology 36(2): 529-538.

Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E, Quirk GJ (2012). Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76(4): 804-812.

Stalnaker TA, Cooch NK, Schoenbaum G (2015). What the orbitofrontal cortex does not do. Nat Neurosci 18(5): 620-627.

Stein DJ, Fineberg NA, Bienvenu OJ, Denys D, Lochner C, Nestadt G, et al (2010). Should OCD be classified as an anxiety disorder in DSM-V? Depress Anxiety 27(6): 495-506.

Stines LR, Feeny NC, Foa EB (2009). Emotional Disorders: Treatment. Encyclopedia of Neuroscience: 929-932.

Strobel C, Marek R, Gooch HM, Sullivan RK, Sah P (2015). Prefrontal and Auditory Input to Intercalated Neurons of the Amygdala. Cell Rep.

Sun N, Yi H, Cassell MD (1994). Evidence for a interface between cortical afferents and brainstem projection neurons in the rat central extended amygdala. J Comp Neurol 340(1): 43-64.

Szeszko PR, Narr KL, Phillips OR, McCormack J, Sevy S, Gunduz-Bruce H, et al (2012). Magnetic resonance imaging predictors of treatment response in first-episode schizophrenia. Schizophr Bull 38(3): 569-578.

Ting JT, Feng G (2011). Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. Current opinion in neurobiology 21(6): 842-848.

Tipps M, Marron Fernandez de Velasco E, Schaeffer A, Wickman K (2018). Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning. eNeuro 5(5).

Todd CL, Grace AA (1999). Modulation of ventral tegmental area dopamine cell activity by the ventral subiculum and entorhinal cortex. Annals of the New York Academy of Sciences 877(1): 688-690.

Tovote P, Fadok JP, Luthi A (2015). Neuronal circuits for fear and anxiety. Nature reviews Neuroscience 16(6): 317-331.

Tranel D, Bechara A, Denburg NL (2002). Asymmetric Functional Roles of Right and Left Ventromedial Prefrontal Cortices in Social Conduct, Decision-Making, and Emotional Processing. Cortex 38(4): 589-612.

van Minnen AH, M. (2002). Fear Activation and Habituation Patterns as Early Process Predictors of Response
to Prolonged Exposure Treatment in PTSD. J Trauma Stress 15(5): 359-367.

Veening JG, Swanson LW, Sawchenko PE (1984). The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: A combined retrograde transport-immunohistochemical study. Brain Res 303(2): 337-357.

Versace A, Thompson WK, Zhou D, Almeida JR, Hassel S, Klein CR, et al (2010). Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces: state versus trait vulnerability markers of depression in bipolar disorder. Biological psychiatry 67(5): 422-431.

Vertes RP (2004). Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51(1): 32-58.

Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ (2006). Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn Mem 13(6): 728-733.

Wallis JD (2011). Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat Neurosci 15(1): 13-19.

Whissell PD, Tohyama S, Martin LJ (2016). The Use of DREADDs to Deconstruct Behavior. Front Genet 7: 70.

Wilson RC, Takahashi YK, Schoenbaum G, Niv Y (2014). Orbitofrontal cortex as a cognitive map of task space. Neuron 81(2): 267-279.

Wolff SBE, Gründemann J, Tovote P, Krabbe S, Jacobson GA, Müller C, et al (2014). Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509(7501): 453-458.

Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K (2011). Optogenetics in neural systems. Neuron 71(1): 9-34.

Zeeb FD, Winstanley CA (2013). Functional disconnection of the orbitofrontal cortex and basolateral amygdala impairs acquisition of a rat gambling task and disrupts animals' ability to alter decision-making behavior after reinforcer devaluation. The Journal of neuroscience : the official journal of the Society for Neuroscience 33(15): 6434-6443.

Zelinski EL, Hong NS, Tyndall AV, Halsall B, McDonald RJ (2010). Prefrontal cortical contributions during discriminative fear conditioning, extinction, and spontaneous recovery in rats. Exp Brain Res 203(2): 285-297.

Zike I, Xu T, Hong N, Veenstra-VanderWeele J (2017). Rodent models of obsessive compulsive disorder: Evaluating validity to interpret emerging neurobiology. Neuroscience 345: 256-273.