중뇌변연계 경로

중뇌-변연계 경로(영어: mesolimbic pathway) 또는 보상 경로(영어: reward pathway)는 뇌의 도파민 경로 중 하나이다. 중뇌의 배쪽 피개부와 전뇌 기저핵의 배쪽 선조체를 연결한다. 배쪽 선조체에는 기댐핵과 후각결절 등이 포함된다. 중뇌-변연계 경로에서 기댐핵으로의 도파민 분비는 유인적 현저성(incentive salience, 보상 자극에 대한 동기와 욕구)을 조절하고 강화와 보상에 관련된 운동 기능 학습을 촉진한다. 또한 주관적인 쾌감의 인식에도 영향을 줄 가능성이 있다. 중뇌-변연계 경로 및 그에 연결된 기댐핵 신경세포의 조절곤란은 탐닉의 형성과 유지에 중요한 역할을 한다. 중뇌-변연계 경로는 배쪽 피개부(VTA)에서 뻗어나와 기댐핵(NAcc)과 후각결절을 포함하는 배쪽 선조체로 가는 도파민신경세포들의 모임이다. 뇌자극보상을 매개하는 신경 경로들의 모임인 안쪽앞뇌다발에 속한다. 중뇌에 위치한 배쪽 피개부는 도파민·GABA·글루탐산 신경세포들로 이루어져 있다. 이 부위의 도파민신경세포는 대뇌다리교뇌핵과 등가쪽 피개핵의 콜린성신경세포로부터 자극을 전달받고, 전전두엽 등 다른 부위의 글루탐산신경세포로부터도 자극을 받는다. 배쪽 선조체에 위치한 기댐핵과 후각결절은 주로 중간크기 가시뉴런(MSN)으로 이루어져 있다. 기댐핵은 각각 변연기능과 운동기능에 관련된 NAcc 껍질(NAcc shell)과 NAcc 핵심(NAcc core)의 두 부분으로 나뉜다. 기댐핵의 중간크기 가시뉴런은 배쪽 피개부의 도파민신경세포와 해마·편도체·안쪽전전두엽의 글루탐산신경세포로부터 자극을 전달받는다. 이러한 자극을 받고 활성화된 중간크기 가시뉴런은 배쪽 창백핵으로 GABA를 분비한다. 중뇌-변연계 경로는 유인적 현저성, 동기부여, 강화학습, 공포 등등 여러 인지 과정을 조절한다. 중뇌-변연계 경로는 동기 부여의 인지에 관여한다. 이 경로에 도파민이 고갈되거나 그 시작 부위에 병변이 생기면, 동물이 보상을 얻으려 행동하는 정도가 줄어든다. 예를 들어 쥐가 니코틴 정맥 주입을 받으려고 손잡이를 누르는 횟수나 먹이를 찾으러 돌아다니는 시간이 감소하는 것을 관찰할 수 있다. 도파민성 약물은 동물이 보상을 얻으려 행동하는 정도를 증가시킬 수 있다. 나아가, 보상을 기대하는 동안에는 중뇌-변연계 경로 신경세포의 발화율이 증가하는데, 이는 갈망(craving)의 기전에 대한 설명이 될 수 있다. 과거에 중뇌-변연계 경로의 도파민 분비는 쾌감의 주된 매개체로 생각되었으나, 현재는 쾌감의 지각에 있어 중뇌-변연계의 역할은 부차적일 뿐이라고 여겨진다. 중뇌-변연계 경로와 그 출력을 받는 특정 종류의 신경세포(예: 기댐핵의 D1-유형 중간크기 가시뉴런)은 탐닉의 신경생물학에서 핵심 역할을 한다. 약물 탐닉은 습관적 약물 사용에 따른 뇌 신경회로의 화학적 변화 때문에 생기는 병이다. 코카인, 알코올, 니코틴 등 흔히 접할 수 있는 중독성 물질은 중뇌-변연계 경로, 특히 기댐핵에서 세포외 도파민 농도를 높이는 것으로 드러났다. 그 기전은 약물의 유형에 따라 다르다. 예를 들어 코카인은 시냅스전 도파민 전달체를 차단하여 시냅스 도파민의 재흡수를 막는다. 또다른 자극제인 암페타민은 시냅스소포의 도파민 분비를 촉진한다. 자극제가 아닌 약물의 경우 리간드 개폐 통로나 G 단백질 연결 수용체와 결합하는 경우가 많은데, 알코올, 니코틴, 테트라하이드로카나비놀(THC) 등이 그 예이다. 이처럼 중뇌-변연계 경로가 활성화되어 도파민을 분비하면 보상을 인지하게 된다. 이렇게 형성된 자극과 보상의 연결은 소거에 저항성이 있으며, 보상을 준 행동을 똑같이 반복하려는 동기의 정도를 높인다. 2017년의 한 연구는 감정적·신체적·성적 학대와 부정적 생애사건은 코카인에 대한 변연계의 높은 반응 수준과 상관관계가 있다고 보고했다. 즉, 학대를 경험한 사람은 코카인 등 약물 사용에 빠지기 쉬운 뇌 신경회로를 가질 확률이 더 높다는 것이다. 중뇌-변연계 경로는 조현병, 우울증, 파킨슨병과 관련이 있다. 또 전자 매체 과용에도 관련돼 있다는 주장이 있다. 각각의 장애는 중뇌-변연계의 서로 다른 구조적 변화를 동반한다. 중뇌-피질 경로 흑색질-선조체 경로 결절-누두체 경로 항정신병제제 지연성 운동장애 내성 (약물) 금단 증상 Dreyer JL (2010). “New insights into the roles of microRNAs in drug addiction and neuroplasticity”. 《Genome Med》 2 (12): 92. doi:10.1186/gm213. PMC 3025434. PMID 21205279.  Ikemoto S (2010). “Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory”. 《Neurosci Biobehav Rev》 35 (2): 129–50. doi:10.1016/j.neubiorev.2010.02.001. PMC 2894302. PMID 20149820. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens  Figure 3: The ventral striatum and self-administration of amphetamine Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, 편집. 《Molecular Neuropharmacology: A Foundation for Clinical Neuroscience》 2판. New York: McGraw-Hill Medical. 147–148, 367, 376쪽. ISBN 978-0-07-148127-4. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience (“wanting”) on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards. ... The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner. ... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.  Malenka RC, Nestler EJ, Hyman SE (2009). 〈Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu〉. Sydor A, Brown RY. 《Molecular Neuropharmacology: A Foundation for Clinical Neuroscience》 2판. New York: McGraw-Hill Medical. 266쪽. ISBN 978-0-07-148127-4. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.  Berridge KC, Kringelbach ML (May 2015). “Pleasure systems in the brain”. 《Neuron》 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633. To summarize: the emerging realization that many diverse pleasures share overlapping brain substrates; better neuroimaging maps for encoding human pleasure in orbitofrontal cortex; identification of hotspots and separable brain mechanisms for generating ‘liking’ and ‘wanting’ for the same reward; identification of larger keyboard patterns of generators for desire and dread within NAc, with multiple modes of function; and the realization that dopamine and most ‘pleasure electrode’ candidates for brain hedonic generators probably did not cause much pleasure after all.  Robison AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic mechanisms of addiction”. 《Nat. Rev. Neurosci.》 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.  Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). “Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms”. 《Journal of Psychoactive Drugs》 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.  Olsen CM (December 2011). “Natural rewards, neuroplasticity, and non-drug addictions”. 《Neuropharmacology》 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.  Ikemoto S (2010). “Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory”. 《Neurosci Biobehav Rev》 35 (2): 129–50. doi:10.1016/j.neubiorev.2010.02.001. PMC 2894302. PMID 20149820. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens Figure 3: The ventral striatum and self-administration of amphetamine You ZB, Chen YQ, Wise RA (2001). “Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation”. 《Neuroscience》 107 (4): 629–39. doi:10.1016/s0306-4522(01)00379-7. PMID 11720786.  Pierce RC, Kumaresan V (2006). “The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?”. 《Neuroscience and Biobehavioral Reviews》 30 (2): 215–38. doi:10.1016/j.neubiorev.2005.04.016. PMID 16099045.  Zhang TA, Maldve RE, Morrisett RA (2006). “Coincident signaling in mesolimbic structures underlying alcohol reinforcement”. 《Biochemical Pharmacology》 72 (8): 919–27. doi:10.1016/j.bcp.2006.04.022. PMID 16764827.  Purves D et al. 2008. Neuroscience. Sinauer 4ed. 754-56 Malenka RC, Nestler EJ, Hyman SE (2009). 〈Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin〉. Sydor A, Brown RY. 《Molecular Neuropharmacology: A Foundation for Clinical Neuroscience》 2판. New York: McGraw-Hill Medical. 147–148, 154–157쪽. ISBN 9780071481274. Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control.  Engert, Veronika; Pruessner, Jens C (2017년 1월 9일). “Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate”. 《Current Neuropharmacology》 6 (4): 322–328. doi:10.2174/157015908787386069. ISSN 1570-159X. PMC 2701285. PMID 19587853.  Pezze, Marie A.; Feldon, Joram (2004년 12월 1일). “Mesolimbic dopaminergic pathways in fear conditioning”. 《Progress in Neurobiology》 74 (5): 301–320. doi:10.1016/j.pneurobio.2004.09.004. ISSN 0301-0082. PMID 15582224.  Salamone, John D.; Correa, Mercè (2012). “The Mysterious Motivational Functions of Mesolimbic Dopamine”. 《Neuron》 76 (3): 470–485. doi:10.1016/j.neuron.2012.10.021. PMC 4450094. PMID 23141060.  Berridge KC, Kringelbach ML (May 2015). “Pleasure systems in the brain”. 《Neuron》 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633. 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PMID 25817514.  Caminiti, Silvia Paola; Presotto, Luca; Baroncini, Damiano; Garibotto, Valentina; Moresco, Rosa Maria; Gianolli, Luigi; Volonté, Maria Antonietta; Antonini, Angelo; Perani, Daniela (2017년 1월 1일). “Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease”. 《NeuroImage: Clinical》 14: 734–740. doi:10.1016/j.nicl.2017.03.011. ISSN 2213-1582. PMC 5379906. PMID 28409113.  “Dopamine, Smartphones & You: A battle for your time”. 《Science in the News》. 2018년 5월 1일. 2019년 5월 10일에 확인함.  위키미디어 공용에 관련된 미디어 분류가 있습니다. 중뇌변연계 경로