Developmental Role of Endocannabinoid Neurotransmission in Reward Learning

内源性大麻素神经传递在奖励学习中的发展作用

• 批准号: RGPIN-2019-05121
• 负责人: Khokhar, Jibran
• 金额: $ 2.4万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746253
• 关键词: Developmental; Role; Endocannabinoid; Neurotransmission; Reward

The endocannabinoid system within the brain consists of retrograde messengers and their receptors; this system suppresses both excitatory and inhibitory transmission, thereby acting as a regulator of synaptic transmission and plasticity. Endocannabinoid signaling within the brain mediates a variety of behaviours ranging from social reward to reward and fear learning to decision-making. Research conducted in our laboratory will revolve around understanding the neurobiological sequelae of endocannabinoid modulation as it relates to reward learning in mammals, especially in the context of ontogenetic fluctuation in endocannabinoid signalling. Fundamental research into how developmental fluctuations in endocannabinoid signalling interact with exogenous modulation (e.g., due to genetic variation, stress etc.,) to impact behavior and learning is important to further our understanding of the basal role of these systems, and how they help to integrate environmental exposures. The long-term objective of this research program is to understand the long-lasting behavioural and brain circuit activity sequelae of both endogenous (e.g., genetic variation in receptor or enzyme function) and exogenous (e.g., stress, social rejection, cannabinoid exposure) endocannabinoid modulation during critical developmental periods, and the causal neural underpinnings of these consequences. For the upcoming 5-year period, my trainees and I will pharmacologically manipulate endocannabinoid signaling during adolescence, which is a critical period for endocannabinoid fluctuations, to study the behavioural and brain circuit changes arising from these manipulations. We hypothesize that manipulation of endocannabinoid signaling during adolescence will produce long-term changes in reward learning through altering corticolimbic circuitry. In objective 1, we will test the effects of selective pharmacological agonism or inverse agonism of either CB1Rs or CB2Rs during different phases of adolescence on instrumental and Pavlovian conditioning with food reward in adulthood. In objective 2, we will test the effects of pharmacological inhibition of the metabolizing enzymes FAAH and MAGL during adolescence on instrumental and Pavlovian conditioning in adulthood. In objective 3, in vivo electrophysiological recordings from brain reward circuitry will be performed in adulthood after adolescent endocannbinoid manipulation, and potential correlations with behavioural changes (in instrumental and Pavlovian learning) will be assessed. The research program proposed here is timely, innovative, and likely to increase our understanding of the fundamental role endocannabinoid signaling plays in our brain's response to genetic and environmental factors during development. In addition, this research will provide a vehicle for much needed training in behavioural neuropharmacology and electrophysiology to the highly qualified personnel, enriching Canada's workforce and improving scientific literacy.

大脑内的内源性大麻素系统由逆行信使及其受体组成；该系统同时抑制兴奋性和抑制性传递，从而调节突触传递和可塑性。大脑内的内源性大麻素信号介导了从社会奖励到奖励、恐惧学习到决策的各种行为。在我们实验室进行的研究将围绕了解内源性大麻素调节的神经生物学后遗症，因为它与哺乳动物的奖励学习有关，特别是在内源性大麻素信号的个体发生波动的背景下。内源性大麻素信号的发育波动如何与外源调节（例如，由于遗传变异，压力等）相互作用以影响行为和学习的基础研究对于进一步了解这些系统的基本作用以及它们如何帮助整合环境暴露非常重要。这项研究计划的长期目标是了解内源性（如受体或酶功能的遗传变异）和外源性（如压力、社会排斥、大麻素暴露）内源性大麻素调节在关键发育时期的长期行为和脑回路活动后遗症，以及这些后果的因果神经基础。在接下来的5年时间里，我和我的学员将在青春期这个内源性大麻素波动的关键时期对内源性大麻素信号进行药理学操作，研究这些操作引起的行为和脑回路的变化。我们假设，青春期内源性大麻素信号的操纵将通过改变皮质边缘电路产生长期的奖励学习变化。在目标1中，我们将测试青春期不同阶段CB1Rs或CB2Rs的选择性药理激动作用或逆激动作用对成年期食物奖励的工具性条件反射和巴甫洛夫条件反射的影响。在目标2中，我们将测试青春期代谢酶FAAH和MAGL的药理抑制对成年期工具条件反射和巴甫洛夫条件反射的影响。在目标3中，在青春期内源性大麻素操作后，将在成年期进行大脑奖励回路的体内电生理记录，并评估与行为改变（工具性和巴甫洛夫学习）的潜在相关性。这里提出的研究计划是及时的，创新的，并且可能增加我们对内源性大麻素信号在我们的大脑对发育过程中遗传和环境因素的反应中所起的基本作用的理解。此外，这项研究将为行为神经药理学和电生理学方面的高素质人才提供急需的培训工具，丰富加拿大的劳动力，提高科学素养。