Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Pozzuoli, NA, Italy.
Department of Experimental Medicine, Division of Pharmacology, University of Campania Luigi Vanvitelli, Napoli, Italy.
Nat Commun. 2021 Oct 21;12(1):6137. doi: 10.1038/s41467-021-26388-4.
The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity.
哺乳动物大脑通过海马齿状回中的模式分离计算机制来存储和区分情景记忆，即个人经历中形成的记忆。与食物相关的行为的决策，例如食物的选择和摄入，可能会因情景记忆检索的改变而受到肥胖受试者的影响。海马齿状回中的成年神经发生调节模式分离。几种分子因素影响成年神经发生，并在新生神经元的发育和可塑性中发挥关键作用。肥胖小鼠中存在食欲素-A/下丘脑泌素-1 和下游内源性大麻素 2-花生四烯酸甘油信号的改变。在这里，我们表明，过量的食欲素-A/2-花生四烯酸甘油/大麻素受体 1 信号导致成年海马神经发生功能障碍，随后抑制可塑性和模式分离受损。通过抑制食欲素-1 受体上的食欲素-A 作用，我们挽救了肥胖小鼠的可塑性和模式分离受损，从而提供了一个分子和功能机制来解释肥胖症中情景记忆的改变。
