Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, P. R. China.
Geriatric Hospital of Nanjing Medical University, Nanjing, 210009, P. R. China.
Mol Psychiatry. 2024 Feb;29(2):306-316. doi: 10.1038/s41380-023-02326-2. Epub 2023 Nov 24.
The hypothalamus plays a crucial role in controlling metabolism and energy balance, with Agouti-related protein (AgRP) neurons and proopiomelanocortin (POMC) neurons being essential components of this process. The proper development of these neurons is important for metabolic regulation in later life. Microglia, the resident immune cells in the brain, have been shown to significantly influence neurodevelopment. However, their role in shaping the postnatal development of hypothalamic neural circuits remains underexplored. In this study, we investigated the dynamic changes of microglia in the hypothalamic arcuate nucleus (ARC) during lactation and their impact on the maturation of AgRP and POMC neurons. We demonstrated that microglial depletion during a critical period of ARC neuron maturation increases the number of AgRP neurons and fiber density, with less effect on POMC neurons. This depletion also resulted in increased neonatal feeding behavior. Mechanistically, microglia can engulf perineuronal net (PNN) components surrounding AgRP neurons both in vivo and ex vivo. The absence of microglia leads to increased PNN formation and enhanced leptin sensitivity in ARC. Our findings suggest that microglia participate in the postnatal development of AgRP neurons by regulating the plasticity of PNN formation. This study contributes to a better understanding of microglia's role in shaping hypothalamic neural circuits during postnatal development and their impact on metabolism regulation.
下丘脑在控制代谢和能量平衡方面起着至关重要的作用,其中 Agouti 相关蛋白 (AgRP) 神经元和 proopiomelanocortin (POMC) 神经元是这一过程的重要组成部分。这些神经元的正常发育对于生命后期的代谢调节至关重要。小胶质细胞是大脑中常驻的免疫细胞,它们对神经发育有显著影响。然而,它们在塑造下丘脑神经回路的出生后发育中的作用仍未得到充分探索。在这项研究中,我们研究了哺乳期下丘脑弓状核 (ARC) 中小胶质细胞的动态变化及其对 AgRP 和 POMC 神经元成熟的影响。我们发现,在 ARC 神经元成熟的关键时期耗尽小胶质细胞会增加 AgRP 神经元的数量和纤维密度,但对 POMC 神经元的影响较小。这种耗竭还导致新生儿摄食行为增加。从机制上讲,小胶质细胞可以在体内和体外吞噬 AgRP 神经元周围的周围神经网 (PNN) 成分。小胶质细胞的缺失导致 ARC 中 PNN 形成增加和瘦素敏感性增强。我们的研究结果表明,小胶质细胞通过调节 PNN 形成的可塑性参与 AgRP 神经元的出生后发育。这项研究有助于更好地理解小胶质细胞在塑造出生后发育过程中下丘脑神经回路以及对代谢调节的影响中的作用。