β-adrenergic signaling promotes morphological maturation of astrocytes in female mice

Astrocytes play essential roles in the developing nervous system, including supporting synapse function. These astrocyte support functions emerge coincident with brain maturation and may be tailored in a region-specific manner. For example, gray matter astrocytes have elaborate synapse-associated processes and are morphologically and molecularly distinct from white-matter astrocytes. This raises the question of whether there are unique environmental cues that promote gray matter astrocyte identity and synaptogenic function. We previously identified adrenergic receptors as preferentially enriched in developing gray versus white matter astrocytes, suggesting that noradrenergic signaling could be a cue that promotes the functional maturation of gray matter astrocytes. We first characterized noradrenergic projections during postnatal brain development in mouse and human, finding that process density was higher in the gray matter and increased concurrently with astrocyte maturation. RNA-sequencing revealed that astrocytes in both species expressed ɑ and β adrenergic receptors. We found that stimulation of β adrenergic receptors increased primary branching of rodent astrocytes in vitro. Conversely, astrocyte-conditional knockout of the β1 adrenergic receptor reduced the size of gray matter astrocytes, and led to dysregulated sensorimotor integration in female mice. These studies suggest that adrenergic signaling to developing astrocytes impacts their morphology and has implications for adult behavior, particularly in female animals. More broadly, they demonstrate a mechanism through which environmental cues impact astrocyte development. Given the key roles of norepinephrine in brain states such as arousal, stress, and learning, these findings could prompt further inquiry into how developmental stressors impact astrocyte development and adult brain function. 8 samples total consisting of 4 biological replicates per group of flow sorted astrocytes from cortical or subcortical tissue at P29

星形胶质细胞(Astrocytes)在发育中的神经系统中发挥核心作用，包括支持突触功能。其支持功能与大脑成熟同步出现，并可呈现区域特异性的分化特征。例如，灰质星形胶质细胞拥有复杂的突触相关突起，在形态学与分子层面均与白质星形胶质细胞存在显著差异。这一现象引出了一个核心问题：是否存在独特的环境信号，能够促进灰质星形胶质细胞的身份维持及其突触发生功能？我们此前已鉴定出肾上腺素能受体(adrenergic receptors)在发育中的灰质星形胶质细胞中较白质星形胶质细胞呈现优先富集，这提示去甲肾上腺素能信号可能是促进灰质星形胶质细胞功能成熟的关键信号之一。本研究首先对小鼠与人类出生后脑发育阶段的去甲肾上腺素能投射进行了系统表征，发现灰质内的突起密度更高，且随星形胶质细胞成熟进程同步升高。RNA测序(RNA-sequencing)结果显示，两个物种的星形胶质细胞均表达α与β肾上腺素能受体。我们发现，体外刺激β肾上腺素能受体可显著增加啮齿类星形胶质细胞的初级突起分支数量。与之相反，星形胶质细胞条件性敲除β1肾上腺素能受体会缩小灰质星形胶质细胞的体积，并导致雌性小鼠出现感觉运动整合功能失调。上述研究表明，针对发育中星形胶质细胞的肾上腺素能信号会影响其形态发育，并对成年动物的行为产生潜在影响，尤其在雌性个体中更为显著。从更广的研究视角来看，本研究揭示了环境信号调控星形胶质细胞发育的具体机制。鉴于去甲肾上腺素在觉醒、应激与学习等脑状态调控中发挥核心作用，本研究成果或将推动后续关于发育性应激因素如何影响星形胶质细胞发育及成年脑功能的探索。本数据集共包含8个样本，均来源于出生后第29天（P29）的皮层或皮层下组织中经流式分选得到的星形胶质细胞，每组设置4个生物学重复。