Department of Psychiatry and Behavioral Sciences and Weill Institute of Neurosciences, University of California at San Francisco, San Francisco, California 94143.
Medical Scientist Training Program and Biomedical Sciences Graduate Program, University of California at San Francisco, San Francisco, California 94143.
J Neurosci. 2023 Dec 13;43(50):8621-8636. doi: 10.1523/JNEUROSCI.0357-23.2023.
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 α- and β-adrenergic receptors. We found that stimulation of β-adrenergic receptors increased primary branching of rodent astrocytes 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. This study demonstrates a role for noradrenergic signaling in the development of gray matter astrocytes. We provide new evidence that the β-adrenergic receptor is robustly expressed by both mouse and human astrocytes, and that conditional KO of the β-adrenergic receptor from female mouse astrocytes impairs gray matter astrocyte maturation. Moreover, female conditional KO mice exhibit behavioral deficits in two paradigms that test sensorimotor function. Given the emerging interest in moving beyond RNA sequencing to probe specific pathways that underlie astrocyte heterogeneity, this study provides a foundation for future investigation into the effect of noradrenergic signaling on astrocyte functions in conditions where noradrenergic signaling is altered, such as stress, arousal, and learning.
星形胶质细胞在发育中的神经系统中发挥着至关重要的作用，包括支持突触功能。这些星形胶质细胞的支持功能与大脑成熟同时出现，并且可能以特定区域的方式进行调整。例如，灰质星形胶质细胞具有精细的突触相关过程，在形态和分子上与白质星形胶质细胞不同。这就提出了一个问题，即是否存在独特的环境线索来促进灰质星形胶质细胞的身份和突触发生功能。我们之前发现，肾上腺素能受体在发育中的灰质星形胶质细胞中优先富集，而在白质星形胶质细胞中富集较少，这表明去甲肾上腺素信号可能是促进灰质星形胶质细胞功能成熟的一个线索。我们首先在小鼠和人类的出生后大脑发育过程中描述了去甲肾上腺素能投射，发现过程密度在灰质中较高，并与星形胶质细胞成熟同时增加。RNA 测序显示，两种物种的星形胶质细胞都表达α-和β-肾上腺素能受体。我们发现，刺激β-肾上腺素能受体增加了啮齿动物星形胶质细胞的初级分支。相反，星形胶质细胞条件性敲除β1-肾上腺素能受体减少了灰质星形胶质细胞的大小，并导致雌性小鼠感觉运动整合失调。这些研究表明，去甲肾上腺素能信号传递到发育中的星形胶质细胞会影响它们的形态，并对成年行为产生影响，特别是在雌性动物中。更广泛地说，它们展示了一种环境线索影响星形胶质细胞发育的机制。鉴于去甲肾上腺素在大脑状态（如觉醒、应激和学习）中的关键作用，这些发现可能会促使进一步研究发育应激源如何影响星形胶质细胞发育和成年大脑功能。本研究证明了去甲肾上腺素能信号在灰质星形胶质细胞发育中的作用。我们提供了新的证据表明，β-肾上腺素能受体在小鼠和人类星形胶质细胞中都强烈表达，并且从雌性小鼠星形胶质细胞中条件性敲除β-肾上腺素能受体会损害灰质星形胶质细胞的成熟。此外，雌性条件性 KO 小鼠在两个测试感觉运动功能的范式中表现出行为缺陷。鉴于人们对超越 RNA 测序以探索星形胶质细胞异质性背后的特定途径的兴趣日益浓厚，本研究为进一步研究去甲肾上腺素能信号在去甲肾上腺素能信号改变的情况下（如应激、觉醒和学习）对星形胶质细胞功能的影响提供了基础。
