Budygin Evgeny, Grinevich Valentina, Wang Zhong-Min, Messi María Laura, Meeker William Ryan, Zhang Jie, Stewart William Matthew, Milligan Carol, Delbono Osvaldo
Department of Internal Medicine, Sections on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Aging Cell. 2025 Jan;24(1):e14342. doi: 10.1111/acel.14342. Epub 2024 Sep 23.
The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior. The neurochemical foundations of these deficits were investigated through fast-scan cyclic voltammetry to measure NE release in the PFC and LC, both in vivo and in brain slices. Additionally, oxygen levels were monitored as a proxy for PFC neuronal function, and NE levels were analyzed in the extracellular space via microdialysis and total content in the PFC. Aged mice exhibited a frequency-dependent increase in NE release in the PFC upon LC stimulation, suggesting alterations in neural responsiveness due to aging. We also recorded slower NE reuptake rates and increased NE content and neuronal activity, indicated by higher oxygen levels and facilitated neuron activation due to membrane depolarization recorded via whole-cell patch-clamp. To understand the basis for LC-driven NE surges in the PFC with aging, we examined the expression levels of two proteins critical for presynaptic NE release and NE reuptake: the α2a-adrenergic receptor and the NE transporter. Both showed a significant decrease in the PFC with aging. These findings support the concept that aging significantly alters the structural and functional dynamics within the LC-PFC neural circuit, impacting NE modulation and neuronal activity, which may underlie the observed declines in cognitive and motor functions in aging populations.
蓝斑（LC）-前额叶皮质（PFC）神经回路对认知、计划、姿势和运动至关重要。本研究探讨去甲肾上腺素（NE）在阐明与年龄相关的认知和运动能力下降的神经生物学基础中的作用。老年小鼠表现出空间学习能力下降、记忆力受损、身体耐力下降以及运动行为的显著变化。通过快速扫描循环伏安法测量体内和脑片中PFC和LC中NE的释放，研究了这些缺陷的神经化学基础。此外，监测氧水平作为PFC神经元功能的指标，并通过微透析分析细胞外空间中的NE水平以及PFC中的总含量。老年小鼠在LC刺激后PFC中NE释放呈频率依赖性增加，表明衰老导致神经反应性改变。我们还记录到NE再摄取速率减慢，NE含量和神经元活动增加，这表现为较高的氧水平以及通过全细胞膜片钳记录的膜去极化促进神经元激活。为了理解衰老过程中LC驱动的PFC中NE激增的基础，我们研究了对突触前NE释放和NE再摄取至关重要的两种蛋白质的表达水平：α2a-肾上腺素能受体和NE转运体。两者在PFC中均随衰老而显著降低。这些发现支持了这样一种观点，即衰老显著改变了LC-PFC神经回路内的结构和功能动态，影响NE调节和神经元活动，这可能是老年人群中观察到的认知和运动功能下降的基础。
