Objective

Arcuate nucleus (ARC) neurons producing Agouti-related peptide (AgRP) and neuropeptide Y (NPY; ARC^AgRP/NPY neurons) are activated under energy-deficit states. ARC^AgRP/NPY neurons innervate the hypothalamic paraventricular nucleus (PVH), and ARC→PVH projections are recognized as key regulators of food intake. Plasma ghrelin levels increase under energy-deficit states and activate ARC^AgRP/NPY neurons by acting on the growth hormone secretagogue receptor (GHSR). Here, we hypothesized that activation of ARC^AgRP/NPY neurons in fasted mice would promote morphological remodeling of the ARC^AgRP/NPY→PVH projections in a GHSR-dependent manner.

Methods

We performed 1) fluorescent immunohistochemistry, 2) imaging of green fluorescent protein (GFP) signal in NPY-GFP mice, and 3) DiI axonal labeling in brains of ad libitum fed or fasted mice with pharmacological or genetic blockage of the GHSR signaling and then estimated the density and strength of ARC^AgRP/NPY→PVH fibers by assessing the mean fluorescence intensity, the absolute area with fluorescent signal, and the intensity of the fluorescent signal in the fluorescent area of the PVH.

Results

We found that 1) the density and strength of ARC^AgRP/NPY fibers increase in the PVH of fasted mice, 2) the morphological remodeling of the ARC^AgRP/NPY→PVH projections correlates with the activation of PVH neurons, and 3) PVH neurons are not activated in ARC-ablated mice. We also found that fasting-induced remodeling of ARC^AgRP/NPY→PVH fibers and PVH activation are impaired in mice with pharmacological or genetic blockage of GHSR signaling.

Conclusion

This evidence shows that the connectivity between hypothalamic circuits controlling food intake can be remodeled in the adult brain, depending on the energy balance conditions, and that GHSR activity is a key regulator of this phenomenon.

中文翻译：

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禁食以生长激素促分泌素受体依赖性方式诱导从弓形核到下丘脑室旁核的成因投射的重塑。

客观的

在能量缺乏状态下激活产生弓形相关肽（AgRP）和神经肽Y（NPY; ARC ^{AgRP / NPY}神经元）的弓形核（ARC）神经元。ARC ^{AgRP / NPY}神经元支配丘脑下丘脑室旁核（PVH），并且ARC→PVH投影被认为是食物摄入的关键调节剂。在能量缺乏状态下，血浆生长素释放肽水平升高，并通过作用于生长激素促分泌素受体（GHSR）来激活ARC ^{AgRP / NPY}神经元。在这里，我们假设禁食小鼠中的ARC ^{AgRP / NPY}神经元的激活将以GHSR依赖的方式促进ARC ^{AgRP / NPY} →PVH投影的形态重塑。

方法

我们进行了1）荧光免疫组化，2）NPY-GFP小鼠中绿色荧光蛋白（GFP）信号的成像，以及3）在GHSR信号传导的药理或遗传阻滞下，随意喂养或禁食小鼠的大脑中进行了DiI轴突标记，然后通过评估平均荧光强度，带有荧光信号的绝对面积以及PVH荧光区域中的荧光信号强度，估算了ARC ^{AgRP / NPY} →PVH纤维的密度和强度。

结果

我们发现1）禁食小鼠PVH中ARC ^{AgRP / NPY}纤维的密度和强度增加，2）ARC ^{AgRP / NPY} →PVH投影的形态重塑与PVH神经元的激活相关，3）PVH神经元在ARC消融小鼠中未激活。我们还发现，在具有GHSR信号的药理或遗传学阻断的小鼠中，空腹诱导的ARC ^{AgRP / NPY} →PVH纤维重塑和PVH激活受到损害。

结论

该证据表明，根据能量平衡条件，成年大脑中控制食物摄入的下丘脑回路之间的连通性可以重塑，而GHSR活性是这一现象的关键调节因素。