PDF(Pubmed)
Abstract：
We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R.
摘要：
我们先前表明，食欲素神经元被缺氧激活，并促进外周化学反射（PCR）介导的低氧通气反应（HVR），主要是通过促进呼吸频率响应。Orexin神经元投射到孤束核（nTS）和下丘脑室旁核（PVN）。PVN对PCR有重要贡献，并含有nTS-促肾上腺皮质激素释放激素（CRH）神经元。我们假设在雄性大鼠中，食欲素神经元通过激活nTS投射的CRH神经元来促进PCR。我们使用神经元束追踪和免疫组织化学（IHC）来量化缺氧激活PVN投射食欲素神经元的程度。我们将其与食欲素受体（OxR）阻断与suvorexant（Suvo，20mg/kg,i.p.）评估食欲素促进PVN中CRH神经元缺氧诱导激活的程度，包括那些投射到nTS的。在不同的大鼠组中，我们测量了系统性食欲素1受体（Ox1R）阻断（SB-334867;1mg/kg）和PVN中特定Ox1R敲除后的PCR。用Suvo阻断OxR减少了缺氧激活的nTS和PVN神经元的数量，包括那些投射到nTS的CRH神经元。低氧增加了活化的PVN-投射食欲素神经元的数量，但对活化的nTS-投射食欲素神经元的数量没有影响。PVN中的全局Ox1R阻断和部分Ox1R敲除显著降低了PCR。Ox1R敲除还减少了nTS中活化的PVN神经元的数量和活化的酪氨酸-羟化酶神经元的数量。我们的发现表明，食欲素通过表达Ox1R的nTS投射CRH神经元促进PCR。重要性陈述先前我们表明食欲素有助于外周化学反射（PCR），但是这种效应的潜在机制仍然未知。在这里，我们表明：1）食欲素受体阻断减少了PVN和nTS的激活；2）缺氧激活了投射到PVN的食欲素神经元，但不是那些投射到nTS的；3）食欲素受体阻断减少了PVN中nTS-投射促肾上腺皮质激素释放激素（CRH）神经元的激活；4）食欲素1受体（Ox1R）阻断和PVN中特定的Ox1R敲低降低了PCR的强度，和5)Ox1R敲除减少nTS中活化的PVN神经元和酪氨酸羟化酶神经元的数量。这些发现表明，PVN-投射食欲素神经元通过Ox1R促进了nTS-投射CRH神经元上的PCR。
