Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss
Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss
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DOI：
10.1523/jneurosci.2714-16.2017
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发表时间：
2017-01-11
影响因子：
5.3
通讯作者：
De Jonghe, Bart C.
中科院分区：
文献类型：
--
作者：
Alhadeff, Amber L.;Holland, Ruby A.;De Jonghe, Bart C.
尽管顺铂化疗有严重的能量平衡副作用，但仍常用于治疗癌症。在大鼠中，顺铂激活孤束核 (NTS) 到臂旁核 (lPBN) 的投射，以及从 lPBN 到杏仁核中央核 (CeA) 的降钙素基因相关肽 (CGRP) 投射。我们之前证明了 CeA 谷氨酸受体信号传导介导顺铂诱导的厌食和体重减轻。在这里，我们使用神经解剖追踪、免疫荧光和共聚焦成像来证明，几乎所有 NTS -> lPBN 和 lPBN -> CeA CGRP 投射都共表达囊泡谷氨酸转运蛋白 2 (VGLUT2)，这提供了兴奋性投射介导顺铂诱导的能量平衡失调的证据。为了测试顺铂诱导的厌食和体重减轻是否需要 lPBN -> CeA 投射神经元，我们在顺铂治疗前使用表达逆行 Cre 重组酶的犬腺病毒 2 与 Cre 依赖性抑制性设计受体独家激活设计药物 (DREADD) 相结合，以化学遗传学方式抑制这些神经元。抑制 lPBN -> CeA 神经元可显着减弱顺铂引起的厌食和体重减轻。使用类似的方法，我们还证明了 NTS -> lPBN 神经元的抑制显着减轻了顺铂引起的厌食和体重减轻。总之，我们的数据支持这样的观点，即兴奋性后脑-前脑投射对于顺铂对能量摄入的不良影响是必要的，阐明了伴随化疗治疗导致病理性厌食和体重减轻的关键神经解剖回路。
Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS -> lPBN and lPBN -> CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN -> CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN -> CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS -> lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment.