Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo 05508-000, Brazil.
Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo 05508-000, Brazil.
J Neurosci. 2023 Oct 4;43(40):6816-6829. doi: 10.1523/JNEUROSCI.0254-23.2023. Epub 2023 Aug 25.
Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of posttraumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence the development of neuropsychiatric diseases. Here, we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SST mice) caused no alterations in energy or glucose metabolism. Notably, SST male mice exhibited increased anxiety-like behavior in the light-dark box and elevated plus maze tests, whereas SST females showed no changes in anxiety. Using auditory Pavlovian fear conditioning, both male and female SST mice exhibited a significant reduction in fear memory. Conversely, GHR ablation in SST neurons did not affect memory in the novel object recognition test. Gene expression was analyzed in a micro punch comprising the central nucleus of the amygdala (CEA) and basolateral (BLA) complex. GHR ablation in SST neurons caused sex-dependent changes in the expression of factors involved in synaptic plasticity and function. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not female mice. GHR ablation in SST neurons also decreases fear memory and affects gene expression in the amygdala, although marked sex differences were observed. Our findings identified for the first time a neurochemically-defined neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases. Hormone action in the brain regulates different neurological aspects, affecting the predisposition to neuropsychiatric disorders, like depression, anxiety, and posttraumatic stress disorder. Growth hormone (GH) receptor is widely expressed in the brain, but the exact function of neuronal GH action is not fully understood. Here, we showed that mice lacking the GH receptor in a group of neurons that express the neuropeptide somatostatin exhibit increased anxiety. However, this effect is only observed in male mice. In contrast, the absence of the GH receptor in somatostatin-expressing neurons decreases fear memory, a key feature of posttraumatic stress disorder, in males and females. Thus, our study identified a specific group of neurons in which GH acts to affect the predisposition to neuropsychiatric diseases.
生长激素 (GH) 分泌功能障碍会增加焦虑症和其他神经精神疾病的患病率。GH 受体 (GHR) 在杏仁核中的信号传递与恐惧记忆有关，而恐惧记忆是创伤后应激障碍的一个关键特征。然而，目前尚不清楚 GH 作用靶向的神经元群体是哪些，以影响神经精神疾病的发展。在这里，我们发现，在扩展杏仁核中约 60%的生长抑素 (SST) 表达神经元对 GH 有直接反应。SST 表达细胞中的 GHR 缺失 (SST 小鼠) 不会导致能量或葡萄糖代谢发生改变。值得注意的是，雄性 SST 小鼠在明暗箱和高架十字迷宫测试中表现出焦虑样行为增加，而雌性 SST 小鼠则没有表现出焦虑变化。使用听觉巴甫洛夫恐惧条件反射，雄性和雌性 SST 小鼠的恐惧记忆均显著减少。相反，SST 神经元中的 GHR 缺失不影响新颖物体识别测试中的记忆。在包括杏仁核中央核 (CEA) 和基底外侧核复合体 (BLA) 的微穿孔中分析了基因表达。SST 神经元中的 GHR 缺失引起了与突触可塑性和功能相关的因子表达的性别依赖性变化。总之，SST 神经元中的 GHR 表达对于调节雄性而非雌性小鼠的焦虑是必要的。SST 神经元中的 GHR 缺失也会降低恐惧记忆并影响杏仁核中的基因表达，但观察到明显的性别差异。我们的研究首次确定了一个神经化学定义的神经元群体，该群体负责调节 GH 对与神经精神疾病相关的行为方面的影响。激素在大脑中的作用调节了不同的神经学方面，影响了神经精神疾病的易感性，如抑郁症、焦虑症和创伤后应激障碍。生长激素 (GH) 受体在大脑中广泛表达，但神经元 GH 作用的确切功能尚未完全了解。在这里，我们发现，缺乏 GH 受体的一组表达神经肽生长抑素的神经元的小鼠表现出焦虑增加。然而，这种影响仅在雄性小鼠中观察到。相比之下，在 SST 表达神经元中缺乏 GH 受体可降低雄性和雌性的恐惧记忆，而恐惧记忆是创伤后应激障碍的一个关键特征。因此，我们的研究确定了一个特定的神经元群体，其中 GH 作用会影响神经精神疾病的易感性。
