Center for Neuroendocrine Studies, University of Massachusetts, Amherst, MA 01003, United States of America.
Center for Neuroendocrine Studies, University of Massachusetts, Amherst, MA 01003, United States of America.
Horm Behav. 2020 May;121:104716. doi: 10.1016/j.yhbeh.2020.104716. Epub 2020 Feb 28.
Decades of work have established the brain as a source of steroid hormones, termed 'neurosteroids'. The neurosteroid neuroestradiol is produced in discrete brain areas and influences cognition, sensory processing, reproduction, neurotransmission, and disease. A prevailing research focus on neuroestradiol has essentially ignored whether its immediate synthesis precursor - the androgen testosterone - is also dynamically regulated within the brain. Testosterone itself can rapidly influence neurophysiology and behavior, and there is indirect evidence that the female brain may synthesize significant quantities of testosterone to regulate cognition, reproduction, and behavior. In songbirds, acoustic communication is regulated by neuroestrogens. Neuroestrogens are rapidly synthetized in the caudomedial nidopallium (NCM) of the auditory cortex of zebra finches in response to song and can influence auditory processing and song discrimination. Here, we examined the in vivo dynamics of NCM levels of the neuroestrogen synthesis precursor, testosterone. Unlike estradiol, testosterone did not appear to fluctuate in the female NCM during song exposure. However, a substantial song-induced elevation of testosterone was revealed in the left hemisphere NCM of females when local aromatization (i.e., conversion to estrogens) was locally blocked. This elevation was eliminated when local androgen synthesis was concomitantly blocked. Further, no parallel elevation was observed in the circulation in response to song playback, consistent with a local, neural origin of testosterone synthesis. To our knowledge, this study provides the first direct demonstration that testosterone fluctuates rapidly in the brain in response to socially-relevant environmental stimuli. Our findings suggest therefore that locally-derived 'neuroandrogens' can dynamically influence brain function and behavior. SIGNIFICANCE STATEMENT: This study demonstrates that androgen synthesis occurs rapidly in vivo in the brain in response to social cues, in a lateralized manner. Specifically, testosterone synthesis occurs within the left secondary auditory cortex when female zebra finches hear male song. Therefore, testosterone could act as a neuromodulator to rapidly shape sensory processing. Androgens have been linked to functions such as the control of female libido, and many steroidal drugs used for contraception, anti-cancer treatments, and sexual dysfunction likely influence the brain synthesis and action of testosterone. The current findings therefore establish a clear role for androgen synthesis in the female brain with implications for understanding neural circuit function and behavior in animals, including humans.
数十年的研究已经证实，大脑是类固醇激素的来源，这些激素被称为“神经甾体”。神经甾体神经雌二醇在特定的脑区产生，影响认知、感觉处理、生殖、神经传递和疾病。目前的研究重点主要集中在神经雌二醇上，而基本上忽略了其直接合成前体——雄激素睾酮——是否也在大脑中受到动态调节。睾酮本身可以迅速影响神经生理学和行为，并且有间接证据表明，女性大脑可能会合成大量的睾酮来调节认知、生殖和行为。在鸣禽中，神经雌激素调节着声学通讯。神经雌激素在斑胸草雀听觉皮层的尾侧中脑背侧区（NCM）中快速合成，以响应歌声，并能影响听觉处理和歌声辨别。在这里，我们研究了 NCM 中神经雌激素合成前体睾酮的体内动态。与雌二醇不同，在雌性暴露于歌声时，NCM 中的睾酮似乎没有波动。然而，当局部阻断芳香化作用（即转化为雌激素）时，在雌性的左侧 NCM 中发现了大量与歌声诱导的睾酮升高。当同时阻断局部雄激素合成时，这种升高就会消除。此外，由于歌声回放而导致的循环中没有观察到平行升高，这与睾酮合成的局部、神经起源一致。据我们所知，这项研究首次直接证明了睾酮会在大脑中迅速波动，以响应与社会相关的环境刺激。因此，我们的研究结果表明，局部产生的“神经雄激素”可以动态地影响大脑功能和行为。意义：这项研究表明，雄激素在大脑中会迅速地在体内合成，以响应社交线索，并呈侧化方式。具体来说，当雌性斑胸草雀听到雄性歌声时，左侧次级听觉皮层内会发生睾酮合成。因此，睾酮可能作为一种神经调质来快速塑造感觉处理。雄激素与女性性欲控制等功能有关，许多用于避孕、抗癌治疗和性功能障碍的甾体药物可能会影响大脑中睾酮的合成和作用。目前的发现为女性大脑中的雄激素合成确立了明确的作用，这对理解动物（包括人类）的神经回路功能和行为具有重要意义。
