Malleret Cassandra, Blanc-Legendre Mélanie, Guillot Laëtitia, Lautrette-Quinveros Harmony, Pavlidi Pavlina, Dalla Christina, Kokras Nikos, Brion François, Toupin Maryne, Chalmel Frédéric, Cousin Xavier, Charlier Thierry Dominique, Pellegrini Elisabeth
Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, Univ Rennes, Rennes, France.
MARBEC, CNRS, Ifremer, IRD, INRAE, Univ Montpellier, Palavas-les-Flots, France.
J Neurochem. 2025 Aug;169(8):e70202. doi: 10.1111/jnc.70202.
Brain aromatase, an enzyme responsible for the local synthesis of estrogens, plays a key role in regulating behavior and neuroplasticity in mammals. In teleost fish, brain aromatase is encoded by the cyp19a1b gene, which is strongly expressed in radial glial cells; however, the specific functions of this enzyme are currently unknown. To investigate its role, a cyp19a1b-mutant zebrafish line was generated using gene-editing techniques. Behavioral, neurogenic, and neurotransmission-related parameters were assessed in adult male and female zebrafish. Behavioral analysis highlighted significant alterations in mutant zebrafish, including changes in swimming activity, boldness, sociability, and aggression, with a stronger effect in males compared to females. Beyond these behavioral modifications, mutant zebrafish exhibited disrupted cell proliferation patterns, as assessed by PCNA immunofluorescence in key forebrain regions. Specifically, proliferation decreased in the telencephalon and in the caudal hypothalamus of mutant zebrafish while increasing in the olfactory bulbs. The number of dopaminergic and serotonergic neurons, visualized by immunofluorescence, remained unchanged. Similarly, HPLC-ED quantification of monoamines and their metabolites showed no significant differences between mutant and wild-type zebrafish. To further explore the impact of the cyp19a1b mutation on gene expression, transcriptomic analysis was performed using BRB-Seq technology. Gene expression analyses identified several processes affected by the mutation, including cell proliferation, apoptosis, estrogen signaling, neuroplasticity, and behavioral regulation, in a sex- and region-dependent manner. In conclusion, our results demonstrate that several behaviors, including locomotor activity, sociability, aggressiveness, and anxiety, exhibit marked sexual dimorphism. They show that the cyp19a1b mutation affects locomotor activity in a context-dependent manner, increases boldness, and reduces aggressiveness. In addition, transcriptomic analyses revealed widespread dysregulation of gene expression, which likely contributes to the observed behavioral alterations. Taken together, these findings underscore the crucial role of brain aromatase in the neurobiological regulation of diverse behaviors.
脑芳香化酶是一种负责局部合成雌激素的酶，在调节哺乳动物的行为和神经可塑性方面发挥着关键作用。在硬骨鱼中，脑芳香化酶由cyp19a1b基因编码，该基因在放射状胶质细胞中强烈表达；然而，这种酶的具体功能目前尚不清楚。为了研究其作用，利用基因编辑技术构建了cyp19a1b突变斑马鱼品系。对成年雄性和雌性斑马鱼的行为、神经发生和神经传递相关参数进行了评估。行为分析突出了突变斑马鱼的显著变化，包括游泳活动、大胆程度、社交能力和攻击性的改变，雄性的影响比雌性更强。除了这些行为改变外，通过关键前脑区域的PCNA免疫荧光评估，突变斑马鱼表现出细胞增殖模式的紊乱。具体而言，突变斑马鱼端脑和尾侧下丘脑的增殖减少，而嗅球中的增殖增加。通过免疫荧光观察到的多巴胺能和5-羟色胺能神经元数量保持不变。同样，高效液相色谱-电化学检测法对单胺及其代谢产物的定量分析显示，突变斑马鱼和野生型斑马鱼之间没有显著差异。为了进一步探索cyp19a1b突变对基因表达的影响，使用BRB-Seq技术进行了转录组分析。基因表达分析确定了几个受突变影响的过程，包括细胞增殖、凋亡、雌激素信号传导、神经可塑性和行为调节，这些过程存在性别和区域依赖性。总之，我们的结果表明，包括运动活动、社交能力、攻击性和焦虑在内的几种行为表现出明显的性别二态性。结果表明，cyp19a1b突变以上下文依赖的方式影响运动活动，增加大胆程度，并降低攻击性。此外，转录组分析揭示了基因表达的广泛失调，这可能导致了观察到的行为改变。综上所述，这些发现强调了脑芳香化酶在多种行为的神经生物学调节中的关键作用。
