What role does the neurotransmitter serotonin play in fertility? A recent study by scientists at Nagoya University in Japan discovered a link between serotonin neurons, glucose availability and reproductive health. Their results suggest that serotonergic neurons in the brain play an important role in maintaining reproductive functions by sensing glucose levels and enhancing the release of reproductive hormones. The research was published in Scientific reports.
Depression is linked to dysfunction of central serotonergic neurons and is known to correlate with reproductive and metabolic disorders. Serotonin reuptake inhibitors, common treatments for depression, highlight the importance of serotonergic signaling in these processes.
However, the specific role of serotonergic neurons in coordinating reproduction and glucose metabolism remains unclear. The researchers aimed to discover how serotonergic neurons in the brain might sense glucose levels and regulate reproductive functions. Understanding this link could pave the way for new therapeutic approaches to treat reproductive disorders in patients suffering from depression.
To study this, the researchers used female rats and goats, focusing on the dorsal raphe nucleus and the arcuate nucleus of the hypothalamus, areas rich in serotonergic neurons and key regulators of reproductive hormones. They used a combination of genetic, pharmacological and physiological techniques to unravel the links between these neurons, glucose sensing and the release of reproductive hormones.
In rats, the team used heterozygous Kiss1-tdTomato rats, which have a genetic marker allowing the identification of kisspeptin neurons, essential for the regulation of reproduction. They carried out RNA sequencing to identify the types of serotonin receptors present in these neurons. The analysis revealed that serotonin-2C receptor (5HT2CR), an excitatory receptor, was significantly expressed in kisspeptin neurons of the arcuate nucleus.
One of the main findings is the significant expression of serotonin 2C receptor (5HT2CR) in kisspeptin neurons of the arcuate nucleus of the hypothalamus. Kisspeptin neurons are crucial regulators of reproduction, responsible for the generation of gonadotropin-releasing hormone (GnRH) pulses, which in turn stimulate the release of luteinizing hormone (LH) necessary for reproductive processes.
The RNA sequencing and double in situ hybridization techniques used in this study confirmed that almost half of the kisspeptin neurons expressed 5HT2CR. This finding suggests that these neurons are direct targets of serotonergic signaling, linking serotonin levels to reproductive function.
In other experiments, the researchers demonstrated that increasing serotonergic activity in the midbasal hypothalamus with fluoxetine, a serotonin reuptake inhibitor, could counteract the suppression of LH pulses induced by a glucoprivic state. (low glucose availability) in female rats.
Normally, low glucose conditions, experimentally induced by administration of 2-deoxy-D-glucose (2DG), suppress LH release, thereby inhibiting reproductive functions. However, administration of fluoxetine restored LH pulse rate, indicating that increased serotonin levels may alleviate the adverse effects of low glucose on reproductive hormone release.
The researchers also showed that direct infusion of glucose into the dorsal raphe nucleus increased serotonin release in the mediobasal hypothalamus. This intervention also restored the frequency of LH pulses suppressed by 2DG-induced glucoprivation. These results suggest that serotonergic neurons in the dorsal raphe can sense glucose levels and adjust reproductive hormone release accordingly, highlighting the dual roles of these neurons in managing glucose metabolism and reproductive function.
To validate these results in another mammalian model, the researchers carried out electrophysiological recordings in goats. They found that central administration of serotonin or a 5HT2CR agonist stimulated GnRH pulse generator activity, leading to increased LH release. Conversely, when a 5HT2CR antagonist was administered, it blocked serotonin-induced stimulation of GnRH pulses, thus confirming the central role of the serotonin-2C receptor in this regulatory process.
The results highlight the importance of serotonergic signaling in the brain’s ability to integrate information about glucose availability and modulate reproductive functions. The study provides evidence that serotonergic neurons, through their ability to sense glucose and interact with kisspeptin neurons via 5HT2CR, play a crucial role in maintaining reproductive health, particularly in the face of metabolic challenges.
Animal models, such as the female rats and goats used in this study, provide valuable insight into biological processes that are often difficult to study directly in humans. Rats and goats, although different from humans, share fundamental aspects of their endocrine and nervous systems. Discoveries made in these animals can thus provide a basis for understanding similar processes in humans.
But human physiology, behavior, and disease pathology are influenced by myriad genetic, environmental, and social factors that are not fully replicated in animal models. For example, although rats and goats can provide information about basic physiological processes, they do not account for the full complexity of human reproductive and metabolic disorders, which can be affected by a wide range of factors, including l diet, lifestyle and psychological stress factors.
Although animal models are critical to the initial findings, additional research involving human subjects is needed to validate and translate these findings into clinical practice.
The study titled “Raphe serotonergic glucose-sensing neurons stimulate KNDy neurons to enhance LH impulses via 5HT2CR: studies in rats and goats” was authored by Sho Nakamura, Takuya Sasaki, Yoshihisa Uenoyama, Naoko Inoue , Marina Nakanishi, Koki Yamada, Ai Morishima, Reika Suzumura, Yuri Kitagawa, Yasuhiro Morita, Satoshi Ohkura and Hiroko Tsukamura.