Howard Hughes Medical Institute researchers have discovered a vast network of neurons in the brain of mice that governs reproduction and controls the effects of reproductive status on other brain functions.
In their studies, the researchers found neural circuits that coordinate a complex interplay between neurons that control reproduction and brain areas that carry the neural signals triggered by odorant molecules and those triggered by pheromones, chemical signals produced by animals. The researchers characterize their findings as an initial step in understanding the far-reaching influence that odors and pheromones may have on reproduction and other behaviors.
The research team, which was led by HHMI investigator Linda B. Buck at the Fred Hutchinson Cancer Research Center, included first author Ulrich Boehm and Zhihua Zou, who did the work as postdoctoral fellows while in Buck's lab. The researchers published their studies in the journal Cell. Related studies by HHMI investigator Catherine Dulac are published in the same issue.
The scientists began their studies by focusing on tracing the neural pathways leading to and from neurons that produce gonadotropin releasing hormone (GnRH), which is also known as luteinizing hormone releasing hormone (LHRH). These neurons regulate sexual physiology -- including onset of puberty, ovulation, and the menstrual cycle in females and testosterone production in males -- by regulating the release of hormones from the pituitary gland. Interestingly, GnRH neurons also appear to be involved in the control of sexual behaviors.
"Consistent with the idea that GnRH neurons might have additional functions beyond controlling the pituitary, other investigators have shown that GnRH axons can be found in many different areas of the brain," said Buck. "Those findings suggested that GnRH neurons were sending signals to other neurons, but the neurons that received the signals were unknown. Even more importantly for us, though certain brain areas had been implicated in pheromone signaling, specific neurons that transmit pheromone signals to GnRH neurons had not been identified."
To map the neural circuits involving GnRH neurons, the researchers used a genetic tracing method that they previously developed for charting neural pathways. They first engineered mice in which GnRH neurons produce barley lectin (BL), a tracer molecule that travels upstream and downstream to connected neurons, and green fluorescent protein (GFP), to mark the producing cells. By visualizing the locations of BL, GFP, and GnRH neurons and their axons, the researchers were able to identify neurons directly connected to GnRH neurons. They also determined which neurons sent signals to GnRH neurons and which neurons received signals from GnRH neurons.
These studies revealed that connections go in both directions between GnRH neurons and relay stations in the brain that process signals from both the olfactory and vomeronasal systems, said Buck.
In mice and other mammals, the olfactory and vomeronasal systems are distinct pathways for sensing chemicals in the environment. While the main olfactory system that begins in the nose processes odors, the vomeronasal (accessory) system receives signals -- triggered by pheromones -- from the vomeronasal organ (VNO) in the nasal septum. However, the systems are not entirely parallel. Buck and her colleagues have shown that the VNO can detect some odorants. And conversely, there is evidence that some pheromone signals require input from the nose in addition to the VNO.
"Our findings suggest that both odor and pheromone relay areas in the brain are sending pheromone signals to GnRH neurons. Moreover, GnRH neurons, in turn, are sending information back to those relay areas," said Buck. "This surprising finding suggests that the GnRH neurons are influencing the processing of odor and pheromone signals in the brain. It may be the brain's way of saying whether or not it wants to receive particular sensory information -- depending on the reproductive circumstances, such as the stage of the female's estrus cycle."
The researchers also sought to determine whether pheromones could trigger olfactory pathways to activate GnRH neurons. To investigate this, they exposed male and female mice, respectively, to female or male sex-related pheromones and measured how neurons that are connected to GnRH neurons reacted. They also exposed the males to clean bedding, which was thought to be a neutral stimulus.
They found that pheromones triggered responses in neurons upstream of GnRH neurons in both odor and pheromone relay areas. "This suggests that there is a redundancy in pheromone detection, with at least some pheromone information being conveyed by both the main and accessory systems," said Buck. "This redundancy is not too surprising, if you consider how important it is to the animal to be able to sense pheromones. The redundancy might guard against the loss of a pheromone receptor from either the VNO or the olfactory epithelium causing a devastating loss of pheromone detection."