Sex in the Brain

The cognitive effects of gonadotropin-releasing hormone.

If you watch the lesser broadcast TV channels, there are many ads for testosterone- elixir of youth, drive, manliness, blaring sales pitches, etc. Is it any good? Curiously, taking testosterone can cause alot of sexual dysfunctions, due to feedback loops that carefully tune its concentration. So generally no, it isn't much good. But that is not to say that it isn't a powerful hormone. A cascade of other events and hormones lead to the production of testosterone, and a recent paper (review) discussed the cognitive effects of one of its upstream inducers, gonadotropin-releasing hormone, or GnRH. 

The story starts on the male Y chromosome, which carries the gene SRY. This is a transcription activator that (working with and through a blizzard of other regulators and developmental processes) is ultimately responsible for switching the primitive gonad to the testicular fate, from its default which is female / ovarian. This newly hatched testis contains Sertoli cells, which secrete anti-Mullerian hormone (AMH, a gene that is activated by SRY directly), which in the embryo drives the regression of female characteristics. At the same time testosterone from testicular Leydig cells drives development of male physiology. The initial Y-driven setup of testosterone is quickly superceded by hormones of the gonadotropin family, one form of which is provided by the placenta. Gonadotropins continue to be essential through development and life to maintain sexual differentiation. This source declines by the third trimester, by which time the pituitary has formed and takes over gonadotropin secretion. It secretes two gondotropin family members, follicular stimulating hormone (FSH) and leutinizing hormone (LH), which each, despite their names, actually have key roles in male as well as female reproductive development and function. After birth, testosterone levels decline and everything is quiescent until puberty, when the hormonal axis driven by the pituitary reactivates.

Some of the molecular/genetic circuitry leading to very early sex differentiation. Note the leading role of SRY in driving male development. Later, ongoing maintenance of this differentiation depends on the gonadotropin hormones.

This pituitary secretion is in turn stimulated by gonadotropin releasing hormone (GnRH), which is the subject of the current story. GnRH is produced by neurons that, in embryogenesis, originate in the nasal / olfactory epithelium and migrate to the hypothalamus, close enough to the pituitary to secrete directly into its blood supply. This circuit is what revs up in puberty and continues in fine-tuned fashion throughout life to maintain normal (or declining) sex functions, getting feedback from the final sex hormones like estrogen and testosterone in general circulation. The interesting point that the current paper brings up is that GnRH is not just generated by neurons pointing at the pituitary. There is a whole other set of neurons in the hypothalamus that also secrete GnRH, but which project (and secrete GnRH) into the cortex and hippocampus- higher regions of the brain. What are these neurons, and this hormone, doing there?

The researchers note that people with Down Syndrome characteristically have both cognitive and sexual defects resembling incomplete development, (among many other issues), the latter of which resemble or reflect a lack of GnRH, suggesting a possible connection. Puberty is a time of heightened cognitive development, and they guessed that this is perhaps what is missing in Down Syndrome. Down Syndrome typically winds up in early-onset Alzheimer disease, which is also characterized by lack of GnRH, as is menopause, and perhaps other conditions. After going through a bunch of mouse studies, the researchers supplemented seven men affected by Down Syndrome with extra GnRH via miniature pumps to their brains, aimed at target areas of this hormone in the cortex. It is noteworthy that GnRH secretion is highly pulsitile, with a roughly 2 hour period, which they found to be essential for a positive effect. 

Results from the small-scale intervention with GnRH injection. Subjects with Down Syndrome had higher cortical connectivity (left) and could draw from a 3-D model marginally more accurately.

The result (also seen in mouse models of Down Syndrome and of Alzheimer's Disease) was that the infusion significantly raised cognitive function over the ensuing months. It is an amazing and intriguing result, indicating that GnRH drives significant development and supports ongoing higher function in the brain, which is quite surprising for a hormone thought to be confined to sexual functions. Whether it can improve cognitive functions in fully developed adults lacking impeding developmental syndromes remains to be seen. Such a finding would be quite unlikely, though, since the GnRH circuit is presumably part of the normal program that establishes the full adult potential of each person, which evolution has strained to refine to the highest possible level. It is not likely to be a magic controller that can be dialed beyond "max" to create super-cognition.

Why does this occur in Down Syndrome? The authors devote a good bit the paper to an interesting further series of experiments, focusing on regulatory micro-RNAs, several of which are encoded in genomic regions duplicated in Down Syndrome. microRNAs are typically regulators that repress transcription, explaining how this whole circuitry of normal development, now including key brain functions, is under-activated in those with Down Syndrome.

The authors offer a subset of regulatory circuitry focusing on micro-RNA repressors of which several are encoded on the trisomic chromosome regions.

"HPG [hypothalamus / pituitary / gonadal hormone] axis activation through GnRH expression at minipuberty (P12; [the phase of testoserone expression in late mouse gestation critical for sexual development]) is regulated by a complex switch consisting of several microRNAs, in particular miR-155 and the miR-200 family, as well as their target transcriptional repressor-activator genes, in particular Zeb1 and Cebpb. Human chromosome 21 and murine chromosome 16 code for at least five of these microRNAs (miR-99a, let-7c, miR-125b-2, miR-802, and miR-155), of which all except miR-802 are selectively enriched in GnRH neurons in WT mice around minipuberty" - main paper

So, testosterone (or estrogen, for that matter) isn't likely to unlock better cognition, but a hormone a couple of steps upstream just might- GnRH. And it does so not through the bloodstream, but through direct injection into key areas of the brain both during development, and also on an ongoing basis through adulthood. Biology as a product of evolution comprises systems that are highly integrated, not to say jury-rigged, which makes biology as a science difficult, being the quest to separate all the variables and delineate what each component and process is doing.

• Should we have helped save the Soviet Union?
• Bill Mitchell on de-growth.
• Overpopulation is destroying the biosphere.
• Map of the week: climate tipping points likely at our current trajectory.