TrpC2 and human evolution.

This feels like the most sensitive post I’ve ever made. If I could do something better I’m happy to consider it.

There are some fascinating mice I’ve wanted to post about. Mice in which the TrpC2 gene has been deleted (TrpC2-/-, +/- is heterozygous). First I need to do a little set up.

Humans and Trp2C.

It’s about most of the rest of vertebrates vs. “old world” primates (parvorder Catarrhini). The old world primates include gibbons and great apes like us, and they lack a vomeronasal organ and accessory olfactory system as I mentioned in the other post some posts ago. So no pheromone system and other things that this system did for us. But I believe the evolutionary event of TrpC2 wreckage in human ancestors had a significant effect on us for better and worse.

The primary (green) and accessory olfactory (red) systems.

And in that other post I pointed out how the accessory olfactory system and pheromones themselves are devoted to a range of behaviors beyond mating. Going into predator and prey or food, and a large range of information about your own kind like age, sex, relatedness, health status and more. Whole information channels now missing, but with still existing brain hardware downstream from that olfactory system.

Olfactory sensory neurons activation cascade from Signal Detection and Coding in the Accessory Olfactory System. Mohrhardt 2018. FPR,V1R, V2R = olfactory receptors.

Trp2C is a cation channel protein, “transient receptor potential 2C” (Ca2+, Na+). It is located in the same part of vomeronasal sensory neurons as the vomeronasal olfactory receptors and is part of the signalling system that activates the neuron during signal transduction. In humans this is a pseudogene, it contains a bunch of extra termination codons that severely truncate the protein making it non-functional. It’s an obvious experiment to delete the gene in a model organism like the mouse and see what happens and so some scientists did that.

Before I introduce the mice I want to emphasize that humans have a whole evolutionary history that includes other accessory olfactory pseudogenes, and other changes I think of as “things sandwiched between stimulus and impulse”. These mice are creatures we made in a lab without the 25-40 million years of extra evolution since we lost our Trp2C. There will be implications for good and bad things.

The TrpC2 deletion mice.

These mice lose their social aggression for one thing. They’ll defend themselves if attacked but don’t do any attacking themselves. Males stop fightng intruder males. Females stop fighting intruder males during lactation. Males stop being aggressive towards juveniles. They don’t seem to form dominance hierarchies (as measured by urine marking patterns, the dominant mouse gets to go everywhere, everyone else goes in a corner). TRICK or TRP? What Trpc2−/− mice tell us about vomeronasal organ mediated innate behaviors. Yu 2015

Females don’t engage in nest building as often and don’t nurse as often, but offspring numbers are the same and they have similar body weight so maybe they nurse more effectively. Trpc2 gene impacts on maternal aggression, accessory olfactory bulb anatomy and brain activity. Hasen 2009.

Males care for offspring more, though not to the level of females. Vomeronasal signal deficiency enhances parental behavior in socially isolated male mice. Orikasa 2017

Examples of lost behaviors? TrpC2-/- mice can’t detect sick mice anymore for one thing. Sensing and avoiding sick conspecifics requires Gαi2+ vomeronasal neurons. Weiss 2023.

And then there’s sexual behavior.

This paper describes the big ideas. The De-Scent of Sexuality: Did Loss of a Pheromone Signaling Protein Permit the Evolution of Same-Sex Sexual Behavior in Primates? Pfau 2021.

The first thing to mention is that all of these behaviors were already present at low levels in wild type mice (as they are in primates with an accessory olfactory system). These studies describe increases in rates of various behaviors. The same goes for the previous behavior but I wanted to make the point here. There’s no “gay gene” here since the same sex behavior was already there. It’s more like existing sex specific behaviors increased rates and spread out to both sides once they lost olfactory control.

From Altered sexual and social behaviors in trp2 mutant mice. Leypold 2002. Red = wild type, Blue = TrpC2-/-. This data is of male mice. “Intromission” ~ thrusting. A tests mount frequency to female mice. B tests mount frequency to male mice in sexually naive or experienced mice. C shows frequency in mounting male vs. female mice.

Both male and female TrpC2-/- mice will mount males or females during intruder experiments instead of fighting. At other times too but this was the really noteworthy experiment since fighting an intruder is the typical response of the non-mutant mice.

From A functional circuit underlying male sexual behaviour in the female mouse brain. Kimchi 2007. Data from male and female mice. Reds = male mice, blues = female mice. Mounting of male or female mice shown horizontally.

It gets more detailed. Female TrpC2-/- mice also scent mark like males, vocalize like males, engage in exploratory anogenital sniffing like males (which males usually do during courtship), and they do this thing where they lift up the other mouse’s rump with their nose like males. The behavior between the male and female TrpC2-/- mice get described differently in the literature early on with the male mice merely engaging in same sex behavior but the females show “male type sexual behaviors”. A functional circuit underlying male sexual behaviour in the female mouse brain. Kimchi 2007.

The tough subject, the bad one.

Trigger warning: implications about child sexual abuse.

A final sexual characteristic of the TrpC2-/- mice is they no longer respond to a protein secreted from juveniles that suppresses such behavior (ESP22). These mice were used in the following paper to study this phenomenon. A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system. Ferrero 2013. These mice express sexual behavior towards juveniles at higher rates than wild type mice. This is the tough subject because it’s explanatory of problems we’re dealing with as a society, just as the other observations are explanatory of things that aren’t problems because of consent and similar developmental stages between individuals.

This is explanatory for why should such things even exist. It’s in the same box as murder, it’s possible for some of us, but implicitly harmful. A violation of power. I’m of the opinion that in order to control ourselves as a group it helps to understand ourselves as a group and I believe these mice help there.

Fascinating Theory of Mind and Default Mode Network concepts associated with a paper.

Social cognitive regions of human association cortex are selectively connected to the amygdala.

This paper is neat in a lot of ways. On one level they repeat and confirm other work at higher resolution (7 Tesla MRI instead of 3 Tesla). On another level did you know the Default Mode Network (DMN) has substructure? And overlaps with Theory of Mind brain networks?

The DMN is the part of the brain that is active when we aren’t paying attention to anything externally, daydreaming, introspecting…the paper also points out that the same regions also involve Theory of Mind, autobiographical memory, self-oriented thought, “episodic projection” (EP, thinking about the past or future), and mental scene construction.

But it turns out that there’s evidence that some of the above in the DMN use slightly different regions for Theory of Mind vs. EP (anterior vs. posterior regions of the parietal lobe). These putatively separate parts of the DMN were called DM-A (EP and mental scene construction) and DM-B (Theory of Mind).

They not only confirmed that work, they had a high enough resolution to look at the amygdala and other subcortical regions. In fact DN-B and Theory of Mind seems to involve the amygdala basolateral (primary and secondary reinforcement), accessory basal (maybe generalized feelings to me), lateral (sensory input from non-olfactory senses), and medial (innate behavior) nuclei. DN-A did not activate the amygdala.

So our amygdalae are active even when not outwardly focused, or necessarily feeling intense, at least for Theory of Mind tasks. I like any paper that adds structure to how the mind and the brain intersect. Understanding how our thoughts are shaped.

Finally I’m going to stop predicting what I’m going to try to post next. My mind is a mess.