Eradicating Evil by Coloring Rodent Neurons?

According to Ghahreman Khodadad (p. 3), Susan Dymecki and her team at Harvard Medical School contribute to deciphering the biological mechanisms underlying “excessive selfishness and aggression.” Ghahreman Khodadad is a remarkable person and on top of that the provider of the CNS’s major endowment for its Public Talk Series. “Dr. K.,” as some Penn neuroscientists lovingly call him, believes that only switching off this “deeply rooted and complex behavioral neurobiological disorder,” the excessive selfishness, can bring peace to human societies.

What follows now is a potentially unintelligible account of the Dymecki Lab’s research as Susan Dymecki presented it on December 4 at Penn, titled: “A Specialized Subtype of Serotonergic Neuron Shapes Social Behavior in Mice.” I did my best to follow along, and the methods of tracing the expression of certain serotonergic neurons are truly fascinating (and somehow totally beyond me).

Nonetheless, I’ll give it a try.

(“P1260441” by Xavier Béjar, CC BY-SA 2.0)

Serotonin is one important factor in the neurobiology associated with aggression. Using rodent models, Dymecki explores the different types of serotonergic neurons (5-HT neurons) and through them the multifold functions of serotonin in mammals. 5-HT neurons live in fields and modulate many behaviors and functions, such as mood, anxiety, aggression, addiction, but also heart rate, body temperature, appetite, respiration, etc. To Dymecki, finding out how 5-HT neurons are organized and how serotonin regulates cognitive/affective and autonomic/homeostatic processes in rodents means a huge step towards an understanding of “excessive selfishness and aggression” in humans.

So far, her lab was able to identify nine different types of 5-HT neurons in mice, to genetically manipulate their activity, to probe their function in mice, and to make inferences to the behavioral contribution of these genes in rodent organisms. Furthermore, Dymecki and her team profiled the transcriptome, i.e., the expression of these genes, and they are working on identifying potential druggable targets enriched in particular kinds of 5-HT neurons. If they are successful here, their research will inform the development of more effective drugs to treat specific serotonergic disorders with fewer side effects.

A rodent.
(“Norway Rats on exhibit at the Smithsonian’s National Zoo” by Smithsonian’s National Zoo, CC BY-NC-ND 2.0)

The methods used to reach these goals are complex and fascinating. Dymecki’s group targets the gene expression, since individual genes are expressed differently in certain serotonergic neurons. Intersectional Genetic Fate Mapping allows the researchers to specifically label molecularly distinct 5-HT neurons. This is based on the expression of transcription factors, receptors, channels, and neuropeptides. The challenge is to mark distinct neuron subtypes, because to this day, there is no method available to mark a 5-HT neuron subtype on the basis of one single gene. However, it is possible to mark neurons when two genes intersect.

Dymecki provided an example for identifying neurons depending on the genes Pet1 and En1: Transgenic reporter allele are inserted into all the serotonergic neurons so the cells express mCherry, a gene that makes the neurons fluoresce red. Building on these genetically marked neurons, the researchers mark the target subtype of 5-HT neuron (green, expressed eGFP).

The Dymecki lab has already been successful in silencing serotonergic neurons associated with the respiratory CO2 chemoreflex by using tox-genetics (long-term switches by suppressing neurotransmitter release) and chemical genetics (medium-term switches by decreasing the excitability of neuron populations). The researchers measure the properties of the organism prior to silencing the 5-HT neuron subtype, then switch off the respective neurons, and finally measure the properties and respiratory response again. Dymecki’s lab indeed found evidence that serotonergic neurons play a fundamental role in the respiratory CO2 chemoreflex. The hope is that similar methods will allow the researchers to find a “dimmer-switch for aggression.”

But this is way down the road.

Even if they succeed quickly, their research has to be translated to humans—on a neurobiological as well as on a behavioral level. Thus, it may take some time before we reach the state of peace Dr. Khodadad is longing for—assuming that he is even right in proposing excessive aggression and selfishness as the #1 problem of our societies. And as much as I would like to believe in a switch for aggressiveness and selfishness, I strongly doubt he’s right on this point.

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