Designer drugs as tools for studying brain development in non-human primates

To investigate the functions of regions within the brain, developmental neuroscience studies have often relied on permanent lesions. As an alternative to permanent lesions, scientists at Yerkes National Primate Research Center sought to test whether chemogenetic techniques could be applied to produce a transient inhibition of the amygdala, well known for regulating emotional responses, in infant non-human primates.

Their findings were recently published online by eNeuro, an open access journal of the Society for Neuroscience.

Amygdala — image from NIMH

Chemogenetics is a way of engineering cells so that they selectively respond to designer drugs, which have minimal effects elsewhere in the brain. It involves injection of a viral vector carrying genes encoding receptors responsive to the designer drug – in this case, clozapine-N-oxide, a metabolite of the antipsychotic clozapine. The technique has mostly been tested in rodents.

“This proof-of-principle study is the first to demonstrate that chemogenetic tools can be used in young infant nonhuman primates to address developmental behavioral neuroscience questions,” says Jessica Raper, PhD, first author of the eNeuro paper and a research associate at Yerkes. “Considering its reversibility and reduced invasiveness, this technique holds promise for developmental studies in which more invasive techniques cannot be employed.”

The amygdala is essential for learning the social and emotional significance of stimuli in the environment. Atypical development and function of the amygdala are implicated in several neurodevelopmental and psychiatric disorders such as autism spectrum disorder, schizophrenia and anxiety disorders.

Two infant rhesus monkeys received viral vector injections in the amygdala at 9 months of age. Chemogenetic inhibition of the amygdala resulted in decreased freezing and anxiety during an acute social stress test, and changed patterns on a socioemotional attention eye tracking task: more attention to the mouth, rather than to the eyes. Inhibition of the amygdala also resulted in increased looking at nonsocial videos, including aversive videos containing snakes and spiders. These changes were reminiscent of, but not identical to, those seen after permanent amygdala lesions in infant monkeys, Raper says.

“Neonatal lesions produce a more extensive array of behavioral changes in response to the social stress test, which were not seen with chemogenetic inhibition of this region,” she says. “Our results may help support the notion that the more extensive behavior changes seen after early lesions are manifested from brain reorganization that occur after permanent damage.”

The scientists checked whether low doses of clozapine-N-oxide produced behavioral changes by themselves, a question arising from previous research on chemogenetics in non-human primates. They did not.

The senior author of the eNeuro paper is Adriana Galvan, PhD, assistant professor of neurology at Emory University School of Medicine and Yerkes National Primate Research Center. The research was supported by the National Institute of Mental Health (P50MH081756) and the NIH Director’s Office of Research Infrastructure Programs (Primate centers: P51OD011132).

 

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Quinn Eastman

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