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Understanding sex-based behaviors may improve psychiatric treatments

Posted by on Thursday, August 6, 2020 in Discoveries, News & Discoveries .

By Sara Eaton

Two white mice standing on a rotating “log” of black plastic. The mice are separated by a plastic or glass division. The viewer faces the mice head on so the plastic or glass divider appears as a simple line betw
There are biological differences in how male and female mice respond to different cues in their environment. Deciphering those differences can help researchers develop drugs that work equally well in all human sexes.

New research from the labs of Erin Calipari and Cody Siciliano, both assistant professors in the Department of Pharmacology, reveals differences in how male and female mice respond to anticipated rewards and punishments and implicates D1 medium spiny neurons as components of stimulus processing. The work was recently published in Neuropsychopharmacology.

In their study, Calipari and Siciliano exposed both female and male mice to positive and negative reinforcement in the presence of distinct noises. When mice heard one noise, they learned to poke their noses through a hole to get sucrose, a sugar. A different noise accompanied small shocks that only ceased when mice completed a nose poke. Finally, the researchers played both noises simultaneously and observed whether mice would seek positive reinforcement or avoid negative reinforcement.

The investigators created a behavioral task called MCOAT, the Multidimensional Cue Outcome Action Task, for their investigation. The MCOAT allows researchers to differentiate innate biological behaviors from learned processing of a stimulus. With both positive and negative reinforcement, mice completed a nose poke. Although the behavior appeared to be the same, the mice had different reasonings behind their actions. Since all mice received the same training in identical environments, researchers concluded that any significant differences in how male and female mice responded to their environment, when presented with both noises playing concurrently, would reveal sex-based behavioral differences.

Calipari and Siciliano found that female mice learned more effectively in response to positive, as opposed to negative, reinforcement. Female mice avoided rewards when there was a risk of punishment; males did not show this bias. Lastly, even though females were less sensitive to shocks than males, they required milder shocks to learn new behaviors.

The researchers also found that medium spiny neurons influence behavior acquisition in mice. MSNs help the striatum, a part of the brain, interpret signals that control motor movements. In this study, the team discovered that chemical inhibition of MSNs while mice learned positive reinforcement caused them to learn less efficiently, while chemical suppression during negative reinforcement instruction precipitated faster learning.

The authors hypothesize that insights into sex-based differences in behavior can reveal how sex affects the development and progression of psychiatric diseases.

“One of the major problems in public health is that we develop drugs mostly in male subjects, even though there are clear sex differences in basic biological processes,” said Calipari. “Therefore, the first step in understanding women’s health—and developing treatments with efficacy in all sexes—is understanding how biological processes (or more specifically in our case, basic behaviors) are similar and different.”

This research was supported by the Brain and Behavior Research Foundation, the Edward Mallinckrodt Jr., Foundation, the National Institutes of Health, the Vanderbilt Academic Pathways Fellowship, the VUMC Faculty Research Scholar Award, and the Whitehall Foundation.