Excess Neonatal Testosterone Causes Male-Specific Social and Fear Memory Deficits in Wild-Type Mice

Area of Science:

• Neuroscience
• Developmental Biology
• Endocrinology

Background:

• Neurodevelopmental disorders show a male bias, with underlying biological mechanisms unclear.
• Gonadal hormones are implicated in sex-specific brain development and may contribute to this bias.
• Testosterone (T) plays a critical role in organizing the male brain during development.

Purpose of the Study:

• To investigate the impact of excess testosterone exposure during a critical developmental window on social and fear-related behaviors.
• To determine if early testosterone exposure influences long-term behavioral outcomes relevant to neurodevelopmental disorders.

Main Methods:

• C57BL/6J wild-type mice received testosterone (T) or vehicle (veh) on Postnatal Day 0 (PN0), a critical period for brain masculinization.
• Behavioral assessments included social approach (juvenile) and contextual fear memory (adult).
• Control groups received T on Postnatal Day 18 (PN18), outside the critical period, to assess timing effects.

Main Results:

• Male mice treated with T on PN0 showed reduced juvenile social approach and impaired adult contextual fear memory compared to controls.
• Female mice treated with T on PN0 did not exhibit these behavioral deficits.
• Testosterone administration on PN18 did not result in similar long-term behavioral impairments in either sex.
• Observed deficits were not attributable to anxiety, locomotion, or body weight changes.

Conclusions:

• Excess testosterone exposure during the critical period of early brain organization induces lasting deficits in social approach and fear learning in males.
• These findings suggest that early-life hormonal imbalances may contribute to the male susceptibility observed in certain neurodevelopmental disorders.
• The timing of testosterone exposure is crucial, with effects observed only when administered during the critical window of brain masculinization.