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Serotonin and Fear: Why Women Remember Scary Events More Than Men
Last reviewed: 09.08.2025
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A study published in Nature Neuroscience reveals the molecular basis for why women are more likely to develop post-traumatic stress disorder (PTSD) after similar stressful events. Rebecca Ravenelle and colleagues showed that increasing serotonin before fear conditioning enhances subsequent memory of the feared stimulus only in female mice, via activation of 5-HT₂C receptors in the anterior distal nucleus of the striatum (adBNST) and its connection to the central nucleus of the amygdala (CeA).
What did the scientists do?
Systemic administration of an SSRI (citalopram) shortly before auditory fear conditioning:
Females showed increased freezing when the tone was subsequently played (a measure of fear), while males showed minimal effect.
Optogenetic stimulation of serotonergic terminals in the adBNST during fear learning:
Caused an increase in c-Fos (a marker of neuronal activation) levels in the adBNST and CeA and enhanced fear memory in females but not in males.
Blockade of 5-HT₂C receptors in the adBNST prevented fear enhancement in females, demonstrating a key role for this receptor.
Electrophysiological recordings showed that serotonin increased high gamma (90–140 Hz) synchrony between the adBNST and CeA in females only, which correlated with enhanced fear recall.
Why is this important?
- Women are twice as likely to suffer from PTSD, and this study suggests a specific neurochemical mechanism that explains this vulnerability.
- 5-HT₂C receptors in the adBNST–CeA pathway serve as a modulation site through which serotonin can enhance fear consolidation in the female brain.
- Targeting this system could potentially open up new preventive or treatment approaches to PTSD that take into account gender differences.
“Our data suggest that the female brain has a particular sensitivity to serotonin in this fear circuit,” says Rebecca Ravenelle, lead author. “This may help explain the higher risk of PTSD in women and guide the development of more personalized therapies.”
The authors highlight three key findings and perspectives:
Selective sensitivity of the female brain
“We showed that serotonin, via 5-HT₂C receptors in the adBNST→CeA pathway, enhances fear consolidation exclusively in females, a finding that highlights the importance of considering sex differences when studying PTSD,” notes Rebecca Ravenelle.Targeting 5-HT₂C as a Therapeutic Strategy
“Blockade of 5-HT₂C receptors abolished heightened fear in females, indicating these receptors as a potential target for preventive intervention in individuals at high risk for PTSD,” comments co-author Dr. Michael Clark.Neuronal Rhythms of Fear
“We show for the first time that the female adBNST–CeA circuit synchronizes in the gamma range when serotonin levels are elevated, and this synchrony correlates with enhanced fear memory,” adds co-author Prof. Emily Chen.
This work highlights the importance of considering sex differences in the neurobiology of emotion and may provide the basis for sex-specific strategies to combat PTSD.