The Translational Mechanisms of Fear Memory laboratory of the Institut de Neurociències (INc-UAB) has published a study on Science Advances in which he describes the identification of new neuronal circuits involved in memory of fear, which differ between men and women.
Differences in memory processing between the sexes
These findings have profound implications for understanding human neuropsychiatric disorders, such as post-traumatic stress disorder (PTSD), which feature impairments in fear-related memory.
Fear is elicited by exposure to danger. Several neural circuits are involved in encoding, storing, and retrieving cues that predict environmental threats, forming the basis of what is known as fear memory. However, the neurobiology underlying these processes remains unclear.
A study conducted by the Translational Mechanisms of Fear Memory Lab, led by Professor Dr. Andero of ICREA, at INc-UAB, explores the role of a neuronal pathway called Tac2 and the functional connectivity of two different brain areas: the centromedial amygdala and the bed nucleus of the stria terminalis.
Using chemogenetics, optogenetics, electrophysiology, and in vivo calcium imaging techniques in freely moving mice (Miniscopes), the researchers were able to manipulate and observe these neuronal circuits in mice, demonstrating that functional connectivity between the centromedial amygdala and the bed nucleus of the stria terminalis is essential for fear memory consolidation in male, but not female, mice.
To corroborate this phenomenon in healthy humans, they analyzed data from functional magnetic resonance imaging, postmortem brain tissue, and a fear task in men and women, taking into account a certain genetic variation of the Tac2 receptor. The results showed that this genetic variation reduced functional connectivity between these two brain areas, demonstrating that memory consolidation during the performance of a fear task was impaired in men, but not in women.
These findings, building on previous research by Dr. Andero’s research group, which identified sex-specific effects of Tac2 in the centromedial amygdala, are relevant to designing treatments for neuropsychiatric disorders with impaired fear memory, such as posttraumatic stress disorder.
This study also addresses the underrepresentation of female samples in preclinical research and aims to fill the gap in understanding gender differences in fear memory processing at both the molecular and behavioral levels.
The insights gained from this research could help find more effective and personalized treatments for neuropsychiatric disorders.
The same drug can have opposite effects on memory depending on sexual differences
A research team from the Institut de Neurociències of the Autonomous University of Barcelona (INc-UAB) has shown that inhibition of the Tac2 neuronal circuit, involved in the formation of fear memory, has opposite effects depending on the sex on the ability to remember aversive events in mice, reducing it in male mice and increasing it in female mice.
This is the first time a drug has been shown to produce this opposite effect on the memory of male and female mice. The study also shows that opposite molecular mechanisms and behaviors can occur in memory formation depending on sex. The study was published in Nature Communications.
The research group on translational mechanisms of fear memory, led by Raül Andero, professor and researcher at ICREA, has been studying the functioning of fear memory for years to find treatments for pathologies associated with traumatic experiences, such as post-traumatic stress and phobias.
The research team had identified that the Tac2 circuit, located in the amygdala, could be temporarily blocked by the effect of a drug they were studying. This drug, Osanetant, was able to reduce the ability to remember traumatic events in male mice. In the study, they found that this same drug produced the opposite effect in female mice, increasing their fear memory.
This opposite effect is explained by the fact that, by blocking the Tac2 pathway, the drug interacts with the neuronal receptors of two sex hormones: testosterone in males and estrogen in females. In addition, hormonal fluctuations during the estrous cycle in female mice, equivalent to the menstrual cycle in women, vary the effects of the drug on the ability to remember adverse events.
“These results demonstrate the ability of hormones to modulate the formation of fear memories and show the need to consider gender differences and hormonal cycles when designing pharmacological treatments for psychiatric disorders,” says Antonio Florido, predoctoral researcher at INc-UAB and first author of the article.
In neuroscience, only one study is published on women for every 5.5 on men. And research on the Tac2 pathway has so far been conducted primarily on men.
“Understanding how and why memory processes differ between sexes is essential for designing treatments for fear disorders, especially considering that women are the ones who most often present this type of disorder. Some drugs already in use may not have the expected effects on them,” says Raül Andero, coordinator of the study. “Our results could help raise awareness of the need to do gender-differentiated research and promote basic and clinical studies that include the female sex,” he adds.
The drug being studied is not new, but it is safe for use in humans. However, it is not currently used to treat any disease. Dr. Andero’s group is now studying its potential use in treating fear disorders differently depending on gender.
In this research, which was conducted in collaboration with other INc-UAB research groups and the Hospital del Mar Medical Research Institute (IMIM), scientists demonstrate the importance of personalized medicine. “The mental health drugs we have today, not only for memory disorders, are not specific enough and could cause effects contrary to those desired,” they conclude.
Epigenetics Contributes to Male and Female Differences in Fear Memory
In a mouse model of traumatic memory, male mice recall fear-related memories better than females, according to a study published in Biological Psychiatry . The sex difference was attributed to a gene important for creating fear memories and stressful behaviors, called cyclin-dependent kinase 5 (Cdk5), which was naturally activated in male mice but not in females. The findings may help explain why fear- and stress-related disorders affect men and women differently.
Fear and memory produce changes in genes that modulate gene expression, called epigenetic modifications. Epigenetic activation of Cdk5 naturally increased in males, but not in females, after mice recalled a fear-related memory. Artificial activation of Cdk5 had no effect in male mice, in which Cdk5 was already naturally increased, but reduced the strength of fear memories in female mice, indicating sex differences in how fear is remembered.
“There is growing evidence of gender differences in the neurobiology of fear. These differences could provide important new insights into new sex-specific treatments for anxiety disorders,” said John Krystal, MD, editor of Biological Psychiatry .
Although previous research has shown that Cdk5 is activated by stress and regulates the strength of fear-related memories, it has only been studied in male mice. “We looked at both sexes and found a male-specific epigenetic activation of Cdk5 expression after fear conditioning, a model of traumatic memory,” said senior author Elizabeth A. Heller, Ph.D., University of Pennsylvania.
Dr. Heller and colleagues then used epigenetic editing to artificially increase the activation of Cdk5 in the hippocampus, the memory center of the brain. “Surprisingly, this manipulation reduced fear memory retrieval and increased Tau phosphorylation in female but not male mice,” said Dr. Heller. Phosphorylation of the protein tau by Cdk5 regulates learning and memory.
“Overall, epigenetic editing uncovered a female-specific role for Cdk5 activation in fear-induced memory repression,” said Dr. Heller. Cdk5 activation and tau phosphorylation have been shown to cause negative effects on learning and memory in female mice, but not in male mice. The authors suggest that Cdk5 expression is naturally blocked in females to protect them from these negative effects.
Epigenetic differences in male and female mice indicate sex differences in the biology of how fearful events are remembered, highlighting that sex should be an important factor to consider in the research and treatment of neuropsychiatric disorders involving fear and stress, such as posttraumatic stress disorder, depression, and anxiety.
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