HDAC1-mediated regulation of GABA signaling within the lateral septum facilitates long-lasting social fear extinction in male mice

Abstract

Social anxiety disorder (SAD) is caused by traumatic social experiences. It is characterized by intense fear and avoidance of social contexts, which can be robustly mimicked by the social fear conditioning (SFC) paradigm. The extinction phase of the SFC paradigm is akin to exposure therapy for SAD and requires learning to disassociate the trauma with the social context. Learning-induced acetylation of histones is critical for extinction memory formation and its endurance. Although class I histone deacetylases (HDACs) regulate the abovementioned learning process, there is a lack of clarity in isoforms and spatial specificity in HDAC function in social learning. Utilizing the SFC paradigm, we functionally characterized the role of HDAC1, specifically in the lateral septum (LS), in regulating the formation of long-term social fear extinction memory. We measured a local increase in activity-inducing HDAC1 phosphorylation at serine residues of social fear-conditioned (SFC+) mice in response to the extinction of social fear. We also found that LS-HDAC1 function negatively correlates with acute social fear extinction learning using pharmacological and viral approaches. Further, inhibition of LS-HDAC1 enhanced the expression of the GABA-A receptor β1 subunit (Gabrb1) in SFC+ mice, and activation of GABA-A receptors facilitated acute extinction learning. Finally, the facilitation of extinction learning by HDAC1 inhibition or GABA-A receptor activation within the LS led to the formation of long-lasting extinction memory, which persisted even 30 days after extinction. Our results show that HDAC1-mediated regulation of GABA signaling in the LS is crucial for the formation of long-lasting social fear extinction memory.

Histone‐deacetylation inhibitors – old tools in new applications may ameliorate the consequences of social isolation on mental health

“…These results contribute to earlier and recent findings in which epigenetic changes, such as DNA methylation and histone deacetylations, were described in response to social isolation stress and where the use of histone‐deacetylation inhibitors was shown to facilitate extinction learning in animals that went through fear conditioning experiments (Bludau et al., 2023). Including the present study by Yan et al.…”

“…These results contribute to earlier and recent findings in which epigenetic changes, such as DNA methylation and histone deacetylations, were described in response to social isolation stress and where the use of histone-deacetylation inhibitors was shown to facilitate extinction learning in animals that went through fear conditioning experiments (Bludau et al, 2023). Including the present study by Yan et al (2024) in this issue of The Journal of Physiology, this epigenetic mechanism has now been observed in several brain regions involved in the response to stress and fear, potentially assigning histone deacetylation to be a general mechanism in the precipitation of stressful situations during life.…”

HDAC1: An Essential and Conserved Member of the Diverse Zn2+-Dependent HDAC Family Driven by Divergent Selection Pressure

“…Further, HDAC1 plays an essential role in many diseases. It provides opportunities for cancer treatment [24], the aging brain and Alzheimer's disease repairment [21], mental disease cure [25], sickle cell disease treatment [26], long-lasting social fear extinction [27], and so on. Therefore, HDAC1 is essential for living organisms and human health.…”