σ1 receptor ligands control a switch between passive and active threat responses

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• Threat responses, such as freezing behavior, are conserved across vertebrates.
• Dysregulated threat responses are implicated in various human mental illnesses.

Purpose of the Study:

• To discover small molecules that modulate threat-evoked freezing behavior.
• To elucidate the molecular mechanisms underlying threat response modulation.

Main Methods:

• Developed a high-throughput zebrafish behavioral assay to screen 10,000 compounds.
• Assessed compound effects on freezing and escape-like behaviors.
• Screened active compounds for binding to 45 candidate targets and performed genetic analysis.

Main Results:

• Identified three compound classes that shift threat responses from freezing to escape.
• Discovered the sigma-1 (σ1) receptor as a key mediator of this behavioral switch.
• Confirmed that σ1 receptor ligands and genetic mutations affect threat responses.

Conclusions:

• The sigma-1 (σ1) receptor plays a crucial role in mediating vertebrate threat responses.
• Pharmacological targeting of σ1 offers a potential strategy for modulating abnormal threat behaviors.