Excessive fear and anxiety are the trademarks of a number of psychiatric disorders, where people with fear-related disorders are thought to over-learn a fear association and/or exhibit an inability to extinguish that fear association. Understanding the mechanisms by which sensory stimuli become associated with a traumatic experience requires understanding how the peripheral nervous system perceives the sensory stimulus and, in turn, transmits such perception to the brain. A significant amount is known regarding the molecular mechanisms underlying the processing of emotional stimuli in the central nervous system;however, very few studies have investigated the mechanisms accompanying emotional learning at the level of specific sensory modalities. The olfactory system provides a molecularly tractable system to understand the structural mechanisms underlying fear-dependent neural processes at the level of a sensory system. Our lab has used olfactory fear conditioning in M71-LacZ transgenic mice to demonstrate increased numbers of M71+ OSNs in the olfactory epithelium following olfactory fear conditioning to acetophenone, an odorant shown to specifically activate the M71 receptor. Further, this increase was directly correlated with an increase in the M71+ glomerular cross-sectional area and volume within the olfactory bulbs. At a functional level, mice exhibit enhanced freezing behavior and increased fear potentiated startle (FPS) to the conditioned odor stimulus after olfactory fear conditioning. Little is known regarding the mechanisms underlying these striking and robust functional and structural changes accompanying olfactory fear conditioning. This proposal will utilize transgenic mice, lentivirus-mediated manipulation of site-specific gene expression, behavioral assays, and immunohistochemical assays to assess cell turnover to explore mechanisms involved in the acquisition of olfactory aversive memories. This proposal will shed light on the mechanisms of olfactory fear learning acquisition at the level of the primary sensory neurons and will also investigate how BDNF-TrkB signaling contributes to behavioral and structural changes following olfactory fear learning. Understanding the changes that occur at the level of the primary olfactory sensory system will shed light on the neurobiological basis of fear related disorders such as PTSD and other anxiety disorders and will provide new insights into mechanisms of prevention of fear over-consolidation, which may lead to novel interventions following trauma exposure in clinical settings.
Understanding the molecular and cellular mechanisms mediating fear regulation is of critical importance for the treatment of fear related disorders, such as Posttraumatic Stress Disorder (PTSD). Through a combination of anatomical, behavioral, molecular, and genetic techniques, these experiments have the potential to delineate the mechanisms that underlie quantifiable structural changes within the olfactory system that follow olfactory fear learning in mammals. Understanding the molecular mechanisms underlying the acquisition of olfactory fear may provide a translationally novel and relevant approach toward better comprehension of the emotional regulation of sensory function and will also lead to improved treatments for fear-related disorders.