Anxiety disorders are characterized by excessive and persistent fear responses that render individuals incapable of engaging in everyday events. Social interactions with non-fearful conspecifics prior or after stressful events can significantly dampen fear responses to aversive stimuli, suggesting an important contribution of social interactions to the amelioration of anxiety symptoms. The broad objective of the proposed work is to determine the neuroanatomical and neurochemical circuits involved in social modulation of fear conditioning by non-fearful conspecifics. In particular, we are interested in understanding the relative contributions of oxytocin signaling in the lateral septum and in the hippocampus in the attenuation of fear seen after interactions with non-fearful models. We have recently developed a paradigm to study social modulation of fear in mice. In this paradigm, two pre-exposures to a non-fearful model attenuate subsequent fear conditioning in a context-specific manner. Oxytocin signaling in the lateral septum and the hippocampus is critical for social learning. In addition the lateral septum and the hippocampus have known roles in fear regulation and spatial learning, respectively. Therefore we hypothesize that oxytocin signaling in the lateral septum is important for the attenuation of fear seen in this paradigm, whereas oxytocin signaling in the hippocampus is important for encoding the contextual representations. In order to test this hypothesis we will perform pharmacological manipulations to activate or inhibit oxytocin signaling in the lateral septum or the hippocampus and determine its effects on context-specific attenuation of fear. In addition we will determine the role of these structures by use of conditional oxytocin receptor (Oxtr) gene knockout that will allow for specific deletion of the Oxtr in the neuroanatomical regions of interest. The neuroanatomical and neurochemical circuits uncovered by this work will serve as the basis for developing potential treatment strategies for anxiety disorders.
Clinical studies have shown the importance of social interactions in both the development and the treatment of post-traumatic stress disorder. The proposed study will employ a novel mouse model that incorporates social and fear learning in order to determine the role of oxytocin signaling in social modulation of fear by interactions with non-fearful individuals of the same species. The neuroanatomical and molecular mechanisms uncovered by this work will serve as the basis for the development of novel treatment strategies for anxiety disorders.
|Mesic, Ivana; Guzman, Yomayra F; Guedea, Anita L et al. (2015) Double Dissociation of the Roles of Metabotropic Glutamate Receptor 5 and Oxytocin Receptor in Discrete Social Behaviors. Neuropsychopharmacology 40:2337-46|
|Guzmán, Yomayra F; Tronson, Natalie C; Sato, Keisuke et al. (2014) Role of oxytocin receptors in modulation of fear by social memory. Psychopharmacology (Berl) 231:2097-105|
|Guzmán, Yomayra F; Tronson, Natalie C; Jovasevic, Vladimir et al. (2013) Fear-enhancing effects of septal oxytocin receptors. Nat Neurosci 16:1185-7|