Fear is an adaptive mechanism for interacting with an uncertain environment. Fear should be evoked at times when danger is likely and suppressed when safety is perceived. Neural activity of fear and safety circuits are believed to underlie these dynamic shifts in fear expression. In particular, circuits in the basolateral amygdala (BLA) are believed to be an important hub for meditating these switches. The BLA integrates diverse input from sensory cortices, frontal cortices, and the thalamus, which carries direct sensory information from sensory organs. Output structures of the BLA ultimately control physiological reactions to stress: changes in heart rate, respiratory rate, and other systems controlled by the hypothalamic-pituitary axis. Thus, if fear circuits in the BLA were activated inappropriately, all f the physiological effects associated with stress would be triggered, though the environment would otherwise be perceived to be safe. This could also arise if safety circuits were unable to properly suppress fear-related signaling. Dysfunction in safety circuits are hypothesized to underlie fear and anxiety disorders, especially post- traumatic stress disorder (PTSD), in which exaggerated and inappropriate fear responses are elicited. Brain imaging studies have identified two prominent changes in patients with PTSD: hyperactivity of the amygdala and hypoactivity of the prefrontal cortex (PFC); thus, it was hypothesized that the amygdala mediates fear, while the PFC mediates safety by a suppression of amygdala activity. This model is of course oversimplified. It remains unclear how the amygdala and PFC interact to mediate switches between fear and safety. To investigate this question, we have previously recorded simultaneously from the BLA and PFC using microelectrodes while mice were exposed to aversive and safe cues. Our results revealed that safety was associated with directional transfer of information from the PFC to the BLA and that directional communication led to a strengthening of fast gamma (70-120 Hz) oscillations in the BLA. This proposal aims to take advantage of this identified neural correlate to probe the specific circuit elements underlying safety signaling using optogenetic approaches simultaneously with in vivo electrophysiology. Oscillatory activity is believed to relate to the activity of inhibitory cells, and indeed, disrupton of inhibition in the amygdala has been shown to infere with the proper suppression of fear in animal models. However, there are many classes of inhibitory interneurons, and we thus seek to further dissect this microcircuitry to identify the neural underpinnings of fear suppression and mPFC-BLA communication. This will be accomplished by separately manipulating the two main classes of interneurons in the BLA, parvalbumin and somatostatin-positive cells.
Fear is an essential adaptive mechanism for interacting with a changing environment, however fear can be maladaptive when triggered excessively or inappropriately, as in post-traumatic stress disorder. Current treatments are unable to relieve symptoms of this disease in a third of patients, likely because the circuits underlying the suppression of fear responses are not well understood. This proposal takes advantage of novel techniques to precisely and reversibly manipulate neural activity in behaving mice to investigate the safety circuits underlying fear discrimination and extinction, which are dysfunctional in PTSD.
| Garcia-Garcia, A L; Canetta, S; Stujenske, J M et al. (2018) Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner. Mol Psychiatry 23:1990-1997 |
| Bolkan, Scott S; Stujenske, Joseph M; Parnaudeau, Sebastien et al. (2017) Thalamic projections sustain prefrontal activity during working memory maintenance. Nat Neurosci 20:987-996 |
