Neural Basis of Individual Differences in Fear Extinction

Veterans Health Administration, Decatur PA

Investigators

Linked publications & trials

Abstract

ABSTRACT While most of the general population, and particularly combat veterans, experience traumatic events, only a relatively small proportion go on to develop post-traumatic stress disorder (PTSD), suggesting there are individual differences in susceptibility to the long-term consequences of traumatic stress. PTSD patients also show impairments in fear extinction, extinction recall, and safety learning, so extinction learning processes form the basis of exposure-based therapies. We have observed individual variation in the both freezing and ultrasonic vocalizations (USVs) during the extinction of cued fear memories in outbred male and female rats, providing a model to study PTSD-like resistance to fear extinction. Veterans with PTSD show a very high prevalence of sleep disturbances, and evidence suggests that sleep disturbances predict the development, severity and treatment responses in PTSD. This proposal examines the role of sleep dysregulation in mediating individual differences in extinguishing fear memories and the neurobiological mechanisms underlying these interactions. Cholinergic inputs from the basal forebrain (BF) provide strong inputs to the prefrontal (PFC)-amygdalar circuit which is important for fear extinction, and our results from prior funding suggest that individual differences in cued fear extinction are related to differences in cholinergic neurotransmission and function. Our overarching hypothesis is that the individual differences in fear extinction emerge from alterations in sleep after traumatic stress. Based on the known role of the cholinergic and orexinergic systems, as well as the kynurenine pathway (KP), in modulating both sleep and fear extinction, we propose that sleep disruptions and resistance to fear extinction are mediated by innate variations in the modulation of the cholinergic system by orexin and the kynurenine pathway. We will investigate the interactions between sleep dysregulation and fear extinction in both males and females using polysomnography recordings of EEG and EMG signals using telemetry during our fear learning and extinction paradigm. Since we have seen sex-dependent differences in USVs during fear learning and extinction, proposed studies examine both freezing and USVs in the 22 kHz and 50 kHz range in our behavioral analyses. Aim 1 will test the hypothesis that either innate disruptions in sleep and/or sleep deprivation are associated with resistance to fear extinction. This Aim investigates the ability of Sleep Deprivation during the fear learning and extinction paradigm to increase the kynurenine metabolite kynurenic acid (KYNA) in the brain and induce disruptions in sleep leading to extinction resistance, and these effects may be due to activation of the orexin/hypocretin system. In Aim 2 we test if targeted inhibition of kynurenine aminotransferase II (KAT II), the enzyme responsible for KYNA formation, can alleviate sleep disturbances and enhance fear extinction recall. The efficacy of KATII inhibition to improve sleep and enhance fear extinction will be compared with a dual orexin receptor antagonist (DORA) suvorexant that is also known to improve sleep. Finally, Aim 3 will interrogate the mechanistic role of BF-PFC cholinergic circuit in fear extinction using chemogenetic approaches, and assess the impact of KYNA and orexin on acetylcholine release in this circuit during fear extinction. Together these studies would provide evidence for novel therapeutic targets that might not only help treat sleep disturbances in Veterans with PTSD but elucidate the role of sleep dysregulation in the development of symptoms associated with PTSD, and potentially improve the efficacy of exposure therapies.