Learning About Safety: Conditioned Inhibition as a Novel Approach to Fear Reduction Targeting the Developing Brain

Date of Award

Spring 2022

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Gee, Dylan


Fear serves an adaptive function by allowing an organism to predict potentially aversive events from environmental cues, increase vigilance, and avoid potential danger. However, fear responses can become maladaptive when they are excessive or prevent an individual from engaging in goal-directed activities (Rothbaum & Davis, 2003). Anxiety disorders, which are characterized by this failure to regulate fear, are the most common psychiatric illnesses, affecting up to one-third of the population (Kessler et al., 2005). Adolescence is a peak time for the onset of mental illness, with anxiety being the most common disorders (Beesdo et al., 2009; Merikangas & Swanson, 2010), highlighting the need for effective interventions early in life. However, current evidence-based treatments for youth are largely based on principles of fear extinction that have been studied and implemented in adulthood. The primary evidence-based psychosocial treatment for anxiety, cognitive behavioral therapy (CBT), is thought to rely on the same neural systems involved in extinction, especially top-down prefrontal control of the amygdala (e.g., Phelps et al., 2004), which undergoes dynamic changes across development (e.g., Casey et al., 2016, 2017; Gee, 2018). Moreover, cross-species studies suggest that fear extinction is diminished during adolescence (McCallum et al., 2010; Pattwell et al., 2012). Taken together, these studies suggest that the most common psychosocial treatment for anxiety disorders targets a process and brain circuitry that is already altered among adolescents. Safety signal learning, based on conditioned inhibition of fear in the presence of safety, has been shown to effectively reduce anxiety-like behavior in animal models and attenuate fear responses in healthy adults (Christianson et al., 2012; Odriozola & Gee, 2021). Cross-species evidence, including evidence presented in this dissertation by Meyer, Odriozola, and colleagues (2019), suggests that safety signal learning may involve connections between the ventral hippocampus and the dorsal anterior cingulate cortex (dACC) in adulthood. Particularly because this hippocampal-dACC pathway may follow a different developmental trajectory than fronto-amygdala circuitry involved in traditional extinction learning (Pattwell et al., 2016), safety cues may provide a novel approach to reducing fear in youth by targeting alternative neurocircuitry. In this dissertation, I present three empirical studies using physiological, behavioral, and neuroimaging (fMRI) data collected during a developmentally-adapted conditioned inhibition task to investigate the neural mechanisms of safety signal learning. In the introductory chapter, I review the existing literature on fear learning and interventions for anxiety disorders and critically review studies on safety signal learning via conditioned inhibition and its potential neural correlates across species (Odriozola & Gee, 2021). In Study 1, I focus on delineating the neural correlates of safety signal learning across species (in humans and mice), showing evidence for recruitment of the hippocampal-dACC pathway, rather than the canonical prefrontal-amygdala pathway involved in extinction (Meyer et al., 2019). In Study 2, I build upon this finding in humans and show differences in safety signal learning across normative anxiety in adulthood. Finally, in Study 3, I investigate safety signal learning and related neural mechanisms across development, using a cross-sectional design with children and adolescents ages 9-19. Taken together, the findings presented in this dissertation provide critical information for understanding the normative development and the neural mechanisms of safety signal learning. I end with a general discussion and a proposal for a translational model that integrates clinical and neurobiological mechanisms by which safety signal learning may reduce fear across development (Odriozola & Gee, 2021). Through this dissertation, I propose that the judicious use of safety signal learning may be an effective and neurodevelopmentally-optimized approach that could be especially beneficial for enhancing treatment efficacy for youth with anxiety disorders by targeting the biological state of the developing brain.

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