Wednesday, January 15, 2025
1/15/2025
Project Summary/Abstract While some individuals cope well with hardship, others are not as resilient. Although studies have focused on the magnitude of fear reactions, clinical evidence suggests that response conflict is at the root of maladaptive coping in psychiatric disease. The proposed research pursues the working hypothesis that norepinephrine (NE), a neurotransmitter observed in high levels in patients suffering from fear and anxiety disorders, elicits behavioral reactions that are in conflict with proactive coping behavior. Work in the field has focused on NE release in the basolateral amygdala (BLA), which drives emotional learning in fear conditioning paradigms. However, NE in the BLA does not affect the expression of fear (freezing reactions). Preliminary and published data show that increased NE activity in the central amygdala (CeA), on the other hand, supports threat (fear) reactions and opposes proactive behaviors. The amygdala receives strong input from the brainstem locus coeruleus (LC), the major source of NE in the brain. The proposed research uses an active avoidance paradigm (AA), in which animals learn to emit a proactive response to avoid a threat, to investigate how LC NE release in the CeA controls the balance between freezing reactions and adaptive actions. To accomplish this, an early life trauma paradigm will be used, which reliably yields animals that are unable to perform AA as adults. We will manipulate the LCàCeA circuit in these so-called ‘poor avoiders’ and ‘good avoider’ controls to identify the behavioral, electrophysiological, and molecular mechanisms underlying AA. We will test the prediction that elevated NE release from LC, and the resulting changes at specific CeA target neurons, will yield a poor avoider phenotype in good avoiders, whereas inhibiting this circuit in poor avoiders will ‘rescue’ AA behavior. We will also assess the molecular identity and electrophysiological profiles of cell subtypes in the CeA, how they are functionally different in good versus poor avoiders, and the role of LC activity in these changes. Together, these studies aim to change how the field views the NE system, from modulating fear memory formation in the BLA, to controlling defensive response selection via action in the CeA. These studies will also challenge the dominant methodological paradigms (e.g., fear conditioning), which miss an essential aspect of animal behavior: the competition between reactive versus proactive responses to perceived threats. Successful completion of these studies will uncover the NE system’s role in adaptive coping behaviors and provide evidence-based support for novel treatments of maladaptive coping, including active coping training combined with drugs to control an overactive NE system.
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