Stress related disorders, including anxiety and post-traumatic stress disorder (PTSD), are major unmet clinical problems that have a higher prevalence and severity in females. The locus coeruleus norepinephrine (LC-NE) system is a sexually dimorphic brain region and a key area activated by stressful stimuli. Through its projections, the LC-NE system forms a major component of circuits that encode behavioral responses to stress. Dysfunctions in the LC-NE system are associated with a variety of stress-induced neuropsychiatric disorders, including PTSD. While it is well known that the LC plays a central role in stress-related behaviors, it remains unclear what inputs drive LC neuron excitability and how they regulate this system in response to stress. At present, studies examining the LC have primarily focused on stress-related peptides such as corticotropin releasing factor (CRF). The release of these peptides within the LC has been shown to be a central factor that drives the LC during stress and is responsible for mediating stress-induced anxiety-like behaviors. The mechanisms by which CRF mediates its effects in the LC however are poorly understood. Despite the importance of CRF and the LC-NE system, few studies have attempted to determine how CRF drives long-term changes in LC neuron excitability. The objective of this proposal is to identify glutamatergic inputs to the LC, determine how they are regulated by CRF and determine how the strength of these inputs is altered following stress. By comparing males and females and examining the role that CRF plays in driving this plasticity, the wide-ranging importance of this work will be to define the circuitry driving LC-NE activation by exposure to anxiety-inducing stressful stimuli.
Stress drives multiple changes within the nervous system, including plasticity of multiple circuits. The locus coeruleus (LC) and noradrenergic system are critical regulators of multiple systems and have been identified as key targets of stress. Despite this, little is known about the neural circuits innervating the LC. A better understanding of the events linking stress to synaptic changes in the LC will be significant as it has the potential to direct new strategies for the treatment of mental health disorders.
