Long-Term Impacts of Acute Stressor Exposure on Locus Coeruleus Function and Anxiety-Like Behavior in Rats

Stress is a physiological state characterized by behavioral arousal that occurs during exposure to harmful or threatening stimuli, and usually facilitates an adaptive behavioral response. The persistence of stress sometimes causes it to become maladaptive, potentially contributing to disease development, including physiological complications with altered neuroendocrine signaling and impaired function of organ systems, and psychological conditions including depression and anxiety. Anxiety disorders in particular are associated with a history of stress and are the most common class of mental disorders, with a lifetime prevalence of 33.7% in the general population. The locus coeruleus (LC) is a major node in the stress response, which integrates input from multiple stress responsive neural circuits and releases norepinephrine throughout the central nervous system (CNS) to promote vigilance and anxiety. Stress-induced adaptations in LC may lead to impaired noradrenergic transmission throughout the CNS and is thought to contribute to mood disorder pathogenesis. Although immediate cellular actions of stress on LC have been extensively studied, the long-term changes in LC are poorly described. It is well-established that acute stress causes the release of corticotropin-releasing factor (CRF) in the CNS, including in LC, where it increases tonic firing to promote increased norepinephrine in target brain areas, thereby promoting anxiety-like behavior. However, LC morphology and stress responsiveness varies among males and females and changes throughout development. In addition, CRF activity on the LC is counteracted by endogenous opioid neurotransmission. The endogenous opioid peptides Leu- and Met-enkephalins act through d and m opioid receptors, which decrease cAMP and increase potassium conductance through a Gi-coupled mechanism, leading to cell hyperpolarization and decreased firing. Therefore, we hypothesized that acute stressor exposure would have variable impacts on LC physiology and anxiety-like behavior in rats of different ages in both sexes. We further postulated that dysregulation of LC following stress is associated with altered function of opioid receptors in LC. To test this, we used a combination of whole-cell patch clamp recordings of LC neurons, rodent assays of anxiety-like behavior, and analysis of gene and protein expression. Finally, by using a viral-genetic method, we assessed the impact of overexpression of δ-opioid receptors in LC on stress responsiveness. Here we report that acute intense stressor exposure results in opposing changes in anxiety-like behavior and LC physiological properties in adolescent male and female rats. No such changes were observed in adult animals. We also found that the same stressor during adolescence in males is associated with impaired δ opioid receptor expression and function, which may contribute to a reduced capacity to terminate the stress response. These results suggest that endogenous opioid signaling in LC, particularly in adolescent males, is a key target, and regulator of, the stress response, and may have critical implications for the development and treatment of various stress-associated pathological conditions

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder

Delta Opioid Receptors and Enkephalinergic Signaling within Locus Coeruleus Promote Stress Resilience

The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. LC is also innervated by several structures that synthesize and release the endogenous opioid peptide enkephalin onto LC upon stressor termination. While the role of CRF neurotransmission within LC in mediating anxiety-like behavior and the behavioral response to stress has been well characterized, the role of enkephalinergic signaling at LC-expressed δ-opioid receptors has been comparatively understudied. We have previously shown that acute stressor exposure increases LC activity and anxiety-like behavior for at least one week. Here, we extend these findings by showing that these effects may be mediated at least in part through stress-induced downregulation of DORs within LC. Furthermore, overexpression of DORs in LC blocks the effects of stress on both LC firing properties and anxiety-like behavior. In addition, intra-LC infusions of enkephalin blocked stress-induced freezing behavior and promoted conditioned place preference. These findings indicate that enkephalinergic neurotransmission at DORs within LC is an important component of the behavioral response to stress and may drive reward-related behavior as well