Locus Ceruleus Norepinephrine Research Articles

NEUROENDOCRINOLOGY OF STRESS

Stimuli that are interpreted by the brain as extreme or threatening, regardless of their modality, elicit an immediate stereotypic response characterized by enhanced cognition, affective immobility, vigilance, autonomic arousal and a global catabolic state. The brain's ability to mobilize this so-called stress response is paralleled by activation of corticotropin-releasing hormone (CRH) in several nuclei, including the hypothalamus, amygdala and locus ceruleus, and stimulation of the locus ceruleus norepinephrine (LC/NE) system in the brain stem. These systems perpetuate one another, interact with several other transmitter systems in the brain and directly activate the hypothalamic-pituitary-adrenal (HPA) axis and the three components of the autonomic nervous system, namely the sympatho-adrenal, the cranio-sacral parasympathetic and the enteric nervous systems. The widespread body system responses to stress are discussed, and the implications of aberrant stress system activity on physical and mental health are outlined. Moreover, the promise of nonpeptide CRH type-1 receptor antagonists to directly target the stress system in the brain is highlighted.

The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.

The stress system coordinates the adaptive response of the organism to real or perceived stressors. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine/ autonomic (LC/NE) systems and their peripheral effectors, the hypothalamic-pituitary-adrenal (HPA) axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. Thus, CRH and the LC/NE system stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the amygdala, which are responsible for the generation of fear. Hypothalamic CRH plays an important role in inhibiting gonadotropin-releasing hormone secretion during stress, while via somatostatin it also inhibits growth hormone, thyrotropin-releasing hormone and thyrotropin secretion, suppressing thus reproduction, growth and thyroid function. Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone and thyrotropin secretion and make the target tissues of sex steroids and growth factors resistant to these substances. In addition, glucocorticoids stimulate hepatic gluconeogenesis, and inhibit or potentiate insulin actions on skeletal muscle and adipose tissue respectively, ultimately promoting visceral adiposity and the metabolic syndrome. Glucocorticoids also have direct effects on the bone, inhibiting osteoblastic activity and causing osteoporosis. Obese subjects with psychiatric manifestations ranging from those of melancholic depression to anxiety with perception of 'uncontrollable' stress, frequently have mild hypercortisolism, while carefully screened obese subjects with no such manifestations are eucortisolemic. The former may have stress-induced glucocorticoid-mediated visceral obesity and metabolic syndrome manifestations, which in the extreme may be called a pseudo-Cushing state that needs to be differentiated from frank Cushing syndrome. Stress-induced hypercortisolism and visceral obesity and their cardiovascular and other sequelae increase the all-cause mortality risk of affected subjects by 2-3-fold and curtail their life expectancy by several years.

The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences.

The cardinal clinical manifestations of major depression with melancholic features include sustained anxiety and dread for the future as well as evidence of physiological hyperarousal (e.g., sustained hyperactivity of the two principal effectors of the stress response, the corticotropin-releasing-hormone, or CRH, system, and the locus ceruleus-norepinephrine, or LC-NE, system). Sustained stress system activation in melancholic depression is thought to confer both behavioral arousal as well as the hypercortisolism, sympathetic nervous system activation, and inhibition of programs for growth and reproduction that consistently occur in this disorder. Data also suggest that activation of the CRH and LC systems in melancholia are involved in the long-term medical consequences of depression such as premature coronary artery disease and osteoporosis, the two-three-fold preponderance of females in the incidence of major depression, and the mechanism of action of antidepressant drugs. In addition, recent data reveal important bidirectional interactions between stress-system hormonal factors in depression and neural substrates implicated in many discrete behavioral alterations in depression (e.g., the medial prefrontal cortex, important in shifting affect based on internal and external cues, the mesolimbic dopaminergic reward system, and the amygdala fear system). We have also advanced data indicating that the hypersomnia, hyperphagia, lethargy, fatigue, and relative apathy of the syndrome of atypical depression are associated with concomitant hypofunctioning of the CRH and LC-NE systems. These data indicate the need for an entirely different therapeutic strategy than that used in melancholia for the treatment of atypical depression, and they suggest that this subtype of major depression will be associated with its own unique repertoire of long-term medical consequences.

New Perspectives on the Functional Organization and Postsynaptic Influences of the Locus Ceruleus Efferent Projection System

This chapter summarizes recent efforts on the design of anatomical and physiological experiments that are capable of bridging the gap between cellular-membrane studies of locus ceruleus-norepinephrine (LC-NE) attributes and more global hypotheses regarding the impact of the LC projection system on sensory neural network function. Recent studies using fluorescent retrograde tracers have shown that LC efferents to target structures along the trigeminal somatosensory pathway in rat exhibit an orderly projection with respect to the crossed trajectory of this ascending sensory system. It has been also found that LC projection neurons to somatosensory structures are organized into overlapping subsets within the nucleus, thus raising the possibility that a significant proportion of these cells may project to multiple, common somatosensory targets via axon collaterals. These studies show that the LC exhibits an internal organization and efferent projection pattern that is consistent with the idea that LC outputs can selectively and coordinately modulate the flow of somatosensory information through forebrain circuits. These findings indicate that NE can augment membrane responses to GABA via a β -receptor-linked/ cyclic adenosine monophosphate (cAMP) cascade of events. As such, these noradrenergic influences on putative transmitter-induced conductance changes are consistent with previously observed effects of iontophoretic NE on single-unit responses to GABA in anesthetized and awake, behaving animals. The results reported here continue to support and refine the idea that the LC efferent system exhibits a high degree of anatomical and physiological specificity with respect to its potential impact on target neuronal circuits. Overall, these advances in the understanding of the organizational principles and physiological specificity of the LC-NE efferent system provide new insights into the role of this monoamine-containing brain-stem nucleus in behavior.

Alterations in Tyrosine Hydroxylase Immunoreactive Neurons of the Locus ceruleus in Pick's Disease

The present study describes qualitative and quantitative investigations of the norepinephrine neurons in the locus ceruleus as well as in the subceruleus region of a case of the rare autosomal dominant Pick's disease as compared with a representative control and a case of senile dementia of the Alzheimer type selected from the ZÜrich Study on Dementia. It confirms previous findings that it is possible to differentiate between the norepinephrine neurons of locus ceruleus in normal brain and that in the SDAT for diagnostic purposes and suggests a similar possibility for Pick's disease. In Pick's disease locus ceruleus norepinephrine neurons appear morphologically altered with smaller somata and loss of dendritic and axonal processes, and when present, are foreshortened and less branched. Locus ceruleus neuron numbers are slightly reduced as compared with the control case.

Monoamine neuron innervation of the hippocampal formation: Alteration by neonatal irradiation

Previous studies showed that postnatal irradiation of the hippocampal formation in the rat results in a marked reduction in the granule cell population of the area dentata with an attendant disruption of its normal cytoarchitecture. The present study was carried out to determine the effect of postnatal hippocampal irradiation on the pattern of hippocampal innervation by locus ceruleus norepinephrine neuron axons and midbrain raphe serotonin neuron axons. Irradiated animals exhibit a normal innervation of Ammon's horn by both norepinephrine and serotonin neuron axons. In the area dentata, however, the normal pattern of innervation is markedly altered, with both an apparent decrease in total innervation and a redistribution of the innervation occurring. These effects are interpreted as representing a failure of development of the growth-promoting factors that determine the normal innervation pattern.