The role of corticotropin-releasing hormone in REM sleep regulation

Curzi, Maria Letizia (2014): The role of corticotropin-releasing hormone in REM sleep regulation: a possible mechanism through the cholinergic system. Dissertation, LMU München: Fakultät für Biologie

Abstract

The neuropeptide corticotropin-releasing hormone (CRH) coordinates neuroendocrine and behavioral responses to stress. Its prolonged hypersecretion produces several signs and symptoms of depression, and is associated with a severe impairment of sleep, in particular reduced sleep intensity, disinhibition of rapid eye movement sleep (REMS), and early morning awakenings. It was recently demonstrated that REMS is upregulated in a conditional mouse model that overexpresses CRH in the forebrain including limbic structures. The results suggest that overexpression of CRH in the forebrain including limbic structures contributes to enhanced REMS, which may apply similarly to the case of depressed patients. However, how limbic CRH affects REMS is still not clear. In general, during REMS, dynamic changes in neurotransmitter activity occur. For example, monoaminergic systems are low, while cholinergic activity becomes high. REMS upregulation seen in depressed patients might be the product of complex interactions between CRH and a neurotransmitter system known to play a role in REMS regulation. In this thesis the role of CRH in the regulation of REMS was further explored. Polysomnographic recordings combined with microinjections, quantitative microdialysis and immunohistochemistry were used to examine whether overexpressed CRH in the forebrain contributes to REMS enhancement by altering the cholinergic system known to play a role in REMS generation. Since CRH overexpression is also present in the limbic system, the present study mainly focused on the amygdala. This limbic structure is strongly implicated in emotional responses closely related to REMS, although only few studies so far have described its interaction with REMS. The results show that injection of a muscarinic antagonist into the central nucleus of the amygdala (CeA) decreases upregulated REMS of homozygous forebrain-specific CRH (CRH-COE Cam) overexpressing mice. Furthermore, homozygous CRH-COE Cam mice possess higher extracellular levels of acetylcholine (ACh) in the CeA than their control littermates, whereas spontaneous locomotor activity is comparable in both genotypes. This suggests that higher ACh is not due to an increase in locomotor activity but is reflected by REMS enhancement. These results indicate that CRH overexpression appears capable of stimulating the cholinergic activity in the amygdala which in turn may lead to upregulated REMS. As seen in depressed patients, this animal model may possess hyper-cholinergic sensitivity that may contribute to REMS disinhibition. Immunohistochemical studies were carried out to confirm this hypothesis: Activation of CRH receptors by microinjection of CRH into the CeA induced an increase of c-Fos expression in cholinergic structures in the brainstem in normal C57BL/6J mice, suggesting that amygdaloid CRH is able to influence the neuronal activity in REMS regulating structures such as the laterodorsal tegmental nucleus (LDT) and the sublaterodorsal tegmental nucleus (SLD). Further, cholinergic neurons in the LDT become more active in homozygous CRH-COE Cam mice than controls in response to sleep deprivation, when REMS rebound occurs, indicating that in this animal model CRH intensifies the mesopontine cholinergic system, which may at least in part result in upregulated REMS. This thesis emphasizes that REMS upregulation seen in depressed patients might be the product of complex interactions between CRH and the cholinergic system. Further investigations will need to complete a detailed picture of the underlying mechanism by which CRH influences REMS.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: CRH, Rem Sleep, Acetylcholine
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 29. Januar 2014
• 1. Bericht­erstatter:in: Landgraf, Rainer