RESUMO
Circulating glucocorticoid levels oscillate with a robust circadian rhythm, yet the physiological relevance of this rhythmicity remains unclear. Here, we show that modulation of circadian glucocorticoid oscillation by enhancing its amplitude leads to anxiolytic-like behavior. We observed that mice with adrenal subcapsular cell hyperplasia (SCH), a common histological change in the adrenals, are less anxious than mice without SCH. This behavioral change was found to be dependent on the higher amplitude of glucocorticoid oscillation, although the total glucocorticoid secretion is not increased in these mice. Genetic and pharmacologic experiments demonstrated that intermediate opioid peptides secreted from SCH activate CXCR7, a ß-arrestin-biased G-protein-coupled receptor (GPCR), to augment circadian oscillation of glucocorticoid levels in a paracrine manner. Furthermore, recapitulating this paracrine axis by subcutaneous administration of a synthetic CXCR7 ligand is sufficient to induce anxiolytic-like behavior. Adrenocortical ß-arrestin-biased GPCR signaling is a potential target for modulating circadian glucocorticoid oscillation and emotional behavior.
Assuntos
Ansiedade/metabolismo , Ritmo Circadiano , Glucocorticoides/metabolismo , Receptores CXCR/metabolismo , Glândulas Suprarrenais/citologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Sequência de Aminoácidos , Animais , Encefalinas/química , Encefalinas/genética , Encefalinas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Alinhamento de SequênciaRESUMO
Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW(-/-) mice. Moreover, the response of NPW(-/-) mice to either formalin-induced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW(-/-) mice in a habituated environment was indistinguishable from that of wild-type mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments.
Assuntos
Aprendizagem da Esquiva , Comportamento Animal , Núcleo Central da Amígdala/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neuropeptídeos/metabolismo , Dor/metabolismo , Animais , Núcleo Central da Amígdala/patologia , Neurônios Dopaminérgicos/patologia , Camundongos , Camundongos Knockout , Neuropeptídeos/genética , Dor/genética , Dor/patologia , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Sleep and wakefulness are regulated primarily by inhibitory interactions between the hypothalamus and brainstem. The expression of the states of rapid eye movement (REM) sleep and non-REM (NREM) sleep also are correlated with the activity of groups of REM-off and REM-on neurons in the dorsal brainstem. However, the contribution of ventral brainstem nuclei to sleep regulation has been little characterized to date. Here we examined sleep and wakefulness in mice deficient in a homeobox transcription factor, Goosecoid-like (Gscl), which is one of the genes deleted in DiGeorge syndrome or 22q11 deletion syndrome. The expression of Gscl is restricted to the interpeduncular nucleus (IP) in the ventral region of the midbrain-hindbrain transition. The IP has reciprocal connections with several cell groups implicated in sleep/wakefulness regulation. Although Gscl(-/-) mice have apparently normal anatomy and connections of the IP, they exhibited a reduced total time spent in REM sleep and fewer REM sleep episodes. In addition, Gscl(-/-) mice showed reduced theta power during REM sleep and increased arousability during REM sleep. Gscl(-/-) mice also lacked the expression of DiGeorge syndrome critical region 14 (Dgcr14) in the IP. These results indicate that the absence of Gscl and Dgcr14 in the IP results in altered regulation of REM sleep.