The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

Two G protein-coupled receptors have been identified that bind corticotropin-releasing factor (CRF) and urocortin (UCN) with high affinity. Hybridization histochemical methods were used to shed light on controversies concerning their localization in rat brain, and to provide normative distributional data in mouse, the standard model for genetic manipulation in mammals. The distribution of CRF-R1 mRNA in mouse was found to be fundamentally similar to that in rat, with expression predominating in the cerebral cortex, sensory relay nuclei, and in the cerebellum and its major afferents. Pronounced species differences in distribution were few, although more subtle variations in the relative strength of R1 expression were seen in several forebrain regions. CRF-R2 mRNA displayed comparable expression in rat and mouse brain, distinct from, and more restricted than that of CRF-R1. Major neuronal sites of CRF-R2 expression included aspects of the olfactory bulb, lateral septal nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamic nucleus, medial and posterior cortical nuclei of the amygdala, ventral hippocampus, mesencephalic raphe nuclei, and novel localizations in the nucleus of the solitary tract and area postrema. Several sites of expression in the limbic forebrain were found to overlap partially with ones of androgen receptor expression. In pituitary, rat and mouse displayed CRF-R1 mRNA signal continuously over the intermediate lobe and over a subset of cells in the anterior lobe, whereas CRF-R2 transcripts were expressed mainly in the posterior lobe. The distinctive expression pattern of CRF-R2 mRNA identifies additional putative central sites of action for CRF and/or UCN. Constitutive expression of CRF-R2 mRNA in the nucleus of the solitary tract, and stress-inducible expression of CRF-R1 transcripts in the paraventricular nucleus may provide a basis for understanding documented effects of CRF-related peptides at a loci shown previously to lack a capacity for CRF-R expression or CRF binding. Other such "mismatches" remain to be reconciled.

Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse

The microbiota, the gut, and the brain communicate through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve (VN), the principal component of the parasympathetic nervous system, is a mixed nerve composed of 80% afferent and 20% efferent fibers. The VN, because of its role in interoceptive awareness, is able to sense the microbiota metabolites through its afferents, to transfer this gut information to the central nervous system where it is integrated in the central autonomic network, and then to generate an adapted or inappropriate response. A cholinergic anti-inflammatory pathway has been described through VN's fibers, which is able to dampen peripheral inflammation and to decrease intestinal permeability, thus very probably modulating microbiota composition. Stress inhibits the VN and has deleterious effects on the gastrointestinal tract and on the microbiota, and is involved in the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) which are both characterized by a dysbiosis. A low vagal tone has been described in IBD and IBS patients thus favoring peripheral inflammation. Targeting the VN, for example through VN stimulation which has anti-inflammatory properties, would be of interest to restore homeostasis in the microbiota-gut-brain axis.

/pdf/the-vagus-nerve-at-the-interface-of-the-microbiota-gut-brain-i8igeurji0.pdf

The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis.

Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.

Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication

The search for a neurohormone specifically controlling ACTH secretion resulted in the discovery of the corticotropin-releasing factor (CRF). This factor, located mainly in a paraventricular-infundibular hypothalamic tract, stimulates ACTH synthesis and secretion through a cAMP-dependent mechanism. The corticotropin-releasing factor is the predominant component of a complex control system of adrenal cortex secretion, which also includes catecholamines and the antidiuretic hormone. Its specificity as stimulant of the corticotropic function makes it an extremely useful tool for physiological and physiopathological studies of the hypothalamus-pituitary-adrenal cortex axis regulation.

Corticotropin releasing factor

Effect of 41-CRF antiserum on the secretion of ACTH, B-Endorphin and α-MSH in the rat

Two peptides have a strong corticotropin releasing factor (CRF) activity: arginine vasopressine (AVP) and a 41-residue peptide (41-CRF). Both peptides are present in high concentration in the PVN of the Rat, a zone of the hypothalamus at which electrical stimulation elicits ACTH release. Since homozygous Brattleboro Rats (Di/Di) congenitally lack endogenous AVP, it was of interest to compare the ACTH and corticosterone release after electrical stimulation of the PVN in Long-Evans (L.E.) and Di/Di Rats. In both L.E. and Di/Di Rats, there is a significant increase in plasma ACTH and corticosterone after electrical stimulation of the PVN. However, corticosterone levels are significantly lower in Di/Di than in L.E. Rats whether the Rats have been stimulated or not. It is concluded that a physiological CRF activity is present in the PVN of Di/Di Rats independently of the CRF like activity of AVP.

[Effects of electric stimulation of the para-ventricular nucleus on corticotropin function in Long-Evans and Brattleboro rats].

Ether stress-induced ACTH and corticosterone secretion is similar in 60 days adrenal medullectomized and intact Long-Evans Rats. Passive immunisation with a 41-CRF antiserum impairs corticotropic function after stress. This decrease is more pronounced in adrenal medullectomized than in intact animals. These results suggest that epinephrine plays a minor role on the stress induced ACTH secretion. This role can be demonstrated only after immunoneutralisation of endogenous 41-CRF.

[Effects of adrenal medullectomy and passive immunization with an anti-CRF antiserum on the corticotropin secretion in response to stress in Long-Evans rats].

Rey M

Papers

Corticotropin releasing factor

Effect of 41-CRF antiserum on the secretion of ACTH, B-Endorphin and α-MSH in the rat

[Effects of electric stimulation of the para-ventricular nucleus on corticotropin function in Long-Evans and Brattleboro rats].

[Effects of adrenal medullectomy and passive immunization with an anti-CRF antiserum on the corticotropin secretion in response to stress in Long-Evans rats].