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Development-Dependent Plasticity in Vasoactive Intestinal Polypeptide Neurons in the Infralimbic Cortex.

ABSTRACT: The onset of several neuropsychiatric disorders including anxiety disorders coincides with adolescence. Consistently, threat extinction, which plays a key role in the regulation of anxiety-related behaviors, is diminished during adolescence. Furthermore, this attenuated threat extinction during adolescence is associated with an altered synaptic plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for threat extinction. However, the mechanism underlying the altered plasticity in the IL-mPFC during adolescence is unclear. Given the purported role of vasoactive intestinal polypeptide expressing interneurons (VIPINs) in disinhibition and hence their potential to affect cortical plasticity, we examined whether VIPINs exhibit an adolescence-specific plasticity in the IL-mPFC. We observed an increase in GABAergic transmission and a decrease in excitability in VIPINs during adolescence. Male mice show a significantly higher VIPIN-pyramidal neuron GABAergic transmission compared with female mice. The observed increase in GABAergic transmission and a decrease in membrane excitability in VIPINs during adolescence could play a role in the altered plasticity in the adolescent IL-mPFC. Furthermore, the suppression of VIPIN-mediated GABAergic transmission in females might be relevant to sex differences in anxiety disorders.

SUBMITTER: Collins SA

PROVIDER: S-EPMC7948133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceVasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP.ObjectiveTo determine whether a 2-hour infusion of VIP would provoke migraine attacks.Design, setting, and participantsA randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month.InterventionsPatients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days.Main outcomes and measuresThe primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo.ResultsTwenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001).Conclusions and relevanceA 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs.Trial registrationClinicalTrials.gov Identifier: NCT04260035.

Project description:Prolactin (PRL) is a versatile hormone and serves a broad variety of physiological functions besides lactation. The release of PRL from lactotrophs in the pituitary has in rodents been shown to be released with a circadian pattern depending on the physiological state of the animal. The circadian release of PRL seems to be complex involving tonic inhibition by dopamine (DA) neurons on lactotrophs and one or even several releasing factors. Because of the circadian releasing pattern of PRL, neurons in the suprachiasmatic nucleus (SCN), "the brain clock," and especially the neurons expressing neuropeptide vasoactive intestinal polypeptide (VIP), have been suggested to be involved in the circadian regulation of PRL. In the present study, we used fluorescence immunohistochemistry, in situ hybridization histochemistry, confocal microscopy, three-dimensional reconstruction, and highly specific antibodies to visualize the occurrence of VIP receptors 1 and 2 (VPAC1 and VPAC2) in mouse brain hypothalamic sections stained in combination with VIP, oxytocin (OXT), arginine vasopressin (AVP), and DA (tyrosine hydroxylase, TH). We demonstrated that VIP fibers most likely originating from the ventral part of the SCN project to OXT neurons in the magnocellular part of the paraventricular nucleus (PVN). In the PVN, VIP fibers were found in close apposition to OXT neuron exclusively expressing the VPAC1 receptor. Furthermore, we demonstrate that neither OXT neurons nor TH or AVP neurons were expressing the VPAC2 receptor. VPAC1 receptor expression was also found on blood vessels but not in neurons expressing AVP or TH. These findings suggest that VIP signaling from the SCN does not directly target DA neurons involved in PRL secretion. Furthermore, the findings support the notion that VIP from neurons in the SCN could regulate circadian release of OXT in the posterior pituitary or modulate OXT neurons as a releasing factor involved in the circadian regulation of PRL from pituitary lactotrophs.

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Development-Dependent Plasticity in Vasoactive Intestinal Polypeptide Neurons in the Infralimbic Cortex.

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