Involvement Of Cholinergic Neurons Research Articles

Septal Signaling Suppresses Seizures Through Stimulating Somatostatin Cells.

Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition Wang Y, Wang Y, Xu C, Wang S, Tan N, Chen C, Chen L, Wu X, Fei F, Cheng H, Lin W, Qi Y, Chen B, Liang J, Zhao J, Xu Z, Guo Y, Zhang S, Li X, Zhou Y, Duan S, Chen Z. Biol Psychiatry. 2020;87(9):843-856. doi:10.1016/j.biopsych.2019.11.014.Background:Previous studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)–hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated.Methods:In the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models.Results:We found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [γ-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the anti-seizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the anti-seizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons.Conclusions:These findings underscore the notable anti-seizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy.”

The Septum–Hippocampal Cholinergic Circuit: A Novel Pathway for Seizure Control

SEE CORRESPONDING ARTICLE ON PAGE 843 Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin InhibitionBiological PsychiatryVol. 87Issue 9PreviewPrevious studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. Full-Text PDF

Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition

BackgroundPrevious studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. MethodsIn the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models. ResultsWe found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [gamma-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the antiseizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the antiseizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons. ConclusionsThese findings underscore the notable antiseizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy.

The Involvement of Cholinergic Neurons in the Spreading of Tau Pathology

Long time ago, it was described the selective loss of cholinergic neurons during the development of Alzheimer disease (AD). Recently, it has been suggested that tau protein may play a role in that loss of cholinergic neurons through a mechanism involving the interaction of extracellular tau with M1/M3 muscarinic receptors present in the cholinergic neurons. This interaction between tau and muscarinic receptors may be a way, although not the only one, to explain the spreading of tau pathology occurring in AD.

Involvement of cholinergic neurons in the regulation of the ghrelin secretory response to feeding in sheep

We previously demonstrated that a transient surge in plasma levels of ghrelin occurs just prior to a scheduled meal and that this surge is modified by the feeding regimen. This suggests that the ghrelin secretion is regulated by the autonomic nervous system, especially the cholinergic projections to the stomach. To test this hypothesis, we investigated changes in plasma ghrelin levels at feeding time in rams by administering cholinergic blockers (atropine and hexamethonium) and a cholinergic accelerator (metoclopramide). The average food intake in each group infused with atropine, hexamethonium, metoclopramide, and saline was 150±28, 137±46, 153±50, and 1075±25 g, respectively. Plasma ghrelin concentrations increased ( P<0.05) after i.v. infusion of hexamethonium and gradually decreased ( P<0.05) after i.v. infusion of metoclopramide. Plasma ghrelin levels in hexamethonium-treated animals were greater ( P<0.05) than those of atropine-treated animals. Plasma ghrelin levels were significantly ( P<0.05) higher in sheep given i.v. infusions of atropine or hexamethonium than the levels in normal- or pair-fed sheep infused with saline. Plasma ghrelin levels were similar in metoclopramide-treated, pair-fed, and control animals. These results support the possibility that ghrelin secretion is regulated by cholinergic neurons of the vagus and that cholinergic activity suppresses ghrelin secretion in sheep.

Involvement of cholinergic neurons in orexin-induced contraction of guinea pig ileum

The mechanism underlying orexin-induced contraction was examined in isolated preparations of guinea pig ileum, in relation to cholinergic transmission. Orexin-A caused contraction of ileal strips in a concentration-dependent manner. 1-(2-Methylbenzoxazol-6-yl)-3-[1,5]napthyridin-4-yl-urea hydrochloride (SB-334867-A) antagonized the orexin-A-induced contraction, with no effects on the acetylcholine-induced contraction and twitch contractions. The orexin-A-induced contraction was inhibited by tetrodotoxin and atropine, but not by hexamethonium, an antagonist of vasoactive intestinal peptide and a mixture of 5-hydroxytryptamine receptor antagonists. Orexin-A evoked an outflow of [ 3H]acetylcholine from the ileal strips preincubated with [ 3H]choline, in a concentration-dependent manner, and the orexin-A-evoked outflow was inhibited by tetrodotoxin, indicating that the outflow of [ 3H]acetylcholine originates from the nerve terminals. The orexin-A-evoked outflow of [ 3H]acetylcholine was antagonized by SB-334867-A. Thus, orexin-A evokes the release of acetylcholine from the enteric cholinergic neurons due to stimulation of the orexin-1 receptors and then causes contractions of guinea pig ileum.

Involvement of cholinergic neurons in the release of dopamine elicited by stimulation of μ-opioid receptors in striatum

The involvement of striatal cholinergic neurons in the release of dopamine (DA) elicited by the (μ-opioid receptor agonist DAGO [ d-Ala 2, NMePhe 4-Gly 5(ol)]enkephalin) was explored. The striatal release of DA was measured by microdialysis in rats anesthetized with chloral hydrate. When infused in the striatum, through the microdialysis probe, DAGO increased the extracellular levels of DA. The previous injection in striatum of AF 64-A, a toxin for cholinergic neurons, or the concomitant infusion of the M 2-muscarinic antagonist methoctramine abolished the effect of DAGO on the DA release. It is concluded that stimulation of μ-opioid receptors, by inhibiting the acetylcholine release which stimulates tonically M 2-muscarinic receptors likely associated with dopaminergic nerve endings, indirectly increases the striatal DA release.

Involvement of cholinergic neurons in intestinal contraction caused by vasoactive intestinal contractor

The mechanism of the contractile response to vasoactive intestinal contractor (VIC) was examined in the isolated guinea-pig small intestine. VIC at 10 −9 to 10 −7 M produced a transient relaxation followed by a contraction, and this contraction was partially inhibited, to the same degree, by either atropine or tetrodotoxin. VIC (10 −8 M) induced an increase in the release of [ 3H]acetylcholine from the ileum preloaded with [ 3H]choline. The VIC-induced acetylcholine release was dependent on external Ca 2+. Thus, the VIC-induced contractions may relate to stimulation of cholinergic neurons and smooth muscle cells.

A longitudinal study of cerebrospinal fluid acetylcholinesterase in delirium: Changes at the acute stage and at one-year followup

Cerebrospinal fluid acetylcholinesterase (CSF AChE) was determined for elderly delirious patients during the acute stage and after a 1-year followup, and the AChE levels were compared with those of age-equivalent controls. At the acute phase, the AChE levels of the delirious patients were in the same range as those of the control group, but during the followup, a slight declining trend was observed. These results do not unambiguously support the previously suggested role of cholinergic dysfunction in the pathogenesis of acute delirium, although the augmented striatal release of AChE in hyperkinetic and mixed delirium may mask the involvement of cholinergic neurons.

Phospholipase A2 and mediation of the activation of short-circuit current in the rat colonic mucosa

Melittin (0.5-2 micrograms ml-1) increased the short-circuit current (ISC) in mucosa-submucosa and mucosa preparations of the rat colon descendens in a dose-dependent manner. In the preparation with the submucosal plexus, quinacrine and indomethacin completely blocked the effect of melittin, indicating activation of phospholipase A2 and production of prostaglandins induced by the drug. The melittin response was also partially sensitive to the lipoxygenase inhibitor, nordihydroguaiaretic acid. Complete inhibition by tetrodotoxin and atropine gives evidence for the involvement of cholinergic neurons in the mediation of the response induced by melittin. In contrast, in the preparation without the submucosal plexus the effect of melittin was only partially inhibited by quinacrine, indomethacin, or by neuronal blockers, suggesting direct interactions of melittin with the epithelium in addition. The effect of melittin resembles to the action of bradykinin, which is neuronally mediated and quinacrine-sensitive in the mucosa-submucosa preparation, and quinacrine-resistant and not neuronally mediated in the mucosa preparation. In the mucosa-submucosa preparation, the melittin response is even partially sensitive to the bradykinin receptor antagonist [D-Phe7]-bradykinin. The results provide evidence for the presence of a quinacrine-sensitive phospholipase A2 in the preparation with and that without the submucosa.