Dual modulatory effects on feedback from a proprioceptor in the crustacean stomatogastric nervous system

Neuromodulatory actions that change the properties of proprioceptors or the muscle movements to which they respond necessarily affect the feedback provided to the central network. Here we further characterize the responses of the gastropyloric receptor 1 (GPR1) and gastropyloric receptor 2 (GPR2) neurons in the stomatogastric nervous system of the crab Cancer borealis to movements and contractions of muscles, and we report how neuromodulation modifies those responses. We observed that the GPR1 response to contractions of the gastric mill 4 (gm4) muscle was absent, or nearly so, when the neuron was quiescent but robust when it was spontaneously active. We also found that the effects of four neuromodulatory substances (GABA, serotonin, proctolin and TNRNFLRFamide) on the GPR1 response to muscle stretch were similar to those previously reported for GPR2. Finally, we showed that an excitatory action on gm4 due to proctolin combined with an inhibitory action on GPR2 due to GABA can allow for larger muscle contractions without increased proprioceptive feedback.

Nodal GABA facilitates axon spike transmission in the spinal cord

SUMMARYGABA is an inhibitory neurotransmitter that produces both postsynaptic and presynaptic inhibition. We describe here an opposing excitatory action of GABA that facilitates spike transmission at nodes of Ranvier in myelinated sensory axons in the spinal cord. This nodal facilitation results from axonal GABAA receptors that depolarize nodes toward threshold, enabling spike propagation past the many branch points that otherwise fail, as observed in spinal cords isolated from mice or rats. Activation of GABAergic neurons, either directly with optogenetics or indirectly with cutaneous stimulation, caused nodal facilitation that increased sensory transmission to motoneurons without postsynaptically exciting motoneurons. This increased transmission with optogenetic or cutaneous stimulation also occurred in awake mice and humans. Optogenetic inhibition of GABAergic neurons decreased sensory transmission, implying that axonal conduction relies on GABA. The concept of nodal facilitation likely generalizes to other large axons in the CNS, enabling recruitment of selective branches and functional pathways.

Antidromic Spike Propagation and Dissimilar Expression of P2X, 5-HT, and TRPV1 Channels in Peripheral vs. Central Sensory Axons in Meninges

Background: The terminal branches of the trigeminal nerve in meninges are supposed to be the origin site of migraine pain. The main function of these peripheral sensory axons is the initiation and propagation of spikes in the orthodromic direction to the second order neurons in the brainstem. The stimulation of the trigeminal ganglion induces the release of the neuropeptide CGRP in meninges suggesting the antidromic propagation of excitation in these fibers. However, the direct evidence on antidromic spike traveling in meningeal afferents is missing.Methods: By recording of spikes from peripheral or central parts of the trigeminal nerve in rat meninges, we explored their functional activity and tested the expression of ATP-, serotonin-, and capsaicin-gated receptors in the distal vs. proximal parts of these nerves.Results: We show the significant antidromic propagation of spontaneous spikes in meningeal nerves which was, however, less intense than the orthodromic nociceptive traffic due to higher number of active fibers in the latter. Application of ATP, serotonin and capsaicin induced a high frequency nociceptive firing in peripheral processes while, in central parts, only ATP and capsaicin were effective. Disconnection of nerve from trigeminal ganglion dramatically reduced the tonic antidromic activity and attenuated the excitatory action of ATP.Conclusion: Our data indicate the bidirectional nociceptive traffic and dissimilar expression of P2X, 5-HT and TRPV1 receptors in proximal vs. distal parts of meningeal afferents, which is important for understanding the peripheral mechanisms of migraine pain.

Integrative review, XIII Paulista Congress of Neurology, May 2021; São Paulo (SP). Efficacy of cannabidiol in improving the quality of life of Parkinson´s Patient; ITPAC-Palmas (TO); 2021

Introduction: Parkinson’s disease (PD) is a neurodegenerative disease, caused by an imbalance between the inhibitory action of dopamine and the excitatory action of acetylcholine due to dopamine restriction, characterized by motor and non-motor symptoms. The phytocannabinoid cannabidiol (CBD) may be effective for the treatment of symptoms in PD, offering better quality of life. Objectives: To verify the evidence for the efficacy of cannabidiol in the treatment of patients with PD about the improvement of quality of life. To analyze its applicability in controlling involuntary movements in PD patients. Methods: A search in the databases LILACS, BIREME, SCIELO, SCIENCE, EBSCO, PUBMED, using the bibliographic research method, and by means of integrative review. The descriptor cannabidiol was associated with the words: therapeutic use, parkinsonism, and quality of life. The selection included articles published between 2000 and 2020, in Portuguese, English and German languages. Results: Therapeutic effects of cannabidiol were promising in PD, such as neuroprotective action, reduction of motor symptoms, cognitive and quality of life improvement with few relevant adverse effects. Among the 16 articles, 8 demonstrate an improvement in symptoms and the others cite improvement in psychiatric and cognitive symptoms, thus reflecting that cannabidiol is a promising for quality of life improvement. Conclusion: Although cannabidiol has shown efficacy in the therapy of Parkinson’s patients in clinical and preclinical studies, there is still a need for further studies and investigations on the therapeutic effects of this compound. Thus, cannabidiol may become a first choice treatment for PD, promote patients and families a better living with the disease, and positive reflexes.

A direct excitatory action of lactate ions in the central respiratory network of bullfrogs, Lithobates catesbeianus

ABSTRACTChemoreceptors that detect O2 and CO2/pH regulate ventilation. However, recent work shows that lactate ions activate arterial chemoreceptors independent of pH to stimulate breathing. Although lactate rises in the central nervous system (CNS) during metabolic challenges, the ability of lactate ions to enhance ventilation by directly targeting the central respiratory network remains unclear. To address this possibility, we isolated the amphibian brainstem–spinal cord and found that small increases in CNS lactate stimulate motor output that causes breathing. In addition, lactate potentiated the excitatory postsynaptic strength of respiratory motor neurons, thereby coupling central lactate to the excitatory drive of neurons that trigger muscle contraction. Lactate did not affect motor output through pH or pyruvate metabolism, arguing for sensitivity to lactate anions per se. In sum, these results introduce a mechanism whereby lactate ions in the CNS match respiratory motor output to metabolic demands.

Cannabidiol activation of vagal afferent neurons requires TRPA1

Cannabidiol is legal in many US states and is used as a panacea for a host of different symptoms; however, little research has been conducted on its cellular actions. The efficacy of CBD in clinical populations has been demonstrated for certain conditions, including some forms of epilepsy, depression, and anxiety, all of which can also be treated with vagal nerve stimulation. Our current work indicates that CBD has direct excitatory effects on vagal afferent neurons that are mediated by TRPA1, augmented by TRPV1, and attenuated following chronic exposure to cannabis vapor. Together, these findings detail a novel excitatory action of CBD at vagal afferent neurons that may contribute to the vagal mimetic effects of CBD and adaptation following chronic cannabis use.

Junctophilin-4 is essential for signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons

Junctions of endoplasmic reticulum and plasma membrane (ER-PM junctions) serve as signaling hubs in prokaryotic cells. ER-PM junctions are present in peripheral sensory neurons and are necessary for pro-inflammatory G protein coupled receptor signalling and for inflammatory pain generation. Yet, the principles of ER-PM junctions assembly and maintenance, as well as their role in inflammatory signaling in sensory neurons are only beginning to emerge. Here we discovered that a member of the junctophilin family of proteins, JPH4, is abundantly expressed in rat dorsal root ganglion (DRG) neurons and is necessary for the formation of store operated Ca2+ entry (SOCE) complex at the ER-PM junctions in response to the G-protein induced ER Ca2+ store depletion. Furthermore, we demonstrate a key role of the JPH4 and ER Ca2+ stores in the maintenance of inflammatory pain. Indeed, knockdown of JPH4 expression in DRG in vivo significantly reduced the duration of pain produced by inflammatory mediator bradykinin. Since the ER supplies Ca2+ for the excitatory action of multiple inflammatory mediators, we suggest that junctional Ca2+ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.

The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

Hearing Performance in the Follicular-Luteal Phase of the Menstrual Cycle

Introduction. Estrogen has a protective role on auditory function. It may have an excitatory action on auditory nerve fibers and can have a neuroprotective effect. Progesterone has a mainly inhibitory action on the central nervous system, which may balance the mainly excitatory action of estrogen. Objective. To determine changes in hearing performance with pure tone audiometry (PTA), tympanometry, distortion product otoacoustic emissions (DPOAEs), and auditory brainstem responses (ABR) as hormonal changes occur from follicular to luteal phase. Materials and Methods. Twenty healthy female volunteers (age 19 ± 30 years) with normal menstrual cycle and without any hearing problems are included in this case-control study. Hearing evaluation was performed on the 13th day of the menstrual cycle (follicular phase) and then on the 22nd day (luteal phase). Results. All of the participants had normal results in follicular phase. In luteal phase, four cases showed abnormalities as follows: reduced hearing thresholds 250 Hz (mean= 15 dBHL), increased amplitudes of DPOAE (mean= 3 dBspl), decreased middle ear pressure (mean= -110 dapa), and delayed ABR interpeak latencies (mean of IPLs I-III= 0.4 and mean of IPLs III-V= 0.6 ms). Conclusions. In some women, changing of ovarian hormones may induce fluctuating hearing and increased progesterone in luteal phase can lead to abnormal outcomes in auditory function. However, elevated estrogen modifies its consequences in follicular phase.

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Huntington’s disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl−-extruding cotransporter KCC2 is accompanied by an increase in the Cl−-importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests.