scholarly journals Endocannabinoid-mediated potentiation of nonnociceptive synapses contributes to behavioral sensitization

2018 ◽  
Vol 119 (2) ◽  
pp. 641-651 ◽  
Author(s):  
Yanqing Wang ◽  
Brian D. Burrell
Keyword(s):  
Behavioral Sensitization ◽  
Neural Circuit ◽  
Critical Role ◽  
Inhibitory Synapses ◽  
Noxious Stimulation ◽  
Direct Stimulation ◽  
Bath Application ◽  
Hirudo Verbana ◽  
Nociceptive Afferents ◽  
Circuit Output

Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect will result in disinhibition and would therefore be expected to produce an increase in neural circuit output. However, there have been no examples directly linking endocannabinoid-mediated disinhibition to a change in a functional neurobehavioral circuit. The present study uses the well-characterized central nervous system of the medicinal leech, Hirudo verbana, to examine the functional/behavioral relevance of endocannabinoid modulation of an identified afferent synapse. Bath application of 2-AG potentiates synaptic transmission by pressure-sensitive sensory neurons (P cells) as well as the magnitude of the defensive shortening reflex elicited by P-cell stimulation. This potentiation requires activation of TRPV-like channels. Endocannabinoid/TRPV signaling was found to produce sensitization of the shortening reflex elicited by either direct stimulation of nearby nociceptive afferents (N cells) or noxious stimulation applied to skin several segments away. In both cases, heterosynaptic potentiation of P-cell synapses was observed in parallel with an increase in the magnitude of elicited shortening and both synaptic and behavioral effects were blocked by pharmacological inhibition of 2-AG synthesis or TRPV-like channel activation. Serotonin (5-HT) is known to play a critical role in sensitization in Hirudo and other animals, and the 5-HT2 receptor antagonist ritanserin also blocked behavioral sensitization and the accompanying synaptic potentiation. These findings suggest a novel, endocannabinoid-mediated contribution to behavioral sensitization that may interact with known 5-HT-dependent modulatory processes. NEW & NOTEWORTHY There is considerable interest in the analgesic potential of cannabinoids. However, there is evidence that the cannabinoid system can have both pro- and antinociceptive effects. This study examines how an endogenous cannabinoid transmitter can potentiate nonnociceptive synapses and enhance their capacity to elicit a nocifensive behavioral response.

scholarly journals Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

2016 ◽  
Vol 116 (2) ◽  
pp. 619-628 ◽  
Author(s):  
Yanqing Wang ◽  
Brian D. Burrell
Keyword(s):  
Neural Circuit ◽  
Critical Role ◽  
Low Frequency ◽  
Inhibitory Synapses ◽  
Primary Role ◽  
Synaptic Modulation ◽  
Hirudo Verbana ◽  
Frequency Stimulation ◽  
Circuit Output

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl−gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl−export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmechneurons, which are depolarized by GABA due to an elevated Cl−equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl−import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npolyneurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl−import. Consequently, the primary role of elevated EClmay be to protect Npolysynapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npolysynapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmechsynapses. These findings demonstrate a critical role of differences in Cl−gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.

Y5 Receptors Mediate Neuropeptide Y Actions at Excitatory Synapses in Area CA3 of the Mouse Hippocampus

2002 ◽  
Vol 87 (1) ◽  
pp. 558-566 ◽  
Author(s):  
Hui Guo ◽  
Peter A. Castro ◽  
Richard D. Palmiter ◽  
Scott C. Baraban
Keyword(s):  
Synaptic Transmission ◽  
Neuropeptide Y ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Receptor Subtype ◽  
Limbic Seizures ◽  
Excitatory Transmission ◽  
Npy Receptor ◽  
Bath Application ◽  
Peptide Agonist

Neuropeptide Y (NPY) is a potent modulator of excitatory synaptic transmission and limbic seizures. NPY is abundantly expressed in the dentate gyrus and is thought to modulate hippocampal excitability via activation of presynaptic Y2 receptors (Y2R). Here we demonstrate that NPY, and commonly used Y2R-preferring (NPY13–36) and Y5 receptor (Y5R)–preferring ([d-Trp32]NPY and hPP) peptide agonists, evoke similar levels of inhibition at excitatory CA3 synapses in hippocampal slices from wild-type control mice (WT). In contrast, NPYergic inhibition of excitatory CA3 synaptic transmission is absent in mice lacking the Y5R subtype (Y5R KO). In both analyses of evoked population spike activity and spontaneous excitatory postsynaptic synaptic currents (EPSCs), NPY agonists induced powerful inhibitory effects in all hippocampal slices from WT mice, whereas these peptides had no effect in slices from Y5R KO mice. In slices from WT mice, NPY (and NPY receptor–preferring agonists) reduced the frequency of spontaneous EPSCs but had no effect on sEPSC amplitude, rise time, or decay time. Furthermore, NPYergic modulation of spontaneous EPSCs in WT mice was mimicked by bath application of a novel Y5R-selective peptide agonist ([cpp]hPP) but not the selective Y2R agonist ([ahx5–24]NPY). In situ hybridization was used to confirm the presence of NPY, Y2, and Y5 mRNA in the hippocampus of WT mice and the absence of Y5R in knockout mice. These results suggest that the Y5 receptor subtype, previously believed to mediate food intake, plays a critical role in modulation of hippocampal excitatory transmission at the hilar-to-CA3 synapse in the mouse.

Synaptic Regulation of Proopiomelanocortin Neurons Can Occur Distal to the Arcuate Nucleus

2007 ◽  
Vol 97 (5) ◽  
pp. 3298-3304 ◽  
Author(s):  
Shane T. Hentges
Keyword(s):  
Cell Body ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Brain Slices ◽  
Gaba Release ◽  
Afferent Input ◽  
Inhibitory Synapses ◽  
Body Region ◽  
Neuron Activity

Energy homeostasis is controlled to a large extent by various signals that are integrated in the hypothalamus. It is generally considered that neurons in each of the hypothalamic nuclei are regulated by afferent projections that terminate within the cell body region of the nucleus. However, here it is shown that hypothalamic proopiomelanocortin (POMC) neurons receive synaptic inputs onto distal dendrites that reside outside of the cell body region in the arcuate nucleus. Previous studies using whole cell recordings from identified neurons in brain slices have shown that cannabinoids reduce GABA release from inhibitory synapses onto the POMC cells. Here it was found that endocannabinoids inhibited GABAergic inhibitory postsynaptic currents in POMC neurons only in intact sagittal brain slices, but not coronal, horizontal, or sagittal slices that were truncated rostrally at the level of the optic chiasm. Thus endocannabinoids inhibited presynaptic GABA release only at an anatomically distinct subset of POMC–neuron dendrites that extends rostrally beyond the arcuate nucleus into preoptic hypothalamic regions. There are two key results. First, the activity of POMC neurons can be regulated by afferent input at sites much farther from the soma than previously recognized. Second, endocannabinoids can act to inhibit inputs only at selective dendrites. POMC neurons play a critical role in the maintenance of body weight. Therefore these data suggest that energy balance may be regulated, in part, by modulation of POMC neuron activity at sites outside of the arcuate nucleus.

Serotonin Transduction Cascades Mediate Variable Changes in Pyloric Network Cycle Frequency in Response to the Same Modulatory Challenge

2008 ◽  
Vol 99 (6) ◽  
pp. 2844-2863 ◽  
Author(s):  
Nadja Spitzer ◽  
Gennady Cymbalyuk ◽  
Hongmei Zhang ◽  
Donald H. Edwards ◽  
Deborah J. Baro
Keyword(s):  
Steady State ◽  
Spiny Lobster ◽  
Cycle Frequency ◽  
Panulirus Interruptus ◽  
Response System ◽  
Pyloric Network ◽  
Bath Application ◽  
The Mean ◽  
Circuit Output ◽  
Sustained Increase

A fundamental question in systems biology addresses the issue of how flexibility is built into modulatory networks such that they can produce context-dependent responses. Here we examine flexibility in the serotonin (5-HT) response system that modulates the cycle frequency (cf) of a rhythmic motor output. We found that depending on the preparation, the same 5-min bath application of 5-HT to the pyloric network of the California spiny lobster, Panulirus interruptus, could produce a significant increase, decrease, or no change in steady-state cf relative to baseline. Interestingly, the mean circuit output was not significantly different among preparations prior to 5-HT application. We developed pharmacological tools to examine the preparation-to-preparation variability in the components of the 5-HT response system. We found that the 5-HT response system consisted of at least three separable components: a 5-HT2βPan-like component mediated a rapid decrease followed by a sustained increase in cf; a 5-HT1αPan-like component produced a small and usually gradual increase in cf; at least one other component associated with an unknown receptor mediated a sustained decrease in cf. The magnitude of the change in cf produced by each component was highly variable, so that when summed they could produce either a net increase, decrease, or no change in cf depending on the preparation. Overall, our research demonstrates that the balance of opposing components of the 5-HT response system determines the direction and magnitude of 5-HT–induced change in steady-state cf relative to baseline.

scholarly journals Effects of Electroacupuncture on Methamphetamine-Induced Behavioral Changes in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Tsung-Jung Ho ◽  
Chiang-Wen Lee ◽  
Zi-Yun Lu ◽  
Hsien-Yuan Lane ◽  
Ming-Horng Tsai ◽  
...  
Keyword(s):  
Behavioral Sensitization ◽  
Critical Role ◽  
Behavioral Changes ◽  
Monoamine Oxidase A ◽  
World Health ◽  
Therapeutic Mechanism ◽  
Mao A ◽  
Health Organization ◽  
Dopaminergic Pathways ◽  
Major Drug

Methamphetamine (METH) is a major drug of abuse worldwide, and no efficient therapeutic strategies for treating METH addiction are currently available. Continuous METH use can cause behavioral upregulation or psychosis. The dopaminergic pathways, particularly the neural circuitry from the ventral tegmental area to the nucleus accumbens (NAc), have a critical role in this behavioral stage. Acupuncture has been used for treating diseases in China for more than 2000 years. According to a World Health Organization report, acupuncture can be used to treat several functional disorders, including substance abuse. In addition, acupuncture is effective against opioids addiction. In this study, we used electroacupuncture (EA) for treating METH-induced behavioral changes and investigated the possible therapeutic mechanism. Results showed that EA at the unilateral Zhubin (KI9)–Taichong (LR3) significantly reduced METH-induced behavioral sensitization and conditioned place preference. In addition, both dopamine and tyrosine hydroxylase (TH) levels decreased but monoamine oxidase A (MAO-A) levels increased in the NAc of the METH-treated mice receiving EA compared with those not receiving EA. EA may be a useful nonpharmacological approach for treating METH-induced behavioral changes, probably because it reduces the METH-induced TH expression and dopamine levels and raises MAO-A expression in the NAc.

scholarly journals Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety

2021 ◽  
Author(s):  
Mariusz Mucha ◽  
Alberto Labrador-Ramos ◽  
Benjamin Attwood ◽  
Malorzata Bajor ◽  
Jaison Kolenchery ◽  
...  
Keyword(s):  
Gaba Receptor ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Receptor Expression ◽  
Inhibitory Synapses ◽  
Tyrosine Kinase Receptor ◽  
Target Cells ◽  
Central Amygdala ◽  
Anchoring Protein ◽  
Fear And Anxiety

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKCδ-positive (PKCδ+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKCδ+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

scholarly journals Processing of motion boundary orientation in macaque V2

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Heng Ma ◽  
Pengcheng Li ◽  
Jiaming Hu ◽  
Xingya Cai ◽  
Qianling Song ◽  
...  
Keyword(s):  
Neural Circuit ◽  
Neuronal Response ◽  
Critical Role ◽  
Neural Mechanisms ◽  
Orientation Discrimination ◽  
Boundary Orientation ◽  
Area V2 ◽  
Correlated Activity ◽  
Object Based ◽  
Motion Boundaries

Human and nonhuman primates are good at identifying an object based on its motion, a task that is believed to be carried out by the ventral visual pathway. However, the neural mechanisms underlying such ability remains unclear. We trained macaque monkeys to do orientation discrimination for motion boundaries (MBs) and recorded neuronal response in area V2 with microelectrode arrays. We found 10.9% of V2 neurons exhibited robust orientation selectivity to MBs, and their responses correlated with monkeys’ orientation-discrimination performances. Furthermore, the responses of V2 direction-selective neurons recorded at the same time showed correlated activity with MB neurons for particular MB stimuli, suggesting that these motion-sensitive neurons made specific functional contributions to MB discrimination tasks. Our findings support the view that V2 plays a critical role in MB analysis and may achieve this through a neural circuit within area V2.

scholarly journals Neural circuit mechanism underlying the feeding controlled by insula-central amygdala pathway

2019 ◽  
Author(s):  
Calvin Zhang-Molina ◽  
Matthew B Schmit ◽  
Haijiang Cai
Keyword(s):  
Neural Circuit ◽  
Insular Cortex ◽  
Central Nucleus ◽  
Synaptic Organization ◽  
Feeding Behaviors ◽  
Electrophysiological Properties ◽  
Network Computer ◽  
Systems Model ◽  
Circuit Structure ◽  
Circuit Output

SummaryCentral nucleus of amygdala (CeA) contains distinct populations of neurons that play opposing roles in feeding. The circuit mechanism of how CeA neurons process information sent from their upstream inputs to regulate feeding is still unclear. Here we show that activation of the neural pathway projecting from insular cortex neurons to CeA suppresses food intake. Surprisingly, we find that the inputs from insular cortex form excitatory connections with similar strength to all types of CeA neurons. To reconcile this puzzling result, and previous findings, we developed a conductance-based dynamical systems model for the CeA neuronal network. Computer simulations showed that both the intrinsic electrophysiological properties of individual CeA neurons and the overall synaptic organization of the CeA circuit play a functionally significant role in shaping the CeA neural dynamics. We successfully identified a specific CeA circuit structure that reproduces the desired circuit output consistent with existing experimentally observed feeding behaviors.

scholarly journals Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2574
Author(s):  
Emily S. Wilson ◽  
Karen Litwa
Keyword(s):  
Mouse Brain ◽  
Synapse Formation ◽  
Neural Circuits ◽  
Neural Circuit ◽  
System Development ◽  
Synaptic Cleft ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Perineuronal Nets ◽  
Potential Formation

The hyaluronan-based extracellular matrix is expressed throughout nervous system development and is well-known for the formation of perineuronal nets around inhibitory interneurons. Since perineuronal nets form postnatally, the role of hyaluronan in the initial formation of neural circuits remains unclear. Neural circuits emerge from the coordinated electrochemical signaling of excitatory and inhibitory synapses. Hyaluronan localizes to the synaptic cleft of developing excitatory synapses in both human cortical spheroids and the neonatal mouse brain and is diminished in the adult mouse brain. Given this developmental-specific synaptic localization, we sought to determine the mechanisms that regulate hyaluronan synthesis and signaling during synapse formation. We demonstrate that hyaluronan synthase-2, HAS2, is sufficient to increase hyaluronan levels in developing neural circuits of human cortical spheroids. This increased hyaluronan production reduces excitatory synaptogenesis, promotes inhibitory synaptogenesis, and suppresses action potential formation. The hyaluronan receptor, CD44, promotes hyaluronan retention and suppresses excitatory synaptogenesis through regulation of RhoGTPase signaling. Our results reveal mechanisms of hyaluronan synthesis, retention, and signaling in developing neural circuits, shedding light on how disease-associated hyaluronan alterations can contribute to synaptic defects.

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