scholarly journals Neurokinin receptor mechanisms in forebrain medial septum modulate nociception in the formalin model of inflammatory pain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Si Yun Ng ◽  
Mohammed Zacky Ariffin ◽  
Sanjay Khanna
Keyword(s):  
Information Processing ◽  
Hippocampal Neurons ◽  
Cholinergic Neurons ◽  
Pyramidal Cells ◽  
Cholinergic Receptor ◽  
Medial Septum ◽  
Affective Valence ◽  
Neurokinin Receptor ◽  
Awake Rat ◽  
Anaesthetized Rat

AbstractThe present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.

Theta Rhythm of Hippocampal CA1 Neuron Activity: Gating by GABAergic Synaptic Depolarization

2001 ◽  
Vol 85 (1) ◽  
pp. 269-279 ◽  
Author(s):  
Miao-Kun Sun ◽  
Wei-Qin Zhao ◽  
Thomas J. Nelson ◽  
Daniel L. Alkon
Keyword(s):  
Carbonic Anhydrase ◽  
Memory Consolidation ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Cholinergic Receptor ◽  
Medial Septum ◽  
Maze Learning ◽  
Neuron Activity ◽  
Gabaergic Interneurons ◽  
Hippocampal Ca1

Information processing and memory consolidation during exploratory behavior require synchronized activity known as hippocampal theta (θ) rhythm. While it is well established that the θ activity depends on cholinergic inputs from the medial septum/vertical limb of the diagonal band nucleus (MS/DBv) and θ discharges of GABAergic interneurons, and can be induced with cholinergic receptor agonists, it is not clear how the increased excitation of pyramidal cells could occur with increased discharges of GABAergic interneurons during θ waves. Here, we show that the characteristic θ activity in adult rat hippocampal CA1 pyramidal cells is associated with GABAergic postsynaptic depolarization and a shift of the reversal potential from Cl−toward HCO3−(whose ionic gradient is regulated by carbonic anhydrase). The θ activity was abolished by GABAAreceptor antagonists and carbonic anhydrase inhibitors, but largely unaffected by blocking glutamate receptors. Carbonic anhydrase inhibition also impaired spatial learning in a watermaze without affecting other sensory/locomotor behaviors. Thus HCO3−-mediated signaling, as regulated by carbonic anhydrase, through reversed polarity of GABAergic postsynaptic responses is implicated in both θ and memory consolidation in rat spatial maze learning. We suggest that this mechanism may be important for the phase forward shift of the place cell discharges for each θ cycle during the animal's traversal of the place field for that cell.

scholarly journals Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice

2021 ◽  
Vol 22 (1) ◽  
pp. 400
Author(s):  
Kazuya Matsuo ◽  
Yasushi Yabuki ◽  
Ronald Melki ◽  
Luc Bousset ◽  
Yuji Owada ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Cognitive Processing ◽  
Dopaminergic Neurons ◽  
Dorsal Striatum ◽  
Cholinergic Neurons ◽  
Medial Septum ◽  
Gabaergic Neurons ◽  
Gamma Aminobutyric Acid ◽  
Fatty Acid Binding

In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, Fabp3 deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies.

Developmental study of benzodiazepine effects on monosynaptic GABAA-mediated IPSPs of rat hippocampal neurons

1993 ◽  
Vol 70 (3) ◽  
pp. 1076-1085 ◽  
Author(s):  
C. Rovira ◽  
Y. Ben-Ari
Keyword(s):  
Hippocampal Neurons ◽  
Receptor Agonist ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Developmental Study ◽  
Type I ◽  
Gamma Aminobutyric Acid ◽  
Adult Rats ◽  
Young Rats ◽  
In Cells

1. The effects of type I (BZ1) and type II (BZ2) benzodiazepine receptor ligands on monosynaptic gamma-aminobutyric acid (GABA)A-mediated inhibitory postsynaptic potentials (IPSPs) and on responses to exogenously applied GABA were studied using intracellular recordings from CA3 pyramidal cells of rat hippocampal slices taken at different postnatal stages [postnatal day 4 (P4)-P35)]. 2. The effects of midazolam, a BZ1 and BZ2 receptor agonist, were tested on the monosynaptic IPSPs at different stages. Monosynaptic, bicuculline-sensitive IPSPs were evoked by hilar stimulation in presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) antagonists [6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and D(-)2-amino-5-phosphonopentanoic acid (50 microM)]. Midazolam at 300 nM maximally increased the duration and amplitude of monosynaptic GABAA-mediated IPSPs in neurons from pups (P4-P6, n = 6) and young (P7-P12, n = 8) and adult (P25-P35, n = 9) rats. All the effects of midazolam on IPSPs were reversed by the antagonist Ro 15-1788 (10 microM). 3. The effect of midazolam was also tested on the response to exogenously applied GABA (5 mM) in the presence of tetrodotoxine [TTX (1 microM)]. In neurons from young rats (n = 9), midazolam (1 nM-1 microM) did not change the responses to exogenously applied GABA, whereas in adult rats (n = 8) midazolam maximally increased GABA currents at 30 nM. 4. The effect of zolpidem, a BZ1 receptor agonist, was tested on monosynaptic IPSPs and GABA currents at different stages. Zolpidem (10 nM-1 microM) was inactive in cells from young rats (n = 12). In neurons from adult rats, zolpidem maximally increased the duration and amplitude of the monosynaptic IPSPs at 300 nM (n = 5) and the amplitude of GABA current at 30-100 nM (n = 5). 5. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (300 nM), an inverse agonist of BZ1 and BZ2 receptors, decreased the amplitude and duration of monosynaptic IPSPs in neurons from pups (n = 3) and young (n = 4) and adult (n = 5) rats. In all cases, full recovery was obtained after exposure to R0 15-1788 (10 microM). DMCM (300 nM-10 microM) failed to reduce GABA responses in cells from young (n = 3) or adult (n = 7) rats. 6. Results indicate that the regulation by benzodiazepine of GABAA-mediated IPSPs varies with the developmental stage.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrophysiological evidence from glutamate microapplications for local excitatory circuits in the CA1 area of rat hippocampal slices

1988 ◽  
Vol 59 (1) ◽  
pp. 110-123 ◽  
Author(s):  
E. P. Christian ◽  
F. E. Dudek
Keyword(s):  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Recording Site ◽  
Postsynaptic Potentials ◽  
Inhibitory Postsynaptic Potentials ◽  
Ca1 Area ◽  
Transverse Slice

1. Evidence for local excitatory synaptic connections in CA1 of the rat hippocampus was obtained by recording excitatory postsynaptic potentials (EPSPs) intracellularly from pyramidal cells during local microapplications of glutamate. 2. Experiments were performed in hippocampal slices cut parallel to (transverse slice) or perpendicular to (longitudinal slice) alvear fibers. In normal solutions, glutamate microdrops (10–20 mM, 10–20 micron diam) applied in CA1 within 400 micron of recorded cells sometimes increased the frequency of inhibitory postsynaptic potentials for 5–10 s in both transverse and longitudinal slices. Increases in EPSP frequency were also occasionally observed, but only in transverse slices. Tetrodotoxin (1 microgram/ml) blocked glutamate-induced increases in PSP frequency, thus indicating that they were not caused by subthreshold effects on presynaptic terminals. Increases in PSP frequency were interpreted to result from glutamate activation of hippocampal neurons with inhibitory and excitatory connections to recorded neurons. 3. In both slice orientations, local excitatory circuits were studied in more isolated conditions by surgically separating CA1 from CA3 (transverse slices) and by blocking GABAergic inhibitory synapses with picrotoxin (5–10 microM). Microdrops were systematically applied at 200 and 400 micron on each side of the recording site. Significant glutamate-induced increases in EPSP frequency were observed in neurons from both slice orientations to microdrops in at least one of the locations. This provided evidence that excitatory synapses are present in both transverse and longitudinal slices. 4. Substantial increases in EPSP frequency only occurred in neurons from longitudinal slices when glutamate was microapplied 200 micron or less from the recording site. In transverse slices, however, large increases in EPSP frequency were observed to glutamate microapplications at 200 or 400 micron. These data suggest that CA1 local excitatory connections project for longer distances in the transverse than in the longitudinal plane of section. 5. Increases in EPSP frequency, averaged across cells, did not differ significantly in the four microapplication sites in either transverse or longitudinal slices. Thus local excitation in CA1 does not appear to be asymmetrically arranged in the way suggested for CA3. 6. The densities of local excitatory circuits in CA1 versus CA3 were studied by quantitatively comparing glutamate-induced increases in EPSP frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasticity in Action of Intrathecal Clonidine to Mechanical but Not Thermal Nociception after Peripheral Nerve Injury

2003 ◽  
Vol 99 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Xavier Paqueron ◽  
Dawn Conklin ◽  
James C. Eisenach
Keyword(s):  
Nerve Injury ◽  
Cholinergic Neurons ◽  
Radiant Heat ◽  
Cholinergic Receptor ◽  
Intrathecal Administration ◽  
Thermal Stimulus ◽  
Thermal Nociception ◽  
Nociceptive Transmission ◽  
Withdrawal Threshold ◽  
Intrathecal Clonidine

Background Intrathecal clonidine reduces tactile allodynia in animal models of neuropathic pain, and this effect is blocked by atropine. However, the role of tonic spinal cholinergic activity and its interaction with alpha2-adrenergic systems in normal and neuropathic conditions and to different sensory methods has not been systematically examined. The authors examined cholinergic receptor involvement in thermal and mechanical sensitivity in normal and neuropathic animals and its interaction with intrathecal clonidine. Methods Normal rats and rats that received L5/L6 spinal nerve ligation were tested with acute radiant heat, paw pressure, and punctate mechanical stimulation before and after the intrathecal administration of saline, the muscarinic receptor antagonist, atropine, or a toxin to destroy cholinergic neurons, and then after intrathecal clonidine. Results Atropine, the cholinergic neuronal toxin, and saline did not alter baseline withdrawal thresholds. In nerve-injured rats, neither saline nor atropine altered antinociception from clonidine to a thermal stimulus, but atropine reduced the effect of clonidine to von Frey filament withdrawal threshold (34 +/- 5.6 vs. 14 +/- 5.8 g [mean +/- SEM], saline vs. atropine; P < 0.05) and to withdrawal threshold to paw pressure after clonidine (174 +/- 18 g vs. 137 +/- 16 g, saline vs. atropine; P < 0.05). Conclusions These data suggest that after nerve injury, mechanical but not thermal antinociception from intrathecal clonidine relies on a muscarinic interaction, because only mechanical antinociception was antagonized by atropine. These results do not favor a regulation of nociceptive transmission by a tonic release of acetylcholine in nerve-injured rats.

Calcium-dependent current generating the afterhyperpolarization of hippocampal neurons

1986 ◽  
Vol 55 (6) ◽  
pp. 1268-1282 ◽  
Author(s):  
B. Lancaster ◽  
P. R. Adams
Keyword(s):  
Voltage Clamp ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Outward Current ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Tail Current ◽  
Calcium Dependent ◽  
K Current

A single-electrode voltage-clamp technique was employed on in vitro hippocampal slices to examine the membrane current responsible for the slow afterhyperpolarization (AHP) in CA1 pyramidal cells. This was achieved by using conventional procedures to evoke an AHP in current clamp, followed rapidly by a switch into voltage clamp (hybrid clamp). The AHP current showed a dependence on extracellular K+, which was close to that predicted for a K+ current by the Nernst equation. The AHP current could be blocked by Cd2+ or norepinephrine. Although the AHP current showed a requirement for voltage-dependent Ca2+ entry, the current did not show any clear intrinsic voltage dependence. Once activated, AHP current is not turned off by hyperpolarizing the membrane potential. The effects of norepinephrine, Cd2+, and tetraethylammonium (TEA) were used to identify an AHP current component to the outward current evoked by depolarizing voltage commands from holding potentials that approximate to the resting potential for these cells. The AHP current can contribute significantly to the outward current during the depolarizing command. Upon repolarization it is evident as a slow outward tail current. This slow tail current had the same time constant as AHP currents evoked by hybrid clamp. Fast components to the tail currents were also observed. These were sensitive to Cd2+ and TEA. They probably represent a voltage-sensitive gKCa, sometimes termed C-current. The strong sensitivity to voltage and TEA displayed by the conventionally described gKCa (IC) are properties inconsistent with the AHP. It seems likely that the AHP current (IAHP) represents a Ca2+-activated K+ current separate from IC and that these two currents coexist in the same cell.

Characterization of an early afterhyperpolarization after a brief train of action potentials in rat hippocampal neurons in vitro

1990 ◽  
Vol 63 (1) ◽  
pp. 72-81 ◽  
Author(s):  
A. Williamson ◽  
B. E. Alger
Keyword(s):  
Action Potentials ◽  
Hippocampal Neurons ◽  
Pyramidal Cells ◽  
Chloride Ions ◽  
Membrane Potentials ◽  
Resting Potential ◽  
K Channel ◽  
Delayed Rectifier ◽  
Extracellular Potassium

1. In rat hippocampal pyramidal cells in vitro, a brief train of action potentials elicited by direct depolarizing current pulses injected through an intracellular recording electrode is followed by a medium-duration afterhyperpolarization (mAHP) and a longer, slow AHP. We studied the mAHP with the use of current-clamp techniques in the presence of dibutyryl cyclic adenosine 3',5'-monophosphate (cAMP) to block the slow AHP and isolate the mAHP. 2. The mAHP evoked at hyperpolarized membrane potentials was complicated by a potential generated by the anomalous rectifier current, IQ. The mAHP is insensitive to chloride ions (Cl-), whereas it is sensitive to the extracellular potassium concentration ([K+]o). 3. At slightly depolarized levels, the mAHP is partially Ca2+ dependent, being enhanced by increased [Ca2+]o and BAY K 8644 and depressed by decreased [Ca2+]o, nifedipine, and Cd2+. The Ca2(+)-dependent component of the mAHP was also reduced by 100 microM tetraethylammonium (TEA) and charybdotoxin (CTX), suggesting it is mediated by the voltage- and Ca2(+)-dependent K+ current, IC. 4. Most of the Ca2(+)-independent mAHP was blocked by carbachol, implying that IM plays a major role. In a few cells, a small Ca2(+)- and carbachol-insensitive mAHP component was detectable, and this component was blocked by 10 mM TEA, suggesting it was mediated by the delayed rectifier current, IK. The K+ channel antagonist 4-aminopyridine (4-AP, 500 microM) did not reduce the mAHP. 5. We infer that the mAHP is a complex potential due either to IQ or to the combined effects of IM and IC. The contributions of each current depend on the recording conditions, with IC playing a role when the cells are activated from depolarized potentials and IM dominating at the usual resting potential. IQ is principally responsible for the mAHP recorded at hyperpolarized membrane potentials.

Reexamination of the effects of MCPG on hippocampal LTP, LTD, and depotentiation

1995 ◽  
Vol 74 (3) ◽  
pp. 1075-1082 ◽  
Author(s):  
D. K. Selig ◽  
H. K. Lee ◽  
M. F. Bear ◽  
R. C. Malenka
Keyword(s):  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Low Frequency ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Frequency Stimulation

1. We examined the effects of the metabotropic glutamate receptor (mGluR) antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) on the induction of long-term potentiation (LTP) long-term depression (LTD), and depotentiation in CA1 hippocampal neurons using extracellular recording techniques. 2. MCPG (500 microM) strongly antagonized the presynaptic inhibitory action of the mGluR agonist 1-aminocyclopentane-(1S,3R)-dicarboxylic acid yet failed to block LTP induced with either tetanic stimulation (100 Hz, 1 s) or theta-burst stimulation. 3. To test the possibility that our failure to block LTP was due to prior activation of a "molecular switch" that in its "on" state obviates the need for mGluR activation to generate LTP, we gave repeated periods of prolonged low-frequency stimulation (LFS; 1 Hz, 10 min), a manipulation reported to turn the switch "off." Although this stimulation saturated LTD, subsequent application of MCPG still failed to block LTP. 4. MCPG did not block LFS-induced depotentiation in older slices (4-6 wk) or LFS-induced LTD in older, young (11-18 days), or neonatal (3-7 days) slices. 5. These results demonstrate that MCPG-sensitive mGluRs are not necessary for the induction of LTP, LTD, or depotentiation in hippocampal CA1 pyramidal cells. The possibility remains, however, that their activation may modify the threshold for the induction of these long-term plastic changes.

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