Effect of electroacupuncture on the nature of changes in the activity of neurons in the 2d somatosensory region of the cerebral cortex

Effects of electroacupuncture (EAP) on the character of spontaneous and evoked neuronal impulse activity changes in the second somatosensory area (S2) of the brain cortex by nociceptive and non-nociceptive stimulation were studied in acute experiments on cats. It was demonstrated that EAP changed the character of S2 neurons activity and formed their new functional state. After EAP activity of non-nociceptive neurons were not changed, evoked activity of nociceptive neurons were inhibited. It is suggested, that EAP preferential blocking the protopathic components of the acute pain.     

Changes in the bioelectric activity in the orbitofrontal and somatosensory areas of the cerebral cortex caused by electroacupuncture

Effects of electroacupuncture (EAP) and intravenous injection of morphine (5 mg/kg) on evoked potentials (EP) elicited in the second somatosensory (S2) and orbitofrontal areas of the brain cortex by nociceptive (the pulp of the upper canine) and non-nociceptive (the upper lip) stimulation were studied in acute experiments on cats. After EAP the EP elicited by nociceptive stimulation of the S2 and orbital gyrus were inhibited 75 and 58%, respectively, with reference to the control level, whereas the EP elicited by non-nociceptive stimulation of the S2 and orbital gyrus rose by 30 and 45%, respectively. Morphine injection produced the same effect on the EP: an increase in the EP during non-nociceptive stimulation and inhibition during nociceptive stimulation. It is suggested that by stimulating the release of endogenous opiates and other neurotransmitters EAP remodels the function of the CNS afferent systems, facilitating the transmission of the non-nociceptive signal through the rapid-conducting lemniscal system, thereby blocking the transmission of the nociceptive signals in the multi-synaptic extralemniscal system.     

Functional architectonics of neuronal antinociceptive mechanisms during the electroacupuncture method of reflex action

The peculiarities of neurone bioelectric activity of sensory thalamic nuclei under electroacupuncture (EAP) stimulation have been studied in acute experiments on cats. EAP stimulation has been established to change spontaneous and evoked activity of neurones of sensory thalamic nuclei, that testifies to the development of a new functional state. The functional state of the cortex, in particular the second somatosensory region has been shown to determine the nature of neurone activation of sensory thalamic nuclei during the EAP stimulation. Schemes of possible organization of functional pools realizing the mechanisms of inhibition of nociceptive signals on central neurones during EAP way of reflex stimulation are suggested.     

The effect of electroacupuncture on the neuronal responses of the oral trigeminal nucleus in the cat during nociceptive and non-nociceptive stimulation

Effects of electroacupuncture (EAP) on the responses of different functional types of neurons of the oral trigeminal nucleus (OTN) by nociceptive and non-nociceptive stimulation were studied in acute experiments on adult cats. It was demonstrated that the main part of neurons of the OTN is a wide dynamic range of neurons. Characteristic feature of the OTN is neurons with low-threshold pulp afferent input. EAP inhibit nociceptive responses of neurons (preferentially nonspecific neurons), while responses to non-nociceptive stimulation are not changed at all. The results are discussed from the point of view that OTN takes part in nociceptive and non-nociceptive reactions.     

Changes in the neuronal reactions of the substantia nigra to nociceptive stimuli during electroacupuncture

The nature of responses of neurones in substance nigra reticular (SNR) part of cats to nociceptive electrical stimulations and change of these responses under the action of electroacupuncture (EA) in the area corresponding to the Tsui-Sang-Li point in man have been studied. The most of the neurons studied (72.1%) responded to nociceptive stimulation either with excitation of inhibition of the impulsive activity. The EA eliminated or changed the effect of nociceptive stimulation in 73.2% of the SNR nociceptive responsive neurones. Intravenous naloxone administration blocked the effect of EA depending on a dose. A conclusion has been made that the SNR neurones are involved in the modulation of nociceptive transmission and that the EA action is directed to some restoration of the nociceptive disturbed balance between the excitatory and inhibitory processes in the SNR neuronal population.     

Changes in somatosensory evoked potentials in patients with vertebrogenic pain syndromes treated by electroacupuncture

Application of electroacupuncture (EAP) of the segmental points to patients with vertebrogenic algesic syndromes decreased amplitude of N150 and P240 waves recorded from vertex to painful electrocutaneous stimulation in the region innervated by an affected root. As distinct from EAP of segmental point auricular EAP not only decreased the amplitude of late components of evoked potentials (EP), but also increased it, direction of EP changes depending on the character of sensitivity disorders. It is suggested that effect of EAP-evoked EP changes in patients with hypalgesia is determined by two oppositively acting factors: by a decrease of nociceptive afferent impulsation intensity as a result of the antinociceptive system activation and by an increase of the afferent impulsation intensity due to recovery of function of central terminals in primary sensory neurons.     

Synapse Density and Dendritic Complexity Are Reduced in the Prefrontal Cortex following Seven Days of Forced Abstinence from Cocaine Self-Administration

Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.     

Gene expression of synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex of the spontaneously hypertensive rat (SHR)

Dopamine is believed to play an important role in the etiology of attention-deficit/hyperactivity disorder (ADHD). In our previous study, we showed that gene expression of dopamine D4 receptor decreased in the spontaneously hypertensive rat (SHR) in the prefrontal cortex (PFC). In the present study, we explored the potential causes of dysfunction in the dopamine system in ADHD. It is the first time that neuronal activities in both juvenile SHR and WKY rats have been measured by functional MRI (fMRI). Our results showed that in PFC the Blood Oxygenation Level Dependent (BOLD) signal response in SHR was much higher than WKY under stressful situations. We tested the effects of acute and repeated administration of amphetamine on behavioral changes in SHR combined with the expression of the neuronal activity marker, c-fos, in the PFC. Meanwhile dopamine-related gene expression was measured in the PFC after repeated administration of amphetamine. We found that potential neuronal damage occurred through deficit of D2-like receptor protective functions in the PFC of the SHR. We also measured the expression of synaptosomal-associated protein 25 (SNAP-25) in SHR in PFC. The results showed decreased expression of SNAP-25 mRNA in the PFC of SHR; this defect disappeared after repeated injection of D-AMP.     

Effects of 5-HT3 receptor blockade on visceral nociceptive neurons in the ventrolateral reticular field of the rat medulla oblongata

The caudal ventrolateral reticular formation of the medulla oblongata is the first layer of visceral nociceptive processing. In experiments on rats, neuronal responses in this zone to nociceptive stimulation of the large intestine were examined and the effects of selective blockade of 5-HT3 receptors on these responses were assessed. By the character of responses to nociceptive colorectal stimulation (CRS), the recorded medullary neurons were divided into three groups—excited, inhibited and indifferent. Intravenous injection of 5-HT3 antagonist granisetron (1 and 2 mg/kg) as well as local application of this agent on the surface of the medulla oblongata (1.25 and 2.5 nmole) suppressed the background and evoked firing of CRS-excited reticular neurons in a dose-dependent manner but did not exert as pronounced influence on the cells inhibited by visceral nociceptive stimulation. Spike activity in the group of CRS-indifferent neurons under similar conditions was 5-HT3-independent. The results obtained provide evidence that 5-HT3 receptors mediate the facilitating effect of serotonin on supraspinal transmission of the abdominal nociceptive stimulus which, at least in part, is realized via selective activation of visceral medullary nociceptive neurons. A shutdown of this mechanism may underlie the analgesic effect of 5-HT3 antagonists in abdominal pain syndromes.     

Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex

Nicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABA(A) receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP.     

Activity in the lateral prefrontal cortex reflects multiple steps of future events in action plans

To achieve a behavioral goal in a complex environment, we must plan multiple steps of motor behavior. On planning a series of actions, we anticipate future events that will occur as a result of each action and mentally organize the temporal sequence of events. To investigate the involvement of the lateral prefrontal cortex (PFC) in such multistep planning, we examined neuronal activity in the PFC of monkeys performing a maze task that required the planning of stepwise cursor movements to reach a goal. During the preparatory period, PFC neurons reflected each of all forthcoming cursor movements, rather than arm movements. In contrast, in the primary motor cortex, most neuronal activity reflected arm movements but little of cursor movements during the preparatory period, as well as during movement execution. Our data suggest that the PFC is involved primarily in planning multiple future events that occur as a consequence of behavioral actions.     

Morphine: Ability to block neuronal activity evoked by a nociceptive stimulus

The effect of morphine on the neuronal activity evoked by a nociceptive stimulus, a foot pinch, was studied in the dorsal raphe nucleus (DR) and in the mesencephalic reticular formation (MRF) of the rat. In the MRF and adjacent areas, neuronal firing was accelerated by the nociceptive stimulus. Morphine blocked this acceleration when administered either microintophoretically or i.v. Three lines of evidence indicate that this is a specific narcotic effect. First, naloxone, a specific narcotic antagonist, antagonized the effect of morphine. Secondly, two morphine agonists, oxymorphone and methadone, blocked the evoked neuronal acceleration like morphine when administered either microiontophoretically or i.v.; naloxone also blocked the effects of the two agonists. Finally, two non-opioid CNS depressants did not block the acceleration in neuronal firing even though microintophoretic ejection currents 2–5 times greater than those for morphine were used. In contrast, neuronal firing in the DR was rarely altered by the nociceptive stimulus or by morphine, administered either microiontophoretically or i.v. Furthermore, morphine did not affect the inhibition produced by 5-HT on neurons in the DR.It is concluded from this study that the MRF is a possible site of action for the antinociceptive effects of morphine. It is also concluded that morphine does not affect the spontaneous neuronal firing rate in the DR and that the DR is not a site of action of the antinociceptive effects of morphine when a foot pinch is used as the nociceptive stimulus.     

Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Neuronal recordings in the medial prefrontal cortex of the rat demonstrate that auditory mismatch responses are purely composed of prediction error signaling activity, independent from the spectral effects that drive the auditory system.     

Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine

Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC), a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking) interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT₂ receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT₁ receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity.     

Potential Protection of Curcumin against Hypoxia-induced Decreases in Beta-III Tubulin Content in Rat Prefrontal Cortical Neurons

The central nervous system (CNS) is highly dependent on adequate supply of oxygen and is sensitive to hypoxia. It is known that hypoxia induces injuries on the brain tissue and the neuronal activity. Curcumin, a yellow pigment obtained from the rhizome of C. longa Linn., has been regarded as a multi-functional drug with antioxidative activity. In the present study, we first demonstrated a significant decrease in the content of β-III tubulin protein in rat prefrontal cortex (PFC) tissues induced by repeated hypoxia, but not in rat cerebellum tissue. These suggest a relatively higher sensitivity and probably a higher vulnerability of rat PFC tissue to hypoxia in vivo. We reconfirmed the effect of hypoxia to primary cultured neurons from rat PFC and found a significant decrease in the contents of β-III tubulin protein after chronic exposure to hypoxia. Moreover, we demonstrated that the hypoxia-induced decrease in β-III tubulin protein content could be restored by curcumin, suggesting a potential protection of curcumin against hypoxia-induced decreases in beta-III tubulin content in rat PFC neurons. Special issue article in honor of Dr. Ji-Sheng Han.     

Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT(2A) and alpha(1)-adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT(2A) receptor antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT(2A) and/or alpha(1)-adrenoceptors.     

Regulating Prefrontal Cortex Activation: An Emerging Role for the 5-HT2A Serotonin Receptor in the Modulation of Emotion-Based Actions?

The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)_2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT_2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.     

Effects of clopheline on impulse activity of neurons in the midbrain and dorsal horn of the spinal cord

Clophelin (1-5 mg/kg) suppresses spinal dorsal horn neuronal nociceptive responses but does not change their touch stimuli reactions in unanesthetized curarized cats. This effect is steady to naloxone (1 mg/kg), yohimbine (5 mg/kg) and removal by prazosin (1 mg/kg). Clophelin depresses nociceptive responses of the central gray matter neurones which generalized pain impulses in the supraspinal structures.     

Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting Ca2+/calmodulin-dependent kinase II in prefrontal cortical pyramidal neurons

We have studied the regulation of AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor channels by serotonin signaling in pyramidal neurons of prefrontal cortex (PFC). Application of serotonin reduced the amplitude of AMPA-evoked currents, an effect mimicked by 5-HT(1A) receptor agonists and blocked by 5-HT(1A) antagonists, indicating the mediation by 5-HT(1A) receptors. The serotonergic modulation of AMPA receptor currents was blocked by protein kinase A (PKA) activators and occluded by PKA inhibitors. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of serotonin on AMPA currents. Furthermore, the serotonergic modulation of AMPA currents was occluded by application of the Ca(2+)/calmodulin-dependent kinase II (CaMKII) inhibitors and blocked by intracellular injection of calmodulin or recombinant CaMKII. Application of serotonin or 5-HT(1A) agonists to PFC slices reduced CaMKII activity and the phosphorylation of AMPA receptor subunit GluR1 at the CaMKII site in a PP1-dependent manner. We concluded that serotonin, by activating 5-HT(1A) receptors, suppress glutamatergic signaling through the inhibition of CaMKII, which is achieved by the inhibition of PKA and ensuing activation of PP1. This modulation demonstrates the critical role of CaMKII in serotonergic regulation of PFC neuronal activity, which may explain the neuropsychiatric behavioral phenotypes seen in CaMKII knockout mice.     

The effect of non-competitive NMDA receptor antagonist MK-801 on neuronal activity in rodent prefrontal cortex: an animal model for cognitive symptoms of schizophrenia

Schizophrenia affects about 1% of the world population and is a major socio-economical problem in ours societies. Cognitive symptoms are particularly resistant to current treatments and are believed to be closely related to an altered function of prefrontal cortex (PFC). Particularly, abnormalities in the plasticity processes in the PFC are a candidate mechanism underlying cognitive symptoms, and the recent evidences in patients are in line with this hypothesis. Animal pharmacological models of cognitive symptoms, notably with non-competitive NMDA receptor antagonists such as MK-801, are commonly used to investigate the underlying cellular and molecular mechanisms of schizophrenia. However, it is still unknown whether in these animal models, impairments in plasticity of PFC neurons are present. In this article, we briefly summarize the current knowledge on the effect of non-competitive NMDA receptor antagonist MK-801 on medial PFC (mPFC) neuronal activity and then introduce a form of plasticity found after acute exposure to MK-801, which was accompanied by cognitive deficits. These observations suggest a potential correlation between cognitive deficits and the aberrant plasticity in the mPFC in the animal model of schizophrenia.