Stimulation Of Insular Cortex Research Articles

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity

In recent studies, brain stimulation has shown promising potential to alleviate chronic pain. Although studies have shown that stimulation of pain-related brain regions can induce pain-relieving effects, few studies have elucidated the mechanisms of brain stimulation in the insular cortex (IC). The present study was conducted to explore the changes in characteristic molecules involved in pain modulation mechanisms and to identify the changes in synaptic plasticity after IC stimulation (ICS). Following ICS, pain-relieving behaviors and changes in proteomics were explored. Neuronal activity in the IC after ICS was observed by optical imaging. Western blotting was used to validate the proteomics data and identify the changes in the expression of glutamatergic receptors associated with synaptic plasticity. Experimental results showed that ICS effectively relieved mechanical allodynia, and proteomics identified specific changes in collapsin response mediator protein 2 (CRMP2). Neuronal activity in the neuropathic rats was significantly decreased after ICS. Neuropathic rats showed increased expression levels of phosphorylated CRMP2, alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), and N-methyl-d-aspartate receptor (NMDAR) subunit 2B (NR2B), which were inhibited by ICS. These results indicate that ICS regulates the synaptic plasticity of ICS through pCRMP2, together with AMPAR and NR2B, to induce pain relief.

Front cover

CNS Neuroscience & TherapeuticsVolume 29, Issue 6 p. i-i COVER IMAGEOpen Access Front cover First published: 11 May 2023 https://doi.org/10.1111/cns.14262AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract The cover image is based on the Original Article Insular cortex stimulation alleviates neuropathic pain via ERK phosphorylation in neurons by Kyeongmin Kim et al., https://doi.org/10.1111/cns.14126. Volume29, Issue6June 2023Pages i-i RelatedInformation

Insular cortex stimulation alleviates neuropathic pain via ERK phosphorylation in neurons.

The clinical use of brain stimulation is attractive for patients who have side effects or tolerance. However, studies on insular cortex (IC) stimulation are lacking in neuropathic pain. The present study aimed to investigate the effects of IC stimulation (ICS) on neuropathic pain and to determine how ICS modulates pain. Changes in pain behaviors were observed following ICS with various parameters in neuropathic rats. Western blotting was performed to assess molecular changes in the expression levels of phosphorylated extracellular signal-regulated kinase (pERK), neurons, astrocytes, and microglia between experimental groups. Immunohistochemistry was performed to investigate the colocalization of pERK with different cell types. The most effective pain-relieving effect was induced at 50 Hz-120 μA in single trial of ICS and it maintained 4 days longer after the termination of repetitive ICS. The expression levels of pERK, astrocytes, and microglia were increased in neuropathic rats. However, after ICS, the expression levels of pERK were decreased, and colocalization of pERK and neurons was reduced in layers 2-3 of the IC. These results indicated that ICS attenuated neuropathic pain by the regulation of pERK in neurons located in layers 2-3 of the IC. This preclinical study may enhance the potential use of ICS and identify the therapeutic mechanisms of ICS in neuropathic pain.

Dexamethasone attenuates the modulatory effect of the insular cortex on the baroreflex in anesthetized rat.

The arterial baroreflex (BR) is an important neural mechanism for the stabilization of arterial pressure (AP). It is known that the insular cortex (IC) and other parts of the central autonomic network (CAN) are able to modulate the BR arc, altering baroreflex sensitivity (BRS). In addition, the sensitivity of the BR changes under the influence of hormones, in particular glucocorticoids (GCs). It has been suggested that GCs may influence BRS by altering the ability of the IC to modulate the BR. This hypothesis has been tested in experiments on rats anesthetized with urethane. It was found that microelectrostimulation of the visceral area in the left IC causes a short-term drop in AP, which is accompanied by bradycardia and impairs BRS. The synthetic GC dexamethasone (DEX) did not significantly affect the magnitude of depressor responses but increased BRS and impaired the effect of IC stimulation on the BR. The results obtained confirm the hypothesis put forward and suggest that GC can attenuate the inhibitory effects of the IC on the BR arc, thereby enhancing the sensitivity of the BR.

Changes in autonomic nervous function and influencing factors in a rat insular cortex electrical kindling model

In mammals, the insular cortex plays an important role in autonomic regulation. In patients with insular epilepsy, seizures are always accompanied by autonomic changes. Accordingly, we aimed to establish an electrical kindling model in autonomic-mediating areas of the insular cortex, and to conduct a long-term observation of epileptic genesis in these animals until sudden unexpected death. To establish this model in adult rats, we implanted stimulation electrodes in the granular cell layer of the insular cortex, which controls the heart rate (HR) and respiratory rate (RR). Subsequently, seizure was induced successfully in 92.3 % of the rats, and typical autonomic changes were observed during these seizures. Interestingly, the model was established more easily in older rats, and the rats in which electrical stimulation led to a greater reduction in the HR. Moreover, death occurred in 25 % of the kindled rats. In conclusion, our kindling model demonstrates the ability of insular cortex stimulation to generate epilepsy. Our model thus offers a practical tool for studies of the role of the insular cortex in sudden unexpected death in epilepsy.

Effects of habenular stimulation frequencies on obstructive sleep apnea induced by stimulation of insular cortex

Effects of habenular stimulation frequencies on obstructive sleep apnea induced by stimulation of insular cortex

Anterior insular cortex stimulation and its effects on emotion recognition.

With the objective to investigate the role of the insula in recognizing emotion, we performed direct electrical stimulation over the anterior insular cortex during awake surgery while simultaneously delivering an emotional sensitivity task. We registered 18 consecutive patients with brain tumors associated with the insular lobe, who were undergoing tumor resection. An emotional sensitivity task was employed to measure the patients' ability to recognize emotions from facial expressions before, during, and after awake surgery. Furthermore, we performed voxel-based lesion symptom mapping (VLSM) to identify the association between relevant brain lesions and emotion recognition. When we performed direct electrical stimulation over the anterior insular cortex during awake surgery, the results showed that the ability to recognize anger was significantly enhanced with the presence of anterior insular stimulation (p < 0.05). Comparing the performance in the emotional sensitivity task before and after surgery, the performance in the anger condition became worse (p < 0.01), but became better in the sadness condition after surgery (p < 0.01). In the case of anger recognition, lower scores in the correct response index were associated with lesions involving the left insula in the VLSM study. Direct electrical stimulation over the anterior insular cortex enhanced anger recognition in patients with insular tumors. In contrast, accuracy of anger recognition was significantly reduced, and sadness was improved, when the performance of emotional sensitivity was compared pre- and post-surgery. Our findings suggest that the insular cortex is involved in changes in emotion recognition, including anger and sadness recognition by modulating arousal level that is closely connected with interoception.

Extracellular glucose-dependent IPSC enhancement by leptin in fast-spiking to pyramidal neuron connections via JAK2-PI3K pathway in the rat insular cortex

Leptin is produced in the adipocytes and plays a pivotal role in regulation of energy balance by controlling appetite and metabolism. Leptin receptors are widely distributed in the brain, especially in the hypothalamus, hippocampus, and neocortex. The insular cortex (IC) processes gustatory and visceral information, which functionally correlate to feeding behavior. However, it is still an open issue whether and how leptin modulates IC neural activities. Our paired whole-cell patch-clamp recordings using IC slice preparations demonstrated that unitary inhibitory postsynaptic currents (uIPSCs) but not uEPSCs were potentiated by leptin in the connections between pyramidal (PNs) and fast-spiking neurons (FSNs). The leptin-induced increase in uIPSC amplitude was accompanied by a decrease in paired-pulse ratio. Under application of inhibitors of JAK2-PI3K but not MAPK pathway, leptin did not change uIPSC amplitude. Variance-mean analysis revealed that leptin increased the release probability but not the quantal size and the number of release site. These electrophysiological findings suggest that the leptin-induced uIPSC increase is mediated by activation of JAK2-PI3K pathway in presynaptic FSNs. An in vivo optical imaging revealed that leptin application decreased excitatory propagation in IC induced by electrical stimulation of IC. These leptin-induced effects were not observed under the low energy states: low glucose concentration (2.5 mM) in vitro and one-day-fasting condition in vivo. However, leptin enhanced uIPSCs under application of low glucose with an AMPK inhibitor. These results suggest that leptin suppresses IC excitation by facilitating GABA release in FSN→PN connections, which may not occur under a hunger state.

Anterior insular cortex stimulation and its effects on emotion recognition

Anterior insular cortex stimulation and its effects on emotion recognition

Effects of Habenular Stimulation Frequencies on Obstructive Sleep Apnea Induced by Stimulation of Insular Cortex.

Objective To investigate the effects of high-frequency stimulation of the habenula (Hb) on obstructive sleep apnea (OSA) induced by stimulation of the insular cortex Method. After OSA was induced by stimulating the insular cortex (Ic) with concentric stimulating electrodes at 100 Hz in rats, the Hb was stimulated at different frequencies (50 Hz, 120 Hz, 130 Hz, and 280 Hz). The changes of apnea events and electromyography (EMG) of the genioglossus were compared before and after stimulation of the Hb. Results With stimulation of the Ic at 100 Hz, apnea events were successfully induced with disappearance of EMG of the genioglossus. After stimulation of the Hb at 130 Hz, apnea events disappeared with significantly increased genioglossal EMG. However, such a change failed to be found at the stimulation frequencies of 50 Hz, 120 Hz, and 280 Hz. Conclusion Stimulation of the Hb at the frequency of 130 Hz could effectively inhibit OSA events induced by stimulation of the Ic.

Effects of habenular stimulation frequencies on obstructive sleep apnea induced by stimulation of insular cortex in rat

Effects of habenular stimulation frequencies on obstructive sleep apnea induced by stimulation of insular cortex in rat

Tolerance to repeated rewarding electrical stimulation of the insular cortex

The insular cortex (IC) has been related to various reinforcing behavioral processes. This study examined the effect of electrical stimulation of the posterior agranular IC on concurrent place preferences. Two groups of animals and their respective controls underwent rewarding brain stimulation every day or on alternate days. While the rats stimulated every other day maintained their preference for the place associated with brain stimulation, those stimulated every day evidenced a reduction in their place preference, suggesting tolerance to the stimulation׳s rewarding effect. A 15% increase in the current intensity produced a recovery of the preferences of the daily-stimulated rats but had no effect on those stimulated on alternate days. These results are discussed in terms of the rewarding effects induced by different electrical and chemical rewarding agents.

Prolonged QTc interval and insula in patients with ischemic stroke: Inductive or abductive reasoning?

While a great emphasis has been placed on pathophysiological mechanisms underlying the long QT syndromes (LQTS), both congenital and acquired forms, little attention has been focused on the mechanisms whereby a brain damage could induce changes in the QTc interval. Until now, there has been no precise explanation for the frequently observed relationship between acute cerebrovascular events and QTc interval prolongation. Many excellent studies with inductive reasoning proposed QTc effects of insular cortex stimulation [1,2] Few and controversial studies with abductive reasoning investigated an association between prolonged QTc and ischemic insular damage.

Age-dependent emergence of caffeine-assisted voltage oscillations in the endopiriform nucleus of rats

The gustatory insular cortex (IC) is connected with not only the somatosensory cortex, but also the endopiriform nucleus (EPN). We have previously revealed that low-frequency electrical stimulation to the IC can elicit membrane potential oscillations at a frequency of 8–10Hz in the somatosensory cortex of rat brain slices under bath-application of caffeine. Using the same procedure, we investigated whether the EPN has the ability to generate oscillations, and whether such oscillations emerge age-dependently. Electrical stimulations were delivered to the IC, and field potentials were recorded from the EPN. In the case of slices made from mature rats, stable field potential oscillations at 8–10Hz were induced in the EPN after repetitive stimulations. Optical recordings revealed that signals traveled from the IC to the EPN by way of the claustrum. Generation of oscillations was N-methyl-d-aspartate (NMDA) receptor activity-dependent, since oscillatory phases disappeared following application of NMDA receptor antagonist. In slices from immature rats, however, oscillations were not induced. IC stimulation can thus age-dependently elicit membrane potential oscillations in the EPN, and the EPN oscillations were NMDA receptor activity-dependent. These findings suggest that developmental changes in properties of the EPN might contribute to development of information integration, including gustatory information.

Anatomical and electrophysiological mechanisms for asymmetrical excitatory propagation in the rat insular cortex: In vivo optical imaging and whole-cell patch-clamp studies

The insular cortex (IC) integrates limbic information from the amygdala and hypothalamic nucleus to multimodal sensory inputs, including visceral, gustatory, and somatosensory information. However, the functional framework of excitation in the IC is still unknown. We performed optical imaging and single pyramidal neuronal staining using a whole-cell patch-clamp technique in urethane-anesthetized rats to elucidate the precise anatomical and physiological features of IC pyramidal neurons, which regulate cortical information processing via their horizontal connections. Optical imaging revealed that electrical stimulation of the granular (GI) or dysgranular (DI) IC elicited characteristic excitatory propagations along the rostrocaudal axis parallel to the rhinal fissure, with a preference toward the rostral direction. Spatial patterns of the dendrites and axons of layer II/III pyramidal cells in the DI/GI support these functional features of excitation; for example, rostrocaudal axonal arbors tend to extend with a rostral directional preference. The mean length of the axons from the soma to the farthest site rostrally was ∼50% longer than that of the caudal length. Pyramidal cells in the DI/GI exhibited spontaneous membrane oscillation in the UP and DOWN states. Similarly to the evoked signals obtained by optical imaging, repetitive electrical stimulation of the caudal IC ∼1 mm away from the recorded cells (five pulses at 50 Hz) induced the summation of evoked excitatory postsynaptic potentials during the DOWN state and profound inhibitory postsynaptic potentials during the UP state. Clarification of the excitation feature with its cellular basis provides new clues about the functional mechanisms of the asymmetric propagation of neural activities in the IC.

Conditioned place preference induced by electrical stimulation of the insular cortex: effects of naloxone

The insular cortex has been related to various sensory, regulatory, and learning processes, which frequently include affective-emotional components. The objective of this study was to investigate the possibility of inducing reinforcing effects by electrical stimulation of this cortical region in Wistar rats. Concurrent conditioned place preference tasks were conducted for this purpose, using two rectangular mazes that differed in dimensions, texture, and spatial orientation. A significant correlation was found in the preferences induced by insular cortex electrical stimulation between the two mazes. Animals showed consistent preference or avoidance behaviors associated with simultaneous insular cortex stimulation. No electrical self-stimulation was achieved. In a second experiment, animals that showed consistent place preference after the simultaneous insular cortex electrical stimulation were administered with 4 mg/ml/kg of naloxone. The results revealed that this opiate antagonist blocked concurrent place preference learning when the task was conducted in a new maze but not when it was conducted in the same maze as that in which the animals had learned the task. These results are discussed in terms of the participation of the insular cortex in various reward and aversion modalities.

Stroke-Induced Sudden-Autonomic Death

HomeStrokeVol. 39, No. 9Stroke-Induced Sudden-Autonomic Death Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBStroke-Induced Sudden-Autonomic DeathAreas of Fatality Beyond the Insula Max J. Hilz, MD, PhD and Stefan Schwab, MD, PhD Max J. HilzMax J. Hilz From the Department of Neurology (M.J.H., S.S.), University Erlangen-Nuremberg, Erlangen, Germany; and the Departments of Neurology, Medicine, Psychiatry (M.J.H.), New York University, New York, NY, USA. Search for more papers by this author and Stefan SchwabStefan Schwab From the Department of Neurology (M.J.H., S.S.), University Erlangen-Nuremberg, Erlangen, Germany; and the Departments of Neurology, Medicine, Psychiatry (M.J.H.), New York University, New York, NY, USA. Search for more papers by this author Originally published17 Jul 2008https://doi.org/10.1161/STROKEAHA.108.518613Stroke. 2008;39:2421–2422Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 17, 2008: Previous Version 1 See related article, pages 2425–2431.Stroke is the third leading cause of death.1,2 Fatal outcome has been primarily related to acute or chronic complications of stroke-induced executive deficits, such as muscle weakness, swallowing disorders, respiratory dysfunction with pneumonia, or cardiac complications.3,4Only during the last 10 or 15 years has there been an increasing interest in and knowledge of associations between cerebral lesions and altered influences of the central autonomic nervous system on cardiovascular and respiratory function.5–7 Oppenheimer et al8–10 suggested a role of the insular cortex in the pathophysiology of sudden death. The group extensively assessed topographically distinct interactions of the left and the right insular cortex with heart rate and blood pressure control.11 There was agreement that insular cortex lesions essentially contribute to clinically relevant alterations of cardiovascular control.8In this issue of Stroke, Rincon and coworkers present an analysis of associations between ischemic stroke location and fatal cardiac outcome, based on the epidemiological data of the Northern Manhattan Stroke study (NOMAS).12,13 Considering neurological syndromes and neuroimaging findings, the authors analyzed outcome during a 5-year follow-up period. Mortality rates or nonfatal myocardial infarctions, and particularly sudden unexpected or unwitnessed death, were associated with the location of brain infarctions. Apart from age, male gender, the National Institutes of Health Stroke Scale (NIHSS), and a history of coronary artery disease, the authors identified infarct locations in the frontal, parietal, temporal lobe, and the insula as predictors of cardiac death as well as composite outcome of cardiac death or myocardial infarction.The frontal lobe, especially the ventromedial prefrontal cortex (VMPFC), has significant modulating effects on cardiovascular responses to emotional stimuli. Unilateral VMPFC lesions compromise responses to even mild emotional stimuli.14 Left VMPFC lesions result in dampened heart rate or blood pressure adjustment to visual emotional stimuli, whereas right-sided VMPFC lesions bear a risk of exaggerated cardiovascular responses with paradoxical heart rate and blood pressure increase.14 Similarly, lateralized effects on resting cardiovascular modulation have been observed after insular stroke.11,15–17Zamrini et al18 and Hilz et al19 observed a hemispheric dominance of sympathetic or parasympathetic activity in temporal lobe epilepsy patients who underwent hemispheric inactivation during the so-called WADA testing procedure before epilepsy surgery.19 In these patients, left-hemispheric inactivation increased sympathetic cardiovascular modulation whereas right-hemispheric inactivity furthered parasympathetic activity.19 After left- or right-hemispheric ischemic stroke, Klingelhoefer and Sander15 observed autonomic changes that were opposite to those in temporal lobe epilepsy patients with hemispheric inactivation but suggested right-sided dominance for sympathetic effects after hemispheric stroke. This discrepancy might be explained by a functional hypoactivity of lesioned autonomic centers after stroke while the same centers may be upregulated in temporal lobe epilepsy patients because of spreading discharges from epileptogenic foci.19 The net results would be diametrical changes in cardiovagal balance of heart rate of blood pressure.Tailored resection of anterior temporal lobe areas lowers sympathetic cardiovascular activation, which may be beneficial in seizure patients with presurgically increased risk of tachy-arrhythmias20 but might also explain a role of the temporal lobe in unexpected death after stroke. An ischemia-induced decrease in sympathetic temporal lobe contribution to autonomic balance is likely to result in a shift toward cardiovagal predominance which then facilitates bradycardia or even asystole.14,19Surprisingly, Rincon and coworkers could not confirm a dominant association of the insular cortex with increased mortality. Some of the discrepancy to findings by Oppenheimer and coworkers21 might be due to the fact that Oppenheimer deduced their conclusions from insular cortex stimulations in rodents, ie, from activation of brain areas that may be silent or dysfunctional after stroke. Thus, the hemispheric autonomic lateralization seen with stimulation might be reduced or inversed in stroke patients because of a predominance of autonomic activity from the nonischemic hemisphere. Of course, these considerations of autonomic balance are a rather mechanistic approach that cannot reflect the complex interactions of autonomic feed-forward and feed-back loops, still poorly understood circuitries and multiple influences from external, endocrine, neuronal, and peripheral input channels.22According to Rincon et al, infarctions involving the left parietal lobe seem to be associated with a particularly increased risk of cardiac events and a 4.45 hazard ratio of cardiac death. The authors found similarly high risk of death after right parietal lobe infarctions when infarct size was taken into account. Probably, the parietal lobe has buffering effects on the insular region which are disinhibited after loss of parietal activity. During acute stroke, discharges from the penumbra and deficient activity from ischemic neurons may add to an autonomic imbalance, whereas chronic stages are more likely dominated by deficient neuronal activity. Only invasive electroencephalographic recordings might reveal whether cardiovascular events such as myocardial infarction or death are related to paroxysmal cerebral hyperactivity or result from centrally mediated bradyarrhythmia.19,20 In pentylenetetrazol treated epileptic cats, Lathers et al demonstrated a “one-to-one” transmission of cerebral epiletogenic discharges onto the heart.23 Such bursts of activity might account for myocardial infractions as observed in the NOMAS study and described in many previous publications.24 Sympathetic overstimulation of the heart may cause increases in troponin I, diffuse myofibrillary necrosis, perivascular and interstitial fibrosis as well as myocyte vacuolization in the absence of ischemic heart disease.24–26However, it so far remains to be speculated whether lack of outflow toward centers of cardiovascular modulation or excessive activation of master controllers of cardiovascular modulation, such as the hypothalamus or amygdale, accounts for the high rate of fatalities in NOMAS after 4 years.Rincon et al made a remarkable observation that the “lethal” contribution of the parietal lobe is not apparent during the first 30 days after stroke, but only with long-term follow-up examination. Recently, the group of Teasdale and coworkers reported an excessively high rate of sudden death in patients who had experienced mild traumatic brain injury years ago.27 The authors report an up to 7-fold increased risk of death in patients who had experienced a mild traumatic brain injury for up to 7 years.27 Evidently, the autonomic control areas assuring cardiovascular stability and survival comprise a fragile system of cerebral regions with so far poorly understood physiology. The NOMAS study does not explain why the parietal lobe lesions are so critically involved in death. However, the study challenges stroke researchers to address not only the urgency of instantaneous stroke treatment but also to further explore the “heart-brain” or “brain-heart” interaction. The NOMAS data demonstrate that time is not only brain but also heart. Oppenheimer and coworkers described the insular cortex as an area associated with increased risk of sudden death.9 Perhaps, the parietal lobe contains areas that are essential for survival. Although acute rescue and recovery dominate the emergency treatment of stroke patients, the need for long-term cardiovascular restabilization and protection against sudden death has, so far, not been adequately recognized. Rincon et al are to be commended for their analysis because it underlines the urgency to identify stroke patients at risk of a “broken heart” during early stages of disease in order to identify pathophysiologic patterns and institute long-term protective treatment.The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Max J. Hilz, MD, PhD, Departments of Neurology, Medicine, and Psychiatry, New York University, 550 First Ave, NB 7W11, New York, NY 10016, USA. 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Brain. 2007; 130: 2520–2527.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Carrarini C, Di Stefano V, Russo M, Dono F, Di Pietro M, Furia N, Onofrj M, Bonanni L, Faustino M and De Angelis M (2022) ECG monitoring of post-stroke occurring arrhythmias: an observational study using 7-day Holter ECG, Scientific Reports, 10.1038/s41598-021-04285-6, 12:1, Online publication date: 1-Dec-2022. Jimenez-Ruiz A, Racosta J, Kimpinski K, Hilz M and Sposato L (2021) Cardiovascular autonomic dysfunction after stroke, Neurological Sciences, 10.1007/s10072-021-05128-y, 42:5, (1751-1758), Online publication date: 1-May-2021. 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Cyclic AMP-dependent attenuation of oscillatory-activity-induced intercortical strengthening of horizontal pathways between insular and parietal cortices

Cyclic AMP (cAMP) is a key intracellular second messenger, and the intracellular cAMP signaling pathway acts to modulate various brain functions. We have previously reported that low-frequency insular cortex stimulation in rat brain slices switches on a voltage oscillator in the parietal cortex that delivers signals horizontally back and forth under caffeine application. The oscillatory activities are N-methyl- d-aspartate (NMDA) receptor-dependent, and the role of oscillation is to strengthen functional intercortical connections. The present study investigated actions of the cAMP signaling pathway on caffeine-induced strengthening of intercortical connections and tried to confirm the role of oscillation on intercortical strengthening by focusing on the cAMP pathway. After induction of parietal oscillation by insular cortex stimulation in caffeine-containing medium, application of membrane-permeable cAMP analog, bromo-cAMP, diminished oscillatory signal delivery from the parietal cortex, but initial insulo-parietal signal propagation remained strong. When oscillatory activities were reduced with co-application of caffeine and bromo-cAMP from the beginning, initial insulo-parietal propagation was established, but amplitudes of propagating wavelets and propagating velocity were reduced. Thus, cAMP-dependent diminution of caffeine-induced NMDA-receptor-dependent oscillatory signal delivery causes attenuation of intercortical strengthening of horizontal pathways between insular and parietal cortices. This finding suggests that the intracellular cAMP signaling pathway has the ability to regulate extracellular communications at the network level, and also that full expression of strengthened intercortical signal communication requires sufficient NMDA-receptor-dependent oscillatory neural activities.

Age-dependent emergence of a parieto-insular corticocortical signal flow in developing rats

By using the procedure that we developed for inducing population oscillation, it was previously demonstrated that insular cortex stimulation can evoke insulo-parietal field potential propagation and synchronized population oscillation in the parietal cortex in slices obtained from mature rats (27–35 days old). By using the same procedure, we have now studied the reciprocal parieto-insular projection. Parietal cortex stimulation elicited synchronized population oscillation in the parietal—but not insular—cortex in mature tissues. In the insular cortex, the initial wavelet of the oscillation generated by parietal cortex stimulation propagated, but the entire oscillation did not. A prior induction—but not simultaneous occurrence—of oscillation in the parietal cortex sufficed to have this initial wavelet propagate. In immature tissue (9–10 days old), both the parietal cortex oscillation and the parieto-insular propagation were induced only with low [Mg 2+] o. This age dependence is exactly the same as we previously observed for the reciprocal insulo-parietal propagation. Given that the parietal cortex receives somatosensory inputs from the oral cavity and the insular cortex receives primarily chemosensory inputs from the same source, the age-dependent changes in the availability of bidirectional signal traffic between these cortices might contribute to the development of multimodal responsiveness of taste neurons.

Lateral hypothalamic area neurotransmission and neuromodulation of the specific cardiac effects of insular cortex stimulation

Microstimulation of the rat posterior insular cortex in phase with the ECG R wave elicits pure cardiac effects unaccompanied by changes in blood pressure or respiration. This technique has successfully demonstrated cardiac chronotropic organisation and arrhythmogenesis within the insula. Pathways exist linking the insular cortex with the lateral hypothalamic area (LHA). Similarly, the LHA has previously been shown to mediate the sympathetic and blood pressure effects of insular cortex stimulation. Therefore it was anticipated that the tachycardia elicited by insular phasic microstimulation would be responsive to LHA manipulations. Insular tachycardia sites in 28 chloralose-anesthetised male Wistar rats were physically stimulated once with each cardiac cycle using 500 μA for 1 min before and after microinfusions (390 nl) into the LHA. The insular tachycardia response was abolished by LHA microinfusions of the synaptic blocker cobaltous chloride (4 mM). LHA microinjection of kynurenic acid (250 mM) attenuated insular tachycardia by 95%. Microinjection of naloxone (30 mM) similarly attenuated the tachycardia by 95%. Met-enkephalin (3.5 mM) was without effect on this response whereas Leu-enkephalin (3.5 mM) and neuropeptide Y (0.01 mM) (NPY) doubled the magnitude of the tachycardia. Dynorphin (0.12 mM), a specific kappa opioid receptor agonist, augmented the response to stimulation of insular tachycardia sites 8-fold. Consequently, it is suggested that the LHA contains an obligatory synapse mediating insular tachycardia and that glutamate is the likely neurotransmitter at this site. Neuromodulation of insular tachycardia may be effected by opiate kappa and NPY receptors, a finding of considerable clinical relevance.