Contact Heat in Magnetoencephalography: A Systematic Review.

BACKGROUND: Contact heat is commonly used in experimental research to evoke brain activity, most frequently acquired with electroencephalography (EEG). Although magnetoencephalography (MEG) improves spatial resolution, using some contact heat stimulators with MEG can present methodological challenges. This systematic review assesses studies that utilise contact heat in MEG, their findings and possible directions for further research. METHODS: Eight electronic databases were searched for relevant studies, in addition to the selected papers' reference lists, citations and ConnectedPapers maps. Best practice recommendations for systematic reviews were followed. Papers met inclusion criteria if they used MEG to record brain activity in conjunction with contact heat, regardless of stimulator equipment or paradigm. RESULTS: Of 646 search results, seven studies met the inclusion criteria. Studies demonstrated effective electromagnetic artefact removal from MEG data, the ability to elicit affective anticipation and differences in deep brain stimulation responders. We identify contact heat stimulus parameters that should be reported in publications to ensure comparisons between data outcomes are consistent. CONCLUSIONS: Contact heat is a viable alternative to laser or electrical stimulation in experimental research, and methods exist to successfully mitigate any electromagnetic noise generated by PATHWAY CHEPS equipment - though there is a dearth of literature exploring the post-stimulus time window.

Atorvastatin enhances kainate-induced gamma oscillations in rat hippocampal slices.

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20-80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate-induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole-cell current-clamp and voltage-clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration-dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post-synaptic currents, but did not affect the frequency of spontaneous excitatory post-synaptic currents. The atorvastatin-induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D-AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate-induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol-lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.

Transition between fast and slow gamma modes in rat hippocampus area CA1 in vitro is modulated by slow CA3 gamma oscillations.

Hippocampal gamma oscillations have been associated with cognitive functions including navigation and memory encoding/retrieval. Gamma oscillations in area CA1 are thought to depend on the oscillatory drive from CA3 (slow gamma) or the entorhinal cortex (fast gamma). Here we show that the local CA1 network can generate its own fast gamma that can be suppressed by slow gamma-paced inputs from CA3. Moderate acetylcholine receptor activation induces fast (45 ± 1 Hz) gamma in rat CA1 minislices and slow (33 ± 1 Hz) gamma in CA3 minislices in vitro. Using pharmacological tools, current-source density analysis and intracellular recordings from pyramidal cells and fast-spiking stratum pyramidale interneurons, we demonstrate that fast gamma in CA1 is of the pyramidal-interneuron network gamma (PING) type, with the firing of principal cells paced by recurrent perisomal IPSCs. The oscillation frequency was only weakly dependent on IPSC amplitude, and decreased to that of CA3 slow gamma by reducing IPSC decay rate or reducing interneuron activation through tonic inhibition of interneurons. Fast gamma in CA1 was replaced by slow CA3-driven gamma in unlesioned slices, which could be mimicked in CA1 minislices by sub-threshold 35 Hz Schaffer collateral stimulation that activated fast-spiking interneurons but hyperpolarised pyramidal cells, suggesting that slow gamma frequency CA3 outputs can suppress the CA1 fast gamma-generating network by feed-forward inhibition and replaces it with a slower gamma oscillation driven by feed-forward inhibition. The transition between the two gamma oscillation modes in CA1 might allow it to alternate between effective communication with the medial entorhinal cortex and CA3, which have different roles in encoding and recall of memory.

Oligomeric ß-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway.

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aß1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aß1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aß1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aß1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aß1-42-induced suppression was confirmed in Aß-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aß1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aß1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aß1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.

Temperature- and concentration-dependence of kainate-induced γ oscillation in rat hippocampal slices under submerged condition.

AIM: Fast neuronal network oscillation at the γ frequency band (γ oscillation: 30-80 Hz) has been studied extensively in hippocampal slices under interface recording condition. The aim of this study is to establish a method for recording γ oscillation in submerged hippocampal slices that allows simultaneously monitoring γ oscillation and the oscillation-related intracellular events, such as intracellular Ca(2+) concentration or mitochondrial membrane potentials. METHODS: Horizontal hippocampal slices (thickness: 300 µm) of adult rats were prepared and placed in a submerged or an interface chamber. Extracellular field recordings were made in the CA3c pyramidal layer of the slices. Kainate, an AMPA/kainate receptor agonist, was applied via perfusion. Data analysis was performed off-line. RESULTS: Addition of kainate (25-1000 nmol/L) induced γ oscillation in both the submerged and interface slices. Kainate increased the γ power in a concentration-dependent manner, but the duration of steady state oscillation was reduced at higher concentrations of kainate. Long-lasting γ oscillation was maintained at the concentrations of 100-300 nmol/L. Under submerged condition, γ oscillation was temperature-dependent, with the maximum power achieved at 29 °C. The induction of γ oscillation under submerged condition also required a fast rate of perfusion (5-7 mL/min) and showed a fast dynamic during development and after the washout. CONCLUSION: The kainite-induced γ oscillation recorded in submerged rat hippocampal slices is useful for studying the intracellular events related to neuronal network activities and may represent a model to reveal the mechanisms underlying the normal neuronal synchronizations and diseased conditions.

Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice.

Aim: Neural network oscillation at gamma frequency band (γ oscillation, 30-80 Hz) is synchronized synaptic potentials important for higher brain processes and altered in normal aging. Recent studies indicate that activation of dopamine 4 receptor (DR4) enhanced hippocampal γ oscillation of young mice and fully recovered the impaired hippocampal synaptic plasticity of aged mice, we determined whether this receptor is involved in aging-related modulation of hippocampal γ oscillation. Methods: We recorded γ oscillations in the hippocampal CA3 region from young and aged C57bl6 mice and investigated the effects of dopamine and the selective dopamine receptor (DR) agonists on γ oscillation. Results: We first found that γ oscillation power (γ power) was reduced in aged mice compared to young mice, which was restored by exogenous application of dopamine (DA). Second, the selective agonists for different D1- and D2-type dopamine receptors increased γ power in young mice but had little or small effect in aged mice. Third, the D4 receptor (D4R) agonist PD168077 caused a large increase of γ power in aged mice but a small increase in young mice, and its effect is blocked by the highly specific D4R antagonist L-745,870 or largely reduced by a NMDAR antagonist. Fourth, D3R agonist had no effect on γ power of either young or aged mice. Conclusion: This study reveals DR subtype-mediated hippocampal γ oscillations is aging-related and DR4 activation restores the impaired γ oscillations in aged brain, and suggests that D4R is the potential target for the improvement of cognitive deficits related to the aging and aging-related diseases.

High-frequency network activity, global increase in neuronal activity, and synchrony expansion precede epileptic seizures in vitro.

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (>100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within approximately 5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.

ERK activation causes epilepsy by stimulating NMDA receptor activity.

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.

In vitro hippocampal gamma oscillation power as an index of in vivo CA3 gamma oscillation strength and spatial reference memory.

Neuronal synchronisation at gamma frequencies (30-100 Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various in vitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro. Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3. The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay. The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory.

The Control of Rat Hippocampal Gamma Oscillation Strength by BK Channel Activity.

Neuronal network oscillations in the gamma frequency band (30-80 Hz, γ oscillations) are associated with the higher brain functions such as perception, attention, learning and memory. BK channels mediate rapid repolarization and fast afterhyperpolarization in neurons and control neuronal excitability, and potentially control hippocampal γ oscillations. In this study, we examined the effects of modulating BK channels on hippocampal γ oscillations in the absence or presence of Ca2+ influx through voltage-gated Ca2+ channels (VGCC) or Ca2+-permeable AMPA receptors (CP-AMPAR). We found that blocking BK channels enhanced γ power, without affecting oscillation frequency or regularity, suggesting that BK channel activity suppresses γ oscillations. Blocking either VGCC or CP-AMPAR itself enhanced γ power, and completely occluded the effect of BK channel blockers on γ oscillations, whereas blocking BK channels first could not prevent a further γ power increase upon blockade of either CP-AMPAR or VGCC. We propose that Ca2+ influx through VGCC or CP-AMPAR during γ oscillations, cause membrane BK channel activation and regulate hippocampal γ oscillation strength by negative feedback.

High-frequency gamma oscillations coexist with low-frequency gamma oscillations in the rat visual cortex in vitro.

Synchronization of neuronal activity in the visual cortex at low (30-70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-gamma; peak frequency approximately 80 Hz at 37 degrees C) that can coexist with low-frequency gamma oscillations (slow-gamma; peak frequency approximately 50 Hz at 37 degrees C) in the same column. Current-source density analysis showed that fast-gamma was associated with rhythmic current sink-source sequences in layer III and slow-gamma with rhythmic current sink-source sequences in layer V. Fast-gamma and slow-gamma were not phase-locked. Slow-gamma power fluctuations were unrelated to fast-gamma power fluctuations, but were modulated by the phase of theta (3-8 Hz) oscillations generated in the deep layers. Fast-gamma was spatially less coherent than slow-gamma. Fast-gamma and slow-gamma were dependent on gamma-aminobutyric acid (GABA)(A) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and gap-junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast-gamma and slow-gamma power were differentially modulated by thiopental and adenosine A(1) receptor blockade, and their frequencies were differentially modulated by N-methyl-D-aspartate (NMDA) receptors, GluK1 subunit-containing receptors and persistent sodium currents. Our data indicate that fast-gamma and slow-gamma both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co-existence of fast-gamma and slow-gamma allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high-frequency gamma oscillations.

Comparison between spontaneous and kainate-induced gamma oscillations in the mouse hippocampus in vitro.

Neuronal synchronization at gamma frequency, implicated in cognition, can be evoked in hippocampal slices by pharmacological activation. We characterized spontaneous small-amplitude gamma oscillations (SgammaO) recorded in area CA3 of mouse hippocampal slices and compared it with kainate-induced gamma oscillations (KgammaO). SgammaO had a lower peak frequency, a more sinusoidal waveform and was spatially less coherent than KgammaO, irrespective of oscillation amplitude. CA3a had the smallest oscillation power, phase-led CA3c by approximately 4 ms and had the highest SgammaO frequency in isolated subslices. During SgammaO CA3c neurons fired at the rebound of inhibitory postsynaptic potentials (IPSPs) that were associated with a current source in stratum lucidum, whereas CA3a neurons often fired from spikelets, 3-4 ms earlier in the cycle, and had smaller IPSPs. Kainate induced faster/larger IPSPs that were associated with an earlier current source in stratum pyramidale. SgammaO and KgammaO power were dependent on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, gap junctions and gamma-aminobutyric acid (GABA)(A) receptors. SgammaO was suppressed by elevating extracellular KCl, blocking N-methyl-d-aspartate (NMDA) receptors or muscarinic receptors, or activating GluR5-containing kainate receptors. SgammaO was not affected by blocking metabotropic glutamate receptors or hyperpolarization-activated currents. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethoxyxanthine (8-CPT) and the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) increased SgammaO power, indicating that endogenous adenosine and/or endocannabinoids suppress or prevent SgammaO in vitro. SgammaO emerges from a similar basic network as KgammaO, but differs in involvement of somatically projecting interneurons and pharmacological modulation profile. These observations advocate the use of SgammaO as a natural model for hippocampal gamma oscillations, particularly during less activated behavioural states.

Near-Death High-Frequency Hyper-Synchronization in the Rat Hippocampus.

Near-death experiences (NDE) are episodes of enhanced perception with impending death, which have been associated with increased high-frequency (13-100 Hz) synchronization of neuronal activity, which is implicated in cognitive processes like perception, attention and memory. To test whether the NDE-associated high-frequency oscillations surge is related to cardiac arrest, recordings were made from the hippocampus of anesthetized rats dying from an overdose of the sedative chloral hydrate (CH). At a lethal dose, CH caused a surge in beta band power in CA3 and CA1 and a surge in gamma band power in CA1. CH increased the inter-regional coherence of high-frequency oscillations within and between hippocampi. Whereas the surge in beta power developed at non-lethal chloral hydrate doses, the surge in gamma power was specific for impending death. In contrast, CH strongly suppressed theta band power in both CA1 and CA3 and reduced inter-regional coherence in the theta band. The simultaneously recorded electrocardiogram showed a small decrease in heart rate but no change in waveform during the high-frequency oscillation surge, with cardiac arrest only developing after the cessation of breathing and collapse of all oscillatory activity. These results demonstrate that the high-frequency oscillation surge just before death is not limited to cardiac arrest and that especially the increase in gamma synchronization in CA1 may contribute to NDE observed both with and without cardiac arrest.

Modulation of Hippocampal Gamma Oscillations by Dopamine in Heterozygous Reeler Mice in vitro.

The reelin haploinsufficient heterozygous reeler mice (HRM), an animal model of schizophrenia, have altered mesolimbic dopaminergic pathways and share similar neurochemical and behavioral properties with patients with schizophrenia. Dysfunctional neural circuitry with impaired gamma (γ) oscillation (30-80 Hz) has been implicated in abnormal cognition in patients with schizophrenia. However, the function of neural circuitry in terms of γ oscillation and its modulation by dopamine (DA) has not been reported in HRM. In this study, first, we recorded γ oscillations in CA3 from wild-type mice (WTM) and HRM hippocampal slices, and we studied the effects of DA on γ oscillations. We found that there was no difference in γ power between WTM and HRM and that DA increased γ power of WTM but not HRM, suggesting that DA modulations of network oscillations in HRM are impaired. Second, we found that N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 itself increased γ power and occluded DA-mediated enhancement of γ power in WTM but partially restored DA modulation of γ oscillations in HRM. Third, inhibition of phosphatidylinositol 3-kinase (PI3K), a downstream molecule of NMDAR, increased γ power and blocked the effects of DA on γ oscillation in WTM and had no significant effect on γ power but largely restored DA modulation of γ oscillations in HRM. Our results reveal that impaired DA function in HRM is associated with dysregulated NMDAR-PI3K signaling, a mechanism that may be relevant in the pathology of schizophrenia.

µ-Opioid receptor activation modulates CA3-to-CA1 gamma oscillation phase-coupling.

In the intact brain, hippocampal area CA1 alternates between low-frequency gamma oscillations (γ), phase-locked to low-frequency γ in CA3, and high-frequency γ, phase-locked to γ in the medial entorhinal cortex. In hippocampal slices, γ in CA1 is phase-locked to CA3 low-frequency γ. However, when Schaffer collaterals are cut, CA1 can generate its own high-frequency γ. Here we test whether (un)coupling of CA1 γ from CA3 γ can be caused by µ-opioid receptor (MOR) modulation. In CA1 minislices isolated from rat ventral hippocampus slices, MOR activation by DAMGO reduced the dominant frequency of intrinsic fast γ, induced by carbachol. In intact slices, DAMGO strongly reduced the dominant frequency of CA3 slow γ, but did not affect γ power consistently. DAMGO suppressed the phase coupling of CA1 γ to CA3 slow γ and increased the power of CA1 intrinsic fast γ, but not in the presence of the MOR antagonist CTAP. The benzodiazepine zolpidem and local application of DAMGO to CA3 both mimicked the reduction in dominant frequency of CA3 slow γ, but did not reduce the phase coupling. Local application of DAMGO to CA1 reduced phase coupling. These results suggest that MOR-expressing CA1 interneurons, feed-forwardly activated by Schaffer collaterals, are responsible for the phase coupling between CA3 γ and CA1 γ. Modulating their activity may switch the CA1 network between low-frequency γ and high-frequency γ, controlling the information flow between CA1 and CA3 or medial entorhinal cortex respectively.

The Modulation of Gamma Oscillations by Methamphetamine in Rat Hippocampal Slices.

Gamma frequency oscillations (γ, 30-100 Hz) have been suggested to underlie various cognitive and motor functions. The psychotomimetic drug methamphetamine (MA) enhances brain γ oscillations associated with changes in psychomotor state. Little is known about the cellular mechanisms of MA modulation on γ oscillations. We explored the effects of multiple intracellular kinases on MA modulation of γ induced by kainate in area CA3 of rat ventral hippocampal slices. We found that dopamine receptor type 1 and 2 (DR1 and DR2) antagonists, the serine/threonine kinase PKB/Akt inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonists prevented the enhancing effect of MA on γ oscillations, whereas none of them affected baseline γ strength. Protein kinase A, phosphoinositide 3-kinase and extracellular signal-related kinases inhibitors had no effect on MA. We propose that the DR1/DR2-Akt-NMDAR pathway plays a critical role for the MA enhancement of γ oscillations. Our study provides an new insight into the mechanisms of acute MA on MA-induced psychosis.

Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice.

Normal aging is characterized with a decline in hippocampal memory functions that is associated with changes in long-term potentiation (LTP) of the CA3-to-CA1 synapse. Age-related deficit of the dopaminergic system may contribute to impairment of CA1 LTP. Here we assessed how the modulation of CA1 LTP by dopamine is affected by aging and how it is dependent on the Ca2+ source. In slices from adult mice, the initial slope of the field potential showed strong LTP, but in slices from aged mice LTP was impaired. Dopamine did not affect LTP in adult slices, but enhanced LTP in aged slices. The dopamine D1/D5 receptor (D1R/D5R) agonist SKF-81297 did not affect LTP in adult but caused a relative small increase in LTP in aged slices; however, although there was no difference in dopamine D4 receptor (D4R) expression, the D4R agonist PD168077 increased LTP in aged slices to a magnitude similar to that in adult slices. The N-Methyl-D-aspartate receptor antagonist D-AP5 reduced LTP in adult slices, but not in aged slices. However, in the presence of D-AP5, PD168077 completely blocked LTP in aged slices. The voltage-dependent calcium channel (VDCC) blocker nifedipine reduced LTP in adult slices, but surprisingly enhanced LTP in aged slices. Furthermore, in the presence of nifedipine, PD168077 caused a strong enhancement of LTP in aged slices to a magnitude exceeding LTP in adult slices. Our results indicate that the full rescue of impaired LTP in aging by the selective D4R activation and that a large potentiation role on LTP by co-application of D4R agonist and VDCC blocker may provide novel strategies for the intervention of cognitive decline of aging and age-related diseases.

Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area.

Neuronal synchronization at gamma band frequency (20-80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 µM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 µM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Acute Ethanol Inhibition of γ Oscillations Is Mediated by Akt and GSK3ß.

Hippocampal network oscillations at gamma band frequency (γ, 30-80 Hz) are closely associated with higher brain functions such as learning and memory. Acute ethanol exposure at intoxicating concentrations (≥50 mM) impairs cognitive function. This study aimed to determine the effects and the mechanisms of acute ethanol exposure on γ oscillations in an in vitro model. Ethanol (25-100 mM) suppressed kainate-induced γ oscillations in CA3 area of the rat hippocampal slices, in a concentration-dependent, reversible manner. The ethanol-induced suppression was reduced by the D1R antagonist SCH23390 or the PKA inhibitor H89, was prevented by the Akt inhibitor triciribine or the GSk3ß inhibitor SB415286, was enhanced by the NMDA receptor antagonist D-AP5, but was not affected by the MAPK inhibitor U0126 or PI3K inhibitor wortmanin. Our results indicate that the intracellular kinases Akt and GSk3ß play a critical role in the ethanol-induced suppression of γ oscillations and reveal new cellular pathways involved in the ethanol-induced cognitive impairment.

NMDA receptor antagonists distort visual grouping in rats performing a modified two-choice visual discrimination task.

RATIONALE: Visual perception is impaired during pathological psychosis, which can be mimicked by NMDA receptor antagonists. However, the underlying mechanisms are poorly understood, partly due to limits of current rodent models for visual integration. OBJECTIVES: The objectives of the study are (1) to develop a rodent task that can differentiate between effects on perception and nonspecific effects on task performance and (2) to test whether NMDA receptor antagonists affect visual perception in rats. METHODS: We used an adaptation of Glass patterns to assess visual grouping in rats using a two-choice visual discrimination task in an infrared touch screen conditioning chamber. After rats learned to discriminate between a radial and a concentric bipole pattern, the ability to discriminate between these patterns was tested at various levels of distortion and a psychometric function was fit to obtain the maximum task performance and signal level needed for half-maximum performance. RESULTS: NMDA receptor antagonists ketamine and phencyclidine at low doses increased the signal quality needed to discriminate between the visual patterns, without affecting the ability to discriminate between undistorted images. At higher doses, the ability to perform the task even with undistorted images was impaired, which was associated with stereotypic behaviour and increased impulsivity. CONCLUSIONS: The Glass pattern-based visual grouping task is able to differentiate the effect of psychotomimetic NMDA receptor antagonists on visual perception from the effects on motor and memory functions. The half-maximum performance signal level allows quantification of cognitive psychosis in rodents, which can be translated to human psychometric functions and can be used in the development of more effective treatments.