Firing Of Pyramidal Neurons Research Articles

The Effect of Orexin-2 and Endocannabinoid-1 Antagonists on Neuronal Activity of Hippocampal CA1 Pyramidal Neurons in Response to Tramadol in Rats.

Background:CA1, as a major structure involved in learning and memory, has been shown to be affected by tramadol addiction. Both orexin and endocannabinoid receptors express in CA1 and play an important role in drug dependency. The aim of this study was to evaluate the modulatory effects of orexin-2 (OX2R) and endocannabinoid-1 (CB1R) receptors on neuronal activity in CA1, in response to tramadol in rats.Materials and Methods:Male Wistar rats were divided into 8 groups (n = 6–7); saline-dimethyl sulfoxide (DMSO), tramadol-DMSO, saline-TCS-OX2-29, saline-AM251, tramadol-TCS-OX2-29, tramadol-AM251, saline-TCS-OX2-29-AM251, tramadol-TCS-OX2-29-AM251. Tramadol was injected intraperitoneally, and then, AM251 (1 nmol/0.3 μL), CB1R antagonist and TCS-OX2-29 (1 nmol/0.3 μL), OX2R antagonist, were microinjected individually or concurrently into the CA1. Using in vivo extracellular single-unit recording, the firing of CA1 pyramidal neurons was investigated.Results:Tramadol decreased neuronal activity in CA1 (P < 0.01) but increased it after micro-injection of DMSO. TCS-OX2-29 increased neuronal activity in saline group (P < 0.05) but decreased it in tramadol group. AM251 had no effect on saline group but decreased neuronal activity in tramadol group (P < 0.05). Concurrent micro-injection of TCS-OX2-29 and AM251 had no effect on saline group but decreased neuronal activity in tramadol group (P < 0.05).Conclusions:Our findings suggest that neural activity in CA1 is rapidly affected by acute use of tramadol, and some of these effects may be induced through the endocannabinoid and orexin systems. Thus, the function of endocannabinoid and orexin systems in CA1 may play a role in tramadol addiction.

Early derailment of firing properties in CA1 pyramidal cells of the ventral hippocampus in an Alzheimer's disease mouse model

Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid β deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive. The understanding of these early alterations is crucial to tackle defective mechanisms.In a previous study we proved that the Tg2576 mouse model of AD displays functional deficits in the dorsal hippocampus and relevant behavioural AD-related alterations. We had shown that these deficits in Tg2576 mice correlate with the precocious degeneration of dopamine (DA) neurons in the Ventral Tegmental Area (VTA) and can be restored by L-DOPA treatment. Due to the distinct functionality and connectivity of dorsal versus ventral hippocampus, here we investigated neuronal excitability and synaptic functionality in the ventral CA1 hippocampal sub-region of Tg2576 mice. We found an age-dependent alteration of cell excitability and firing in pyramidal neurons starting at 3 months of age, that correlates with reduced levels in the ventral CA1 of tyrosine hydroxylase – the rate-limiting enzyme of DA synthesis. Additionally, at odds with the dorsal hippocampus, we found no alterations in basal glutamatergic transmission and long-term plasticity of ventral neurons in 8-month old Tg2576 mice compared to age-matched controls. Last, we used computational analysis to model the early derailments of firing properties observed and hypothesize that the neuronal alterations found could depend on dysfunctional sodium and potassium conductances, leading to anticipated depolarization-block of action potential firing. The present study depicts that impairment of cell excitability and homeostatic control of firing in ventral CA1 pyramidal neurons is a prodromal feature in Tg2576 AD mice.

Laminar specificity of the auditory awareness negativity under multitone masking: A biophysical modeling study

Electroencephalography (EEG) and magnetoencephalography (MEG) are excellent mediums for capturing human neural activity on a millisecond time scale, yet little is known about their underlying laminar and biophysical basis. Here, we used a reduced but realistic cortical circuit model—Human Neocortical Neurosolver (HNN)—to shed light on the laminar specificity of brain responses associated with auditory conscious perception under multitone masking. HNN provides a canonical model of a neocortical column circuit, including both excitatory pyramidal and inhibitory basket neurons in layers II/III and layer V. We found that the difference in event-related responses between perceived and unperceived target tones could be accounted for by additional input to supragranular layers arriving from either the non-lemniscal thalamus or cortico-cortical feedback connections. Layer-specific spiking activity of the circuit revealed that the additional negative-going peak that was present for detected but not undetected target tones was accompanied by increased firing of layer-V pyramidal neurons. These results are consistent with current cellular models of conscious processing and help bridge the gap between the macro and micro levels of analysis of perception-related brain activity.

Infralimbic cortex pyramidal neuron GIRK signaling contributes to regulation of cognitive flexibility but not affect-related behavior in male mice

Dysfunction of the infralimbic cortical (ILC) region of the medial prefrontal cortex (mPFC) is thought to be an underlying factor in both affect- and cognition-related behavioral deficits that co-occur across neuropsychiatric disorders. Increasing evidence highlights pathological imbalances in prefrontal pyramidal neuron excitability and associated aberrant firing as an underlying factor in this dysfunction. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of mPFC pyramidal neurons, however the functional role of these channels in ILC-dependent regulation of behavior and pyramidal neuron excitation is unknown. The present study used a viral-cre approach in male mice harboring a ‘floxed’ version of the kcnj3 (Girk1) gene, to disrupt GIRK1-containing channel expression in pyramidal neurons within the ILC. Loss of GIRK1-dependent signaling increased excitability and spike firing of pyramidal neurons but did not alter affective behavior measured in an elevated plus maze, forced swim test, or progressive ratio test of motivation. Alternatively, ablation of GIRK1 impaired performance in an operant-based attentional set-shifting task designed to assess cognitive flexibility. These data highlight a unique role for GIRK1 signaling in ILC pyramidal neurons in the regulation of strategy shifting but not affect and suggest that these channels may represent a therapeutic target for treatment of cognitive deficits in neuropsychiatric disease.

Reliable Sensory Processing in Mouse Visual Cortex through Cooperative Interactions between Somatostatin and Parvalbumin Interneurons.

Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). However, under certain conditions, neurons can respond reliably with highly precise responses to the same visual stimuli from trial to trial. This suggests that there exists intrinsic neural circuit mechanisms that dynamically modulate the intertrial variability of visual cortical neurons. Here, we sought to elucidate the role of different inhibitory interneurons (INs) in reliable coding in mouse V1. To study the interactions between somatostatin-expressing interneurons (SST-INs) and parvalbumin-expressing interneurons (PV-INs), we used a dual-color calcium imaging technique that allowed us to simultaneously monitor these two neural ensembles while awake mice, of both sexes, passively viewed natural movies. SST neurons were more active during epochs of reliable pyramidal neuron firing, whereas PV neurons were more active during epochs of unreliable firing. SST neuron activity lagged that of PV neurons, consistent with a feedback inhibitory SST→PV circuit. To dissect the role of this circuit in pyramidal neuron activity, we used temporally limited optogenetic activation and inactivation of SST and PV interneurons during periods of reliable and unreliable pyramidal cell firing. Transient firing of SST neurons increased pyramidal neuron reliability by actively suppressing PV neurons, a proposal that was supported by a rate-based model of V1 neurons. These results identify a cooperative functional role for the SST→PV circuit in modulating the reliability of pyramidal neuron activity.SIGNIFICANCE STATEMENT Cortical neurons often respond to identical sensory stimuli with large variability. However, under certain conditions, the same neurons can also respond highly reliably. The circuit mechanisms that contribute to this modulation remain unknown. Here, we used novel dual-wavelength calcium imaging and temporally selective optical perturbation to identify an inhibitory neural circuit in visual cortex that can modulate the reliability of pyramidal neurons to naturalistic visual stimuli. Our results, supported by computational models, suggest that somatostatin interneurons increase pyramidal neuron reliability by suppressing parvalbumin interneurons via the inhibitory SST→PV circuit. These findings reveal a novel role of the SST→PV circuit in modulating the fidelity of neural coding critical for visual perception.

Total sleep deprivation-induced electrophysiological activities changes in rat hippocampal CA1 detected by microelectrode arrays

Total sleep deprivation (TSD) produces impairments in cognitive on individuals. The measurement of rat hippocampal CA1 neural activity after TSD is of importance to understand the harmful effect induced by TSD on the cellular level. In this work, the deficit of spatial learning and memory maintenance caused by TSD was demonstrated in the Morris Water Maze test. And a novel 16-site micro-electrode array we designed and fabricated was successfully implanted into the target area of rat brain to measure the neuronal activities in rat hippocampal CA1 before and after TSD. The probe was successfully implanted into the target area of brain. The detection results showed that the neuronal firing of both Pyramidal neurons and interneurons in CA1 got elevated, and the fluctuation of local field potential (LFP) became more frequent after TSD, indicating that TSD exerted excitatory effects on CA1 neurons. Besides, the power of spike firing and LFP got significantly increased in low frequency band, especially theta band after TSD, accompanied by the increased occurrence of OFF period during spike firing. It is concluded that the disturbed theta activity induced by TSD in hippocampus was associated with the altered excitatory/inhibitory balance of neurons in the brain. And the increased occurrence of OFF period in neuronal firing after TSD disrupted the propagation of theta activity in the brain, which might partially explain the overall decline in spatial learning performance of rats.

This Month in Anesthesiology

This Month in Anesthesiology

Fast-spiking Interneurons Contribute to Propofol-induced Facilitation of Firing Synchrony in Pyramidal Neurons of the Rat Insular Cortex.

The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 μM propofol application. Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.

Spike frequency-dependent inhibition and excitation of neural activity by high-frequency ultrasound.

Ultrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the after-hyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents but potentiate firing in response to higher-input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) after-hyperpolarization, which increases the rate of recovery from inactivation. Based on these results, we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels through heating or mechanical effects of acoustic radiation force. Finite-element modeling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (<2°C) increase in temperature, with possible additional contributions from mechanical effects.

GnRH protective effects against amyloid β-induced cognitive decline: A potential role of the 17β-estradiol

IntroductionThe 17β-estradiol (E2) enhances hippocampal dendritic spine synapses, facilitates learning processes, and exerts neuroprotection. Brain estrogen decline has been reported in Alzheimer's disease. The role of GnRH in modulating steroid biosynthesis convinced us to examine whether hippocampal GnRH administration could enhance the local E2 levels and overcome the development of cognition decline in amyloid β (Aβ) neurotoxicity. To explore if GnRH acts through regulating E2 synthesis, letrozole, an aromatase inhibitor, has been applied in combination with GnRH. MethodsFemale rats received an intracerebroventricular injection of Aβ. The GnRH and, or letrozole were injected into the CA1 for 14 consecutive days. Working memory, novel object recognition memory, and anxiety-like behavior were evaluated. Serum and hippocampal E2 levels were measured. Hippocampal mRNA expression of GnRH (GnRH-R) and E2 (ERα and ERβ) receptors was assessed. GnRH effect on the excitability of pyramidal cells was studied by in vivo single-unit recording. ResultsGnRH increased hippocampal E2 levels, evoked an increase in the spontaneous firing of pyramidal neurons, and caused mRNA overexpression of hippocampal GnRH receptors. GnRH prevented the adverse effects of Aβ on working memory, NOR index, and anxiogenic behavior. Letrozole did not reverse GnRH modulatory effects on hippocampal E2 levels and neuroprotection. ConclusionGnRH prevented the Aβ-induced memory deficit, which may be mediated through hippocampal E2 levels enhancement. The electrophysiological analysis revealed the enhanced neuronal excitability in the CA1 region. All these data suggest that GnRH might be a promising candidate that reduces anxiety and improves memory indices in the context of Aβ neurotoxicity.

Activation of CB1 receptors on GABAergic interneurons in the ventrolateral orbital cortex induces analgesia

The prefrontal ventrolateral orbital cortex (VLO) is involved in antinociception. It has been found that dopamine receptors, adrenoceptors, serotonin receptors and μ-opioid receptors are involved in this effect through direct/indirect activation of the VLO output neurons. However, the effect of CB1 receptors on the VLO modulation of pain has not been studied. In this study, we investigated whether activation of CB1 receptors in the VLO modulates nociception. A common peroneal nerve (CPN) ligation model was used to induce neuropathic pain in male mice. On day 13 after CPN ligation, spontaneous firing of the VLO pyramidal neurons was recorded and CB1 receptor level in the VLO was detected. Mechanical allodynia was measured after HU210 was microinjected into the VLO. Relative contribution of CB1 receptors on GABAergic neurons and glutamatergic neurons was determined by CB1 receptor knockdown using a viral strategy. Our data indicated that on day 13 after nerve injury, spontaneous firing of the VLO pyramidal neurons reduced significantly but was enhanced by intraperitoneal injection of HU210 (20 μg/kg), a potent CB1 receptor agonist. Expression of CB1 receptor in the VLO was up-regulated. Microinjection of HU210 into the VLO attenuated allodynia, and this effect was blocked by pre-microinjection of specific CB1 receptor antagonist AM281. Deletion of CB1 receptors on GABAergic neurons in the VLO can completely block HU210-induced analgesia. Thus, it can be concluded that activation of CB1 receptors on GABAergic interneurons in the VLO may be involved in analgesia effect of cannabinoids.

Slow-decaying presynaptic calcium dynamics gate long-lasting asynchronous release at the hippocampal mossy fiber to CA3 pyramidal cell synapse.

Action potentials trigger two modes of neurotransmitter release, with a fast synchronous component and a temporally delayed asynchronous release. Asynchronous release contributes to information transfer at synapses, including at the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse where it controls the timing of postsynaptic CA3 pyramidal neuron firing. Here, we identified and characterized the main determinants of asynchronous release at the MF–CA3 synapse. We found that asynchronous release at MF–CA3 synapses can last on the order of seconds following repetitive MF stimulation. Elevating the stimulation frequency or the external Ca2+ concentration increased the rate of asynchronous release, thus, arguing that presynaptic Ca2+ dynamics is the major determinant of asynchronous release rate. Direct MF bouton Ca2+ imaging revealed slow Ca2+ decay kinetics of action potential (AP) burst‐evoked Ca2+ transients. Finally, we observed that asynchronous release was preferentially mediated by Ca2+ influx through P/Q‐type voltage‐gated Ca2+ channels, while the contribution of N‐type VGCCs was limited. Overall, our results uncover the determinants of long‐lasting asynchronous release from MF terminals and suggest that asynchronous release could influence CA3 pyramidal cell firing up to seconds following termination of granule cell bursting.

Serotonin-2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition.

Previous research has implicated the serotonin-2B (5-HT2B) receptor as a possible contributor to the antidepressant-like response. Aripiprazole has been successfully used in combination with selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant depression and it, among all receptors, exhibits the highest affinity for the 5-HT2B receptor. However, the potential contribution of such an antagonistic action on 5-HT2B receptors in the context of adjunct therapy is not known. In vivo electrophysiological recordings of ventral tegmental area (VTA) dopamine (DA) neurons, dorsal raphe nucleus (DRN) 5-HT neurons and pyramidal neurons in the medial prefrontal cortex (mPFC), and the hippocampus were conducted in anaesthetized Sprague-Dawley rats after the administration of 5-HT2B receptor ligands alone or in combination with the SSRI escitalopram. An escitalopram-induced decrease in DA, but not 5-HT firing activity, was rescued by 2-day co-administration of the selective 5-HT2B receptor antagonist LY266097. In the mPFC, 14-day escitalopram administration alone had no effect on pyramidal neuron firing and burst activity, whereas, aripiprazole administered alone or in combination with escitalopram for 14 days increased pyramidal neuron firing and burst activity. Likewise, the administration of LY266097 alone or its addition on the last 3 days of a 14-day escitalopram regimen increased pyramidal neuron firing and burst activity. These results indicated that 5-HT2B receptors play, at least in part, a role in this enhancement. In the hippocampus, 5-HT2B receptor activation by BW723c86 decreased escitalopram-induced inhibition of 5-HT reuptake, which was reversed by a 5-HT2B receptor antagonist. Altogether, these results put into evidence the possibility that 5-HT2B receptor blockade contributes to the therapeutic effect of aripiprazole addition to SSRIs in depression.

Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer (S)-CE-123 on Mesocorticolimbic Dopamine System.

Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the S-enantiomer of CE-123 ((S)-CE-123) and R-modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that (S)-CE-123, but not R-modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, (S)-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to R-modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after (S)-CE-123. Neither (S)-CE-123 nor R-modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of (S)-CE-123, and show a minor impact on reward-related dopaminergic areas.

Sex and region-specific effects of high fat diet on PNNs in obesity susceptible rats

Perineuronal nets (PNNs) are specialized extracellular matrix structures that primarily surround fast-spiking parvalbumin (PV)-containing interneurons within the PFC. They regulate PV neuron function and plasticity to maintain cortical excitatory/inhibitory balance. For example, reductions in PNN intensity are associated with reduced local inhibition and enhanced pyramidal neuron firing. We previously found that exposure to dietary high fat reduced PNN intensity within the PFC of male Sprague-Dawley (SD) rats. However, how high fat affects PNNs in the PFC of females or in obesity-vulnerable vs. –resistant models is unknown. Therefore, we gave male and female SD, selectively bred obesity-prone (OP), and obesity-resistant rats (OR) free access to standard lab chow or 60% high fat for 21 days. We then measured the number of PNN positive cells and PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as the number of PV positive neurons using immunohistochemistry. We found sex and region-specific effects of dietary high fat on PNN intensity, in the absence of robust changes in cell number. Effects were comparable in SD and OP but differed in OR rats. Specifically, high fat reduced PNN intensities in male SD and OP rats but increased PNN intensities in female SD and OP rats. In contrast, effects in ORs were opposite, with males showing increases in PNN intensity and females showing a reduction in intensity. Finally, these effects were also region specific, with diet-induced reductions in PNN intensity found in the prelimbic PFC (PL-PFC) and ventral medial orbital frontal cortex (vmOFC) of SD and OP males in the absence of changes in the infralimbic PFC (IL-PFC), and increases in PNN intensity in the IL-PFC of SD and OP females in the absence of changes in other regions. These results are discussed in light of roles PNNs may play in influencing PFC neuronal activity and the differential role of these sub-regions in food-seeking and motivation.

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B−/− mouse model of ASD. Male and female Shank3B−/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.

Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells

Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time. The application of the TRPC4 blocker ML204, TRPC5 blocker clemizole hydrochloride, and TRPC4 and 5 blocker Pico145, all significantly inhibited persistent firing. In addition, intracellular application of TRPC4 and TRPC5 antibodies significantly reduced persistent firing. Taken together these results indicate that TRPC4 and 5 channels support persistent firing in CA1 pyramidal neurons. Finally, we discuss possible scenarios causing these controversial observations on the role of TRPC channels in persistent firing.

Oscillation-Driven Memory Encoding, Maintenance and Recall in an Entorhinal-Hippocampal Circuit Model

Theta and gamma oscillations are thought to be crucial for information processing across multiple brain regions, but how these oscillations promote multi-area computation remains largely unclear. To explore such mechanisms in working memory, we constructed a neural network model involving parvalbumin-positive, somatostatin-positive and vasoactive intestinal polypeptide-positive interneurons in the hippocampal area CA1 and superficial and deep layers of entorhinal cortex, assuming that self-sustained firing of entorhinal pyramidal neurons underlies spatial working memory. We compared the model behavior with neural activity recorded during delayed nonmatching-to-place tasks. Our model predicts that acetylcholine differently regulates the balance between intra-area versus inter-area computations depending on cognitive demands at memory encoding, maintenance and recall. Furthermore, both modeling and data analysis reveal that entorhinal cortex participates in retrieving as well as encoding spatial memory, where gamma oscillation facilitates recall. Our model gives a mechanistic account for the crucial roles of oscillatory phase-locked firing in working memory.

Identifying neuronal correlates of dying and resuscitation in a model of reversible brain anoxia

We developed a new rodent model of reversible brain anoxia and performed continuous electrocorticographic (ECoG) and intracellular recordings of neocortical neurons to identify in real-time the cellular and network dynamics that successively emerge throughout the dying-to-recovery process. Along with a global decrease in ECoG amplitude, deprivation of oxygen supply resulted in an early surge of beta-gamma activities, accompanied by rhythmic membrane depolarizations and regular firing in pyramidal neurons. ECoG and intracellular signals were then dominated by low-frequency activities which progressively declined towards isoelectric levels. Cortical neurons during the isoelectric state underwent a massive membrane potential depolarizing shift, captured in the ECoG as a large amplitude triphasic wave known as the “wave-of-death” (WoD). This neuronal anoxic depolarization, associated with a block of action potentials and a loss of cell integrative properties, could however be reversed if brain re-oxygenation was rapidly restored (within 2–3.5 min). The subsequent slow repolarization of neocortical neurons resulted in a second identifiable ECoG wave we termed “wave-of-resuscitation” since it inaugurated the progressive regaining of pre-anoxic synaptic and firing activities. These results demonstrate that the WoD is not a biomarker of an irremediable death and unveil the cellular correlates of a novel ECoG wave that may be predictive of a successful recovery. The identification of real-time biomarkers of onset and termination of cell anoxic insult could benefit research on interventional strategies to optimize resuscitation procedures.

Modeling dopaminergic modulation of clustered gamma rhythms

Abstract Gamma rhythm (20–100 Hz) plays a key role in numerous cognitive tasks: working memory, sensory processing and in routing of information across neural circuits. In comparison with lower frequency oscillations in the brain, gamma-rhythm associated firing of the individual neurons is sparse and the activity is locally distributed in the cortex. Such “weak” rhythm results from synchronous firing of pyramidal neurons in an interplay with the local inhibitory interneurons in a pyramidal-interneuron gamma or PING. Experimental evidence shows that individual pyramidal neurons during such oscillations tend to fire at rates below gamma, with the population showing clear oscillations and synchrony. One possible way to describe such features is that this oscillation is generated within local synchronous neuronal clusters. The number of such synchronous clusters defines the overall coherence of the rhythm and its spatial structure. The number of clusters in turn depends on the properties of the synaptic coupling and the intrinsic properties of the constituent neurons. We previously showed that a slow spike frequency adaptation current in the pyramidal neurons can effectively control cluster numbers. These slow adaptation currents are modulated by endogenous brain neuromodulators such as dopamine, whose level is in turn related to cognitive task requirements. Hence we postulate that dopaminergic modulation can effectively control the clustering of weak and its coherence. In this paper we study how dopaminergic modulation of the network and cell properties impacts the cluster formation process in a PING network model.