Paired-pulse Responses Research Articles

Repeated Morphine Exposure Alters Temporoamonic-CA1 Synaptic Plasticity in Male Rat Hippocampus

In this study, the electrophysiological and biochemical consequences of repeated exposure to morphine in male rats on glutamatergic synaptic transmission, synaptic plasticity, the expression of GABA receptors and glutamate receptors at the temporoammonic-CA1 synapse along the longitudinal axis of the hippocampus (dorsal, intermediate, ventral, DH, IH, VH, respectively) were investigated. Slice electrophysiological methods, qRT-PCR, and western blotting techniques were used to characterize synaptic plasticity properties. We showed that repeated morphine exposure (RME) reduced excitatory synaptic transmission and ability for long-term potentiation (LTP) in the VH as well as eliminated the dorsoventral difference in paired-pulse responses. A decreased expression of NR2B subunit in the VH and an increased expression GABAA receptor of α1 and α5 subunits in the DH were observed following RME. Furthermore, RME did not affect the expression of NR2A, AMPA receptor subunits, and γ2GABAA and GABAB receptors in either segment of the hippocampus. In sum, the impact of morphine may differ depending on the region of the hippocampus studied. A distinct change in the short- and long-term synaptic plasticity along the hippocampus long axis due to repeated morphine exposure, partially mediated by a change in the expression profile of glutamatergic receptor subunits. These findings can be useful in further understanding the cellular mechanism underlying deficits in information storage and, more generally, cognitive processes resulting from chronic opioid abuse.

In vivo synaptic potency, short-term and long-term plasticity at the hippocampal Schaffer collateral-CA1 synapses: Role of different light–dark cycles in male rats

The changes in the light–dark(L/D) cycle could modify cellular mechanisms in some brain regions. The present study compared the effects of various L/D cycles on invivo synaptic potency, short-term and long-term plasticity in the hippocampal CA1 area, adrenal glands weight(AGWs), corticosterone (CORT) levels, and body weight differences(BWD) in male rats.Male rats were assigned into different L/D cycle groups: L4/D20, L8/D16, L12/D12(control), L16/D8, and L20/D4. The slope, amplitude, and the area under curve(AUC) related to the field excitatory postsynaptic potentials(fEPSPs) were assessed, using the input–output(I/O) functions, paired-pulse(PP) responses at different interpulse intervals, and after the induction of long-term potentiation(LTP) in the hippocampal CA1 area. Also, the CORT levels, AGWs, and BWDs were measured in all groups.The slope, amplitude, and AUC of fEPSP in the I/O functions, all three phases of PP, before and after the LTP induction, were significantly decreased in all experimental groups, especially in the L20/D4 and L4/D20 groups. As such, the CORT levels and AGWs were significantly increased in all experimental groups, especially in the L20/D4 group.Overall, the uncommon L/D cycles (minimum and particularly maximum durations of light) significantly reduced the cellular mechanism of learning and memory. Also, downtrends were observed in synaptic potency, as well as short-term and long-term plasticity. The changes in PP with high interpulse intervals, or activity of GABAB receptors, were more significant than the changes in other PP phases with different L/D durations. Additionally, the CORT levels, adrenal glands, and body weight gain occurred time-independently concerning different L/D lengths.

The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC

(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC.

Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Decreased excitatory drive onto hilar neuronal nitric oxide synthase expressing interneurons in chronic models of epilepsy

Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. In addition, we studied the properties of miniature excitatory postsynaptic current (mEPSC) and paired-pulse response ratio (PPR) of evoked EPSC in nNOS interneurons using whole cell recording techniques. Results showed that there were fewer nNOS-immunoreactive interneurons of chronically epileptic animals. Importantly, patch-clamp recordings revealed reduction in mEPSC frequency, indicating diminished global excitatory input. In contrast, PPR of evoked EPSC following the granule cell layer stimulation was increased in epileptic animals suggesting reduced neurotransmitter release from granule cell input. In summary, we propose that impaired excitatory drive onto hippocampal nNOS interneurons may be implicated in the development of refractory epilepsy.

Synaptic metaplasticity emulation in a freestanding oxide-based neuromorphic transistor with dual in-plane gates

Synaptic plasticity is a basic characteristic of synapses and plays an important role in the computation, learning and memory of human brain. Metaplasticity is a higher-order form of synaptic plasticity, which regulates the ability of synapses to generate synaptic plasticity and has a great regulating effect on later learning, memory and coping behaviors. At present, there are rarely reports on the emulation of synaptic metaplasticity in synaptic transistor. In this article, flexible dual-gate indium-zinc-oxide neuromorphic devices on freestanding solid-state proton conducting chitosan electrolyte membrane are designed for metaplasticity emulation. The key synaptic plasticity functions including excitatory postsynaptic current, synaptic paired-pulse response and synaptic pulse train response can be effectively regulated by the priming pulse stimuli. Besides, configurable synaptic depression and synaptic potentiation effect can be realized in such device. These results can expand the potential applications of the multi-terminal electrolyte-gated oxide transistors for flexible dynamic neuromorphic platforms.

Paired-pulse Inhibition and Disinhibition of the Dentate Gyrus Following Orexin Receptors Inactivation in the Basolateral Amygdala.

Introduction:The Basolateral Amygdala (BLA) substantially affects neuronal transmission and synaptic plasticity processes through the dentate gyrus. Orexin neuropeptides play different roles in the sleep/wakefulness cycle, feeding, learning, and memory. The present study aimed to investigate the function of the orexin receptors of the BLA in the hippocampal local interneuron circuits.Methods:For this, the region’s paired-pulse responses from the Dentate Gyrus (DG) were recorded. Within the procedure, SB-334867-A (12μg/0.5μL) and TCS-OX2-29 (10μg/0.5μL (orexin 1 & 2 receptors antagonists, respectively), were administered into both sides of the BLA areas of the rat brain. Dimethyl Sulfoxide (DMSO) was used as the solvent in the control animals with a volume of 0.5μL.Results:Our data indicated that the Paired-pulse (PP) responses were not affected by the inactivation of the orexin receptors of the BLA.Conclusion:Due to not observing any significant changes in the short form of synaptic plasticity, after inactivation of the orexin system of the BLA, we hypothesize that the orexinergic fibers to the basolateral part of the amygdala influence the long-term synaptic efficacy; however, the primary processing of information in short-term plasticity model is not affected by the same system. The elementary processing of the data by the amygdala might happen through the action of other neurotransmitter systems.HighlightsThe neuronal transmission of DG following orexin receptors antagonism of the BLA.Paired-pulse responses were not affected by the orexin 1 receptors antagonism.Paired-pulse responses were not affected by the orexin 2 receptors antagonism.Plain Language SummaryThe orexinergic system has modulatory effects by sending projection fibers to several parts of the brain, such as the hippocampus and amygdala. Orexin neuropeptides activate basolateral amygdala neural circuits during different arousal states. Although, this system plays a vital role in creating appropriate behavioral reactions, the primary processing of the information in short-term plasticity model is not affected by it.

Modulation of long-term and short-term plasticity in the dentate gyrus granule cells by activating the β-adrenergic receptors of the basolateral amygdala

The beta-adrenergic receptors of the basolateral amygdala (BLA) are involved in modulating emotional memory formation in the hippocampus. The molecular mechanisms of this involvement are still unclear. In this study, we investigate the effects of the beta-adrenergic receptors of the BLA involvements during the major cellular mechanisms that underlie memory formation in hippocampal sub-regions. Wistar rats were injected with the selective beta receptor agonist, clenbuterol (15 ng/0.5 μl) bilaterally into the BLA. Then, the long-term potentiation (LTP) and the paired-pulse responses were recorded. Control rats were injected by saline at the same volume. Our data indicated that the injection of clenbuterol into the BLA area enhanced the amplitude of the population spike (PS) but not the slope of the excitatory postsynaptic potential (EPSP). In addition, short-term plasticity in the dentate gyrus (DG) region was significantly changed at 500 ms inter-pulse interval. These results suggest that the activation of the beta-adrenergic receptors of the BLA can improve LTP induction, which depends on the short-term plasticity with a mechanism related to the GABAergic transmission. Thus, it can be concluded that the adrenergic system of the BLA engages with long-term and short-term plasticity.

Effect of ceftriaxone on paired-pulse response and long-term potentiation of hippocampal dentate gyrus neurons in rats with Alzheimer-like disease

AimsGlutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the β-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. Materials and methodsMale Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 μl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. Key findingsResults of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SignificanceTherefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.

Abstract TP588: Underlying Mechanisms Of Preconditioning Against Stroke: Lack Of Ischemic Neuroprotectant Sirt1 Increases Long-term Potentiation Induction In Mice

Sirt1 has been implicated to play a major role in ischemic preconditioning (IPC)—a phenomenon whereby a sublethal episode of ischemia induces tolerance to a subsequent prolonged ischemic insult, such as stroke. Both IPC and pharmacological mimetics (i.e. resveratrol) upregulate Sirt1 activity and expression. Since Sirt1 is thought to regulate the expression of proteins involved in synaptic plasticity, neuroprotection afforded by Sirt1 may be explained by changes in these processes. For this reason, we investigated the effects of Sirt1 deficiency on long-term potentiation (LTP). Using inducible, neuronal-specific Sirt1 knockout mice, acute brain slices were prepared and extracellular field recordings were taken in the CA1 region of the hippocampus. Sirt1 deficiency significantly increased LTP induction (2.08 ± 0.065 fold change relative to a 1.46 ± 0.054 change in wild-type mice; n = 10-11, p = 0.022), suggesting Sirt1 may function to repress the transcription of genes associated with LTP. Paired-pulse facilitation was also significantly increased, where neuronal Sirt1 knockout mice had a 2.10 ± 0.047 fold increase in the paired-pulse response after LTP compared to that of the wild-type control (1.60 ± 0.040; n = 10-11, p = 0.001). These changes were indicative of presynaptic involvement. To test whether similar changes in plasticity occur during the late phase of preconditioning, wild-type mice were treated with resveratrol or a vehicle control and subjected to electrophysiological recordings ex vivo 48 hours later. However, no differences in LTP induction or paired-pulse facilitation were observed. Thus, it is unclear whether protection mediated by resveratrol preconditioning involves changes in synaptic plasticity. Since Sirt1 is capable of deacetylating many histone and non-histone proteins, its effects on transcription and gene expression may vary depending on its activity and period of activation. It is probable that during the extended window of ischemic tolerance, Sirt1 may exert different effects than that of the early or classical late phase. Thus, future studies investigating the effects of Sirt1 on plasticity across different time windows of IPC may shed light on new, more direct targets that can mimic or facilitate preconditioning.

Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats.

Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer's disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD.

Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction.

The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with ryanodine (1 μM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory ryanodine (20 μM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naïve) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 μM ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naïve slices pre-incubated with inhibitory ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naïve control slices. We posit that inhibitory ryanodine suppressed LTD-induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR-mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses.

Platform Session – NIBS: Spatiotemporal dynamics of single and paired pulse TMS-EEG responses in healthy subjects

Introduction Transcranial magnetic stimulation (TMS) is used for assessing cortical excitability in a variety of neurological disorders. Additional information from inhibitory and excitatory networks can be obtained with paired pulse stimulation. Combining TMS with electroencephalography (EEG) allows assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spread and distribution of single and paired pulse TMS-EEG responses in healthy controls. As cortical excitability is modified in various central nervous system disorders and for central acting drugs, these patterns can serve as a reference for future neurological and pharmacological studies. Methods Thirty healthy subjects (10 males, mean age 28.4 ± 8.2 years) underwent a single and paired pulse TMS-EEG session. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 50, 100, 150, 200, 250 and 300 ms. The cluster based permutation test (FieldTrip; http://www.fieldtriptoolbox.org ) was used to analyze the spatiotemporal dynamics of the TMS-EEG response. Significant clusters were formed based on adjacent time bins and neighboring electrodes using 64-channel EEG data. Results Single pulse TMS-EEG responses showed the characteristic P30, N45, P55, N100 and P180 components at channel Cz. The P30 cluster was located centro-parietal in the ipsilateral hemisphere, the N45 centro-frontal contralateral, the P55 parieto-temporal ipsilateral, the N100 central contralateral and the P180 central contralateral and parieto-temporal ipsilateral. Both hemispheres showed a mirrored single pulse TMS-EEG response. For ISI 250 ms, the paired pulse TMS-EEG response also showed the characteristic components at Cz. However, the amplitudes were much smaller compared to single pulse stimulation. Furthermore, fewer, smaller and shorter-lasting significant clusters were found. For ISI 100 ms, no TMS-EEG components were visible at Cz and the response amplitude was much smaller compared to the single pulse response. Next, we will also compare single and paired pulse responses for the other ISIs (50, 150, 200 and 300 ms). Conclusion Stimulation of both hemispheres showed a mirrored single pulse TMS-EEG response. Paired pulse stimulation resulted in fewer, smaller and shorter-lasting clusters compared to single pulse TMS. In combination with a smaller response amplitude, this indicates inhibition of cortical excitability after a conditioning first stimulus. These spatiotemporal dynamics of the single and paired pulse TMS-EEG responses in healthy controls can serve as reference values for future TMS-EEG studies.

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D1 - and D2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A2A receptors (A2A R) also control PFC-related responses and A2A R antagonists are potential anti-psychotic drugs. As tight antagonistic A2A R-D2 R and synergistic A2A R-D1 R interactions occur in other brain regions, we now investigated the crosstalk between A2A R and D1 /D2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D2 R-like antagonist sulpiride but not by the D1 R antagonist SCH23390 and was mimicked by the D2 R agonist sumanirole, but not by the agonists of either D4 R (A-412997) or D3 R (PD128907). Dopamine inhibition was prevented by the A2A R antagonist, SCH58261, and attenuated in A2A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A2A R and D2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A2A R-D2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A2A R antagonists.

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

BackgroundInhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2–3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively.Objective/Hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI. MethodsPpTMS-EEG was applied to the left motor cortex in 16 healthy subjects in a randomized, double-blind placebo-controlled crossover design, testing the effects of a single oral dose 20 mg of diazepam, a positive modulator at the GABAA receptor, vs. 50 mg of the GABAB receptor agonist baclofen on SICI of TEPs. ResultsWe found significant SICI of the N100 and P180 TEPs prior to drug intake. Diazepam reduced SICI of the N100 TEP, while baclofen enhanced it. Compared to our previous ppTMS-EEG results on LICI, the SICI effects on TEPs, including their drug modulation, were largely analogous. ConclusionsFindings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle.

P.2.021 - Functional changes in the dorsolateral striatum in loss of control over reward seeking

Substance addiction inflicts an enormous burden on patients with formidable costs to society. Loss of control over substance use is a hallmark of addiction. It marks the stage where substance use has progressed from casual to compulsive and persists despite negative consequences. It is thought that this progression arises after lengthy and excessive substance use, as a result of neurobiological dysfunctions. One of the neural mechanisms that has been proposed to contribute to loss of control use is exaggerated involvement of the dorsolateral striatum (DLS), which mediates habitual behaviour [1,2]. This study examines how changes in DLS functioning contribute to loss of control over reward seeking. First, we assessed the effect of long-term exposure to alcohol on synaptic plasticity in a cortical projection onto neurons in the DLS. To map cortical inputs towards the DLS, rats were bilaterally injected with a retrograde rabies virus (Rabies-SadDG-GFP) in the DLS. Using immunohistochemistry, we found GFP expression in different cortical areas, including the primary and secondary motor cortex. Next, voluntary home-cage alcohol consumption was monitored in outbred Lister-Hooded rats. We used a two-month intermittent alcohol access paradigm and found substantial individual variation in alcohol intake, consistent with our previous findings. Based on a rank score of their voluntary alcohol intake, low and high consuming animals were then selected and bilaterally injected with an adeno-associated Channelrhodopsin virus (AAV5-CamKII-Chr2-eYFP) targeted at the identified motor cortices that project onto neurons in the DLS. Whole-cell patch clamp recordings were performed to measure optically induced excitatory post-synaptic currents in neurons in the DLS. Our preliminary results indicate increased facilitation of paired-pulse responses in the DLS in rats that show a high voluntary alcohol consumption. This increase is caused by reduced amplitude of the first post-synaptic response, indicative of a reduced presynaptic release probability. In parallel, we assessed whether activation of the DLS is sufficient to drive habitual behaviour and loss of control over sucrose seeking. To investigate habitual behavior, changes in sensitivity for outcome devaluation were measured after pre-feeding animals with either sucrose or chow before operant training. Loss of control over sucrose seeking was examined in a task in which we measure continued responding during a conditioned cue that predicts probabilistic footshock punishment. To enhance neuronal activity of the DLS, rats received bilateral injections of an adeno-associated DREADD virus (AAV5-hSyn-hMD3q-mCherry). Systemic clozapine N-oxide (CNO) injections did not change the sensitivity to outcome devaluation. Furthermore, we show that the presentation of the footshock-predictive cue profoundly suppresses responding for sucrose, but this is unaffected by CNO injections. In sum, our data indicate that long-term ingestion of large quantities of alcohol modulates short-term synaptic plasticity in glutamatergic cortical inputs into the DLS. However, chemogenetic activation of the DLS does not seem sufficient to evoke habitual or compulsive behaviour.

Altered functional efficacy of hippocampal interneuron during epileptogenesis following febrile seizures.

Febrile seizure (FS) is the most common seizure type in infants and young children. FS may induce functional changes in the hippocampal circuitries. Abnormality of excitatory and inhibitory neurotransmissions was previously related to wide-spread seizure attack in the hippocampus following recurrent seizure onset. To clarify the involvement of expressional changes and functional alterations of hippocampal interneurons with epileptogenesis following FS, we investigated long-term effects following recurrent seizure in a hyperthermia-induced seizure animal model. At 12 weeks following FS, the recurrent seizure time period, local field potentials (LFP) revealed high amplitude potential and a sharp wave characteristic of epilepsy. Mossy fiber reorganization in the hippocampus was also detected as abnormal synaptic connection at 8 weeks. Calretinin (CR) -positive interneurons were transiently enhanced during epileptogenic period at 7-9 weeks after FS in the CA1 and DG region and it is double labeled with VGLUT-1. However, although GABAA-α1 immunoreactivities were un-changed as similar to control hippocampus at 7-9 weeks after seizure onset, its expression was significantly enhanced at 4 weeks and 12 weeks and it is colocalized with GABA. Furthermore, the field excitatory postsynaptic potential (fEPSP) and the paired-pulse responses including population spike (PS) latency, excitability ratio and PS2/PS1 ratio were markedly altered in the CA1 and DG region at 12 weeks after FS. Therefore, our findings in present study indicate that these time-dependent changes may be based on the persistent alterations of hippocampal neuronal circuits in balance between excitatory and inhibitory responses, and may lead to the epileptogenesis and spread of seizure activity following FS.

Corticospinal excitability measurements using transcranial magnetic stimulation are valid with intramuscular electromyography

ObjectivesMuscular targets that are deep or inaccessible to surface electromyography (sEMG) require intrinsic recording using fine-wire electromyography (fEMG). It is unknown if fEMG validly record cortically evoked muscle responses compared to sEMG. The purpose of this investigation was to establish the validity and agreement of fEMG compared to sEMG to quantify typical transcranial magnetic stimulation (TMS) measures pre and post repetitive TMS (rTMS). The hypotheses were that fEMG would demonstrate excellent validity and agreement compared with sEMG.Materials and methodsIn ten healthy volunteers, paired pulse and cortical silent period (CSP) TMS measures were collected before and after 1200 pulses of 1Hz rTMS to the motor cortex. Data were simultaneously recorded with sEMG and fEMG in the first dorsal interosseous. Concurrent validity (r and rho) and agreement (Tukey mean-difference) were calculated.ResultsfEMG quantified corticospinal excitability with good to excellent validity compared to sEMG data at both pretest (r = 0.77–0.97) and posttest (r = 0.83–0.92). Pairwise comparisons indicated no difference between sEMG and fEMG for all outcomes; however, Tukey mean-difference plots display increased variance and questionable agreement for paired pulse outcomes. CSP displayed the highest estimates of validity and agreement. Paired pulse MEP responses recorded with fEMG displayed reduced validity, agreement and less sensitivity to changes in MEP amplitude compared to sEMG. Change scores following rTMS were not significantly different between sEMG and fEMG.ConclusionfEMG electrodes are a valid means to measure CSP and paired pulse MEP responses. CSP displays the highest validity estimates, while caution is warranted when assessing paired pulse responses with fEMG. Corticospinal excitability and neuromodulatory aftereffects from rTMS may be assessed using fEMG.

T019 models of neuronal response to suprathreshold electric fields

Introduction Existing models of non-invasive brain stimulation focus almost exclusively on the calculation and analysis the electric field distribution. This information is necessary but insufficient to predict the effect of the stimulation, which also depends on the response of neurons and neuronal networks to the applied electric field. Objectives To determine the current status of models of neuronal response to suprathreshold electric fields induced by transcranial magnetic stimulation (TMS) and point out limitations and future perspectives. Materials & methods Presentation of a critical overview of studies that model the effect of TMS on neurons and neuronal networks. Results In neuronal stimulation, changes in membrane potential are driven by ionic currents through membrane channels. Action potentials are due to the response of voltage-dependent channels to suprathreshold stimuli. It is well established that only the component of the electric field tangent to the trajectory of a neuron, E s , can alter its membrane potential. In TMS, changes in membrane polarization are most pronounced at terminations and bends, and are proportional to E s and the membrane length constant, λ . These results are usually modelled in terms of Hodgkin–Huxley (HH) type models for the membrane, and the cable model for elongated neuronal structures. The few published studies modelling suprathreshold neuronal responses to TMS vary considerably in their approach. Studies trying to identify stimulation sites looked in more detail at the distribution of the induced electric field and at the neuronal paths within that field. Another study included a detailed description of the morphology and the electrophysiological parameters of a single neuron to investigate the characteristics of the neuronal response to TMS. In the best known study, a detailed model of the motor thalamocortical system implemented. This model could reproduced the generation of I-waves and paired pulse responses. Conclusion Investigating different features of neuronal responses to suprathreshold stimuli requires modelling at different scales, from single neuron to complex networks. The choice of an appropriate scale will depend on the question to be addressed.

Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice

Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice