Alarin potentiates ongoing epileptiform activity in rat brain slices: an in vitro electrophysiological study.

Alarin is a newly discovered neuropeptide that belongs to the galanin peptide family with a wide range of bioactivity in the nervous system. Its function in the brain's autonomic areas has been studied, and it has been reported that alarin is involved in the regulation of excitability in hypothalamic neurons. Its role in the regulation of excitability in the hippocampus, however, is unknown. In this study, we investigated if alarin induced any synchronous discharges or epileptiform activity, and if it had any effect on already initiated epileptiform discharges. We used thick acute horizontal hippocampal slices obtained from 30­ to 35­day­old rats. Extracellular field potential recordings were evaluated in the CA1 region of the hippocampus. Our data demonstrated that, alarin application did not result in any epileptiform activity or abnormal discharges. 4­aminopyridine was applied to induce epileptiform activity in the slices. We found that alarin increased the frequency of interictal­like events and the mean power of local field potentials in the CA1 region of the hippocampus, which was induced by 4­aminopyridine. These results demonstrated for the first time that alarin has a modulatory effect on synchronized neuronal discharges and showed the contribution of the neuropeptide alarin to epilepsy­like conditions.

Effects of housing conditions on stress, depressive like behavior and sensory-motor performances of C57BL/6 mice.

BACKGROUND: The effects of housing conditions on animal physiology, behavior or stress are still debated. The aim of this study was to investigate the effects of three different housing systems, individually ventilated cages (IVC), classical small cages with floor surface area of 500 cm2 (CC500) and classical large cages with floor surface area of 800 cm2 (CC800) on body weight, sensory-motor performances, depression-like behavior, plasma corticosterone and brain oxidative stress parameters in C57BL/6 mice. The mice housed in one of the cages from birth to 6 months of age. Hang wire and adhesive removal tests were performed to evaluate somatosensory and motor performances. The extent of depression was determined by the forced swim test. Blood corticosterone levels were measured. In addition, brain malondialdehyde (MDA), total antioxidant status (TAS) and total oxidant status (TOS) levels were analyzed. RESULTS: The depression-like behavior of the groups was similar. Although there were no significant differences in hang wire test among groups, CC500 group required longer durations in adhesive removal test. The body weight and plasma corticosterone levels of CC800 group were significantly higher than other groups. The oxidative stress parameters were highest in CC500 cage. CONCLUSIONS: Our study showed that the least stressful housing condition was IVC cage systems. Interestingly, the number of mice in the classical cages had a significant effect on stress levels and sensory-motor performance.

Fisetin decreases the duration of ictal-like discharges in mouse hippocampal slices.

There is an increasing interest in the biological and therapeutic effects of fisetin, a natural phenolic compound. Fisetin has affinity on some neuronal targets and may have the potential to modulate neuronal activity. In this study the effects of acute application of fisetin on synchronized events were evaluated electro-physiologically. Besides, interaction of fisetin with closely related channels were investigated in silico. Acute horizontal hippocampal slices were obtained from 32- to 36-day-old C57BL/6 mice. Extracellular field potentials were recorded from CA3 region of the hippocampus. Bath application of 4 aminopyridine (4AP, 100 µM) initiated ictal- and interictal-like synchronized epileptiform discharges in the brain slices. Fifty micromolar fisetin was applied to the recording chamber during the epileptiform activity. The duration and frequencies of both ictal-like and interictal-like activities were calculated from the electrophysiological records. Molecular docking was performed to reveal interaction of fisetin on GABA-A, NMDA, AMPA receptors, and HCN2 channel, which are neuronal structures directly involved in recorded activity. Although fisetin does not affect basal neuronal activity in brain slice, it reduced the duration of ictal-like discharges significantly. Molecular docking results indicated that fisetin has no effect on GABA-A, NMDA, and AMPA receptors. However, fisetin binds to the (5JON) HCN2 channel strongly with the binding energy of -7.66 kcal/mol. Reduction on the duration of 4AP-induced ictal-like discharges can be explained as HCN channels can cause an inhibitory effect via enhancing M-type K + channels which increase K outward currents.

The regulation of adipokines related to obesity and diabetes is sensitive to BDNF levels and adipose tissue location.

PURPOSE: The role of BDNF in adipose tissue metabolism is poorly understood. We investigated the effects of decreased levels of BDNF on the expression of major adipokines in different fat depots (e.g., subcutaneous and epididymal) of mouse groups fed three different diet protocols. METHODS: BDNF heterozygous (+ / -) mice were used to evaluate the effect of reduced BDNF levels. Six groups of C57BL/6 J breed wild type (WT) and BDNF (+ / -) mice were formed. These groups were fed, respectively, a control diet (CD), a high-fat diet (HFD), and a high-sucrose diet (HSD) for 4 months. Serum samples and adipose tissues were used for biochemical assays. The serum concentrations and tissue expression levels of leptin, adiponectin, and resistin were measured. RESULTS: Compared to the CD-fed WT group (control group), serum leptin and leptin expression levels were found to be higher in all experimental groups. Serum adiponectin levels were lower in the BDNF (+ / -) groups and HFD-fed WT group than in the control group. Epididymal adiponectin expression was found to be lower in the HFD-fed BDNF (+ / -) group and higher in HSD-fed groups than in the control group. Compared to the control group, adiponectin expression increased in the WT groups in subcutaneous adipose tissue. Serum resistin levels were elevated in the HFD-fed groups. Resistin expression in epididymal adipose tissue was lower in the CD-fed and HFD-fed groups than in the control group. CONCLUSIONS: BDNF levels and diet differentially affect the expression of adipokines in different fat tissues in the body. BDNF may play a protective role in obesity and diabetes.

Phoenixin-14 reduces the frequency of interictal-like events in mice brain slices.

Phoenixin-14 (PNX-14) has a wide bioactivity in the central nervous system. Its role in the hypothalamus has been investigated, and it has been reported that it is involved in the regulation of excitability in hypothalamic neurons. However, its role in the regulation of excitability in entorhinal cortex and the hippocampus is unknown. In this study, we investigated whether i. PNX-14 induces any synchronous discharges or epileptiform activity and ii. PNX-14 has any effect on already initiated epileptiform discharges. We used 350 µm thick acute horizontal hippocampal-entorhinal cortex slices obtained from 30- to 35-day-old mice. Extracellular field potential recordings were evaluated in the entorhinal cortex and hippocampus CA1 region. Bath application of PNX-14 did not initiate any epileptiform activity or abnormal discharges. 4-Aminopyridine was applied to induce epileptiform activity in the slices. We found that 200 nM PNX-14 reduced the frequency of interictal-like events in both the entorhinal cortex and hippocampus CA1 region which was induced by 4-aminopyridine. Furthermore, PNX-14 led to a similar suppression in the total power of local field potentials of 1-120 Hz. The frequency or the duration of the ictal events was not affected. These results exhibited for the first time that PNX-14 has a modulatory effect on synchronized neuronal discharges which should be considered in future therapeutic approaches.

The TrkB agonist 7,8-dihydroxyflavone improves sensory-motor performance and reduces lipid peroxidation in old mice.

7,8-Dihydroxyflavone (7,8-DHF) is a natural flavonoid compound that act as Trk-B agonist. 7,8-DHF is also a potent antioxidant. When applied systematically, 7,8-DHF can pass through blood-brain barrier and exhibit potential therapeutic effects in several animal models of neurodegenerative disorders. This study investigates the remedial effects of 7,8-DHF on behavioral impairments and biochemical changes associated with aging with a species emphasis on cortex. For this purpose three experimental groups were formed which are young control group, old group and old-DHF groups. 5 mg/kg 7,8-DHF was administered intraperitoneally to old-DHF group for 3 weeks. We assessed the hang wire and adhesive removal performances of mice. Also, oxidative stress, neuroinflammation and synaptic protein levels in the cortex were measured. We observed that chronic administration of 7,8-DHF improved behavioral performance of old mice. Besides, 7,8-DHF reversed MDA level which was increased in old control animals. However, 3 weeks application of 7,8-DHF failed to recover the levels of neuroinflammation markers (TNF-α and IL-6) and synaptic proteins (PSD-95 and Synaptophysin) which were reduced in old group. These findings demonstrate that improvement of age-dependent behavioral impairments and MDA levels by 7,8-DHF could be attributed to its antioxidant actions.

Renal response to tunicamycin-induced endoplasmic reticulum stress in BDNF heterozygous mice.

BACKGROUND: The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported. OBJECTIVES: The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress. MATERIAL AND METHODS: Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/-)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/-), WT+Tm, and BDNF(+/-)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function. RESULTS: Circulating and tissue BDNF levels were significantly lower in the BDNF(+/-) and BDNF(+/-)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/-)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/-)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/-)+Tm (p < 0.05) groups. CONCLUSIONS: This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.

7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices.

In the central nervous system, Tropomyosin-receptor-kinase B (TrkB) signaling is involved in neuronal survival, differentiation as well as in regulation of synaptic transmission and excitability. As its powerful potential to modulate neuronal functions, TrkB pathway is an attractive target for novel drugs and treatment of common neurological disorders. 7,8-Dihydroxyflavone (DHF), a TrkB receptor agonist, has similar properties with neurotrophin Brain Derived Neurotropic Factor (BDNF). DHF is reported to have a number of beneficial effects in neuroprotection, against depression and improving learning and memory. However, the outcome of acute application of DHF on the excitability of neuronal circuits is not clear. Especially the effects of DHF on synchronized epileptiform activity are not known. In this study, we investigated whether DHF induces epileptiform activity in brain slices and DHF has any effect on already initiated epileptiform discharges. We used acute horizontal hippocampal-entorhinal cortex slices obtained from 30 to 35 days of mice. Extracellular field potential recordings were obtained from entorhinal cortex (EC) and hippocampus CA1 region. DHF did not initiate any epileptiform activity or abnormal discharges. However, DHF increased the frequency of 4 aminopyridine (4AP) induced ictal and interictal events in both EC and CA1. The duration of induced ictal charges were also prolonged upon DHF application. In a number of slices, both EC and CA1, DHF led to ictogenesis. These results suggest that the acute activation of TrkB by DHF has a powerful potential on synchronized neuronal discharges which should be considered in future therapeutical approaches.

Effect of a high sucrose and high fat diet in BDNF (+/-) mice on oxidative stress markers in adipose tissues.

The purpose of this study was to investigate the effects of a high fat and a high sucrosediet in wild type and BDNF (+/-) mice on oxidative stress in epididymal and subcutaneousadipose tissues by measuring different markers of oxidative stress and antioxidant enzymes. Wild type (WT) and BDNF (+/-) male mice were divided into six groups receiving fed control diet (CD), high sucrose diet (HSD), or high fat diet (HFD) for four months. Levels of 3-nitrotyrosine (3-NT) increased in the HFD-fed BDNF (+/-) mice, while 4-hydroxynonenal (4-HNE) levels increased in the CD and HFD-fed BDNF (+/-) groups. Malondialdehyde (MDA) levels decreased in subcutaneous tissue compared to epididymal adipose tissue, independently of diet type. Superoxide dismutase (SOD) activity was reduced by HFD (p < 0.05), butglutathione peroxidase (GSH-Px) activity was increased by HSD in epididymal adipose tissuein BDNF (+/-) mice (p < 0.05). GSH-Px activities was increased by CD and HFD in subcutaneous adipose tissue of BDNF (+/-) (p < 0.05). SOD2 and GSH-Px3 expressions were only decreased by HSD in epididymal and subcutaneous adipose tissues of BDNF (+/-) mice (p < 0.05). In conclusion, reduced BDNF may increase OS in epididymal adipose tissue, but not in subcutaneous adipose tissue following HSD and HFD.

Endoplasmic reticulum stress in the livers of BDNF heterozygous knockout mice.

Context: Involvement of endoplasmic reticulum (ER) stress and brain-derived neurotrophic factor (BDNF) in hepatic lipid metabolism has been reported previously. Objective: The effects of chronic BDNF deficiency on ER stress response in the livers were examined in this study. Methods: BDNF(+/-) mice, characterised by BDNF deficiency, and their wild-type (WT) littermates were used. The ER stress was induced by tunicamycin (Tm) (0.5 mg/kg, intraperitoneal). Animals were divided into four groups; WT, WT + Tm, BDNF(+/-), and BDNF(+/-)+Tm. Results: At the basal conditions, BDNF deficiency did not affect hepatic cell death or lipid accumulation. However, during ER stress, BDNF(+/-)+Tm group showed increased apoptosis, GADD153 immunostaining, sterol regulatory element-binding protein-1c (SREBP-1c) level, and steatosis compared to the WT + Tm group. Conclusion: Endogenous BDNF might be protective against apoptosis through GADD153 suppression and steatosis via SREBP-1c suppression during ER stress. This effect of BDNF might be clinically important for type 2 diabetes and obesity, which are related with both ER stress and BDNF deficiency.

Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice.

Brain Derived Neurotropic Factor (BDNF) is a neutrophic factor that is required for the normal neuronal development and function. BDNF is involved in regulation of synapses as well as neuronal excitability. Entorhinal Cortex (EC) is a key brain area involved in many physiological and pathological processes. In this study we investigated the effects of chronically reduced BDNF levels on layer 3 pyramidal neurons of EC. We aimed to assess the effects of reduced levels of BDNF on firing properties, spontaneous synaptic currents and excitation/inhibition balance from acute brain slices. Patch clamp recordings were obtained from pyramidal neurons of Entorhinal Cortex Layer 3. Findings of BDNF heterozygous (BDNF (+/-)) mice compared to their wild-type littermates at the age of 23-28 days. Action potential threshold was shifted (p = 0,002) to depolarized potentials and spike frequency was smaller in response to somatic current injection steps in BDNF (+/-) mice. Spontaneous synaptic currents were also affected. sEPSC amplitude (p = 0,009), sIPSC frequency (p = 0,001) and sIPSC amplitudes (p = 0,023) were reduced in BDNF (+/-). Decay times of sIPSCs were longer in BDNF (+/-) (p = 0,014). Calculated balance of excitatory/inhibitory balance was shifted in the favor of excitation in BDNF (+/-) mice (p = 0,01). These findings suggest that reductions in concentrations of BDNF results in altered status of excitability and excitation/inhibition imbalance. However, these differences observed in BDNF (+/-) seem to have opposing effects on neuronal activity.

Brain-derived neurotropic factor (BDNF) heterozygous mice are more susceptible to synaptic protein loss in cerebral cortex during high fat diet.

In this study we aimed to investigate whether reduced BDNF levels aggravate the susceptibility of the brain to hazardous effects of high fat diet. For this purpose, we fed BDNF heterozygous mice and wild type littermates with normal and high fat diet for 16 weeks. Concentrations of two synaptic proteins (SNAP-25 and PSD-95) and oxidative stress parameters (MDA, SOD, CAT) were evaluated in the cortex after diet period. Interestingly, body weights of BDNF heterozygous groups fed with control diet were higher than their littermates and heterozygous mice fed with HFD were the heaviest in all experimental groups. MDA levels were significantly elevated in both HFD groups (wild type and BDNF(+/-)). Synaptic markers PSD-95 and SNAP-25 markedly decreased in BDNF(+/-) group fed with HFD compared to other groups. In conclusion, we suggest that endogenous BDNF has an important and possibly protective role in diet-induced changes in the cortex.

Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study.

In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin-treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 µl). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability.

Chronic application of topiramate and carbamazepine differentially affects the EEG and penicillin-induced epileptiform activity in rats.

Carbamazepine (CBZ) and topiramate (TPM) are among commonly used antiepileptic drugs. The acute actions of these drugs are well known but the effects of long-term use on partially induced epileptiform characteristics are yet to be clarified. The rats were received CBZ (154 mg/kg/day), TPM (10 mg/kg/day) or tap water by gavage. We investigated penicillin-induced cortical epileptiform activity and electroencephalogram spectral power of rats by using electrocorticogram recordings. Animals were anesthetized with i.p. urethane (1·25 g/kg). Analysis of electroencephalogram recordings prior to epileptiform activity revealed that 3-week treatment of CBZ significantly increased relative power of delta (P<0·01) while reduced alpha (P<0·017) and beta (P<0·017) relative power compared to both control group and TPM group. TPM had no effect on absolute power and relative power of any frequency band. TPM treatment of 21 days significantly reduced the spike frequency (P<0·01). This preventive effect was missing in CBZ-treated rats. Upon the application of the last dose of drugs during ongoing epileptiform activity, the drugs suppressed the epileptiform activity. However, TPM was more rapid and effective than CBZ. In conclusion, our in vivo electrophysiological data suggest that TPM is more effective in animal model of partial epilepsy at the applied doses in this study.

Comparison of focally induced epileptiform activities in C57BL/6 and BALB/c mice by using in vivo EEG recording.

Epilepsy characterized by repeated seizures is influenced by genetic factors. Seizure response of inbred mouse strains changes depending on the variety of stimuli including chemical (e.g., pentylenetetrazole, nicotine, cocaine, NMDA, kainate), physical (e.g., auditory) or electrical. In this study, we compared the susceptibilities of C57BL/6 and BALB/c mice strains to penicillin induced epileptiform activity (a focally induced, experimental epilepsy model), by analyzing the spike onset latency, spike amplitude and spike frequency. The power spectrums of baseline EEGs were also investigated. We found no alterations of spike onset latencies between the C57 and BALB mice. However, spike amplitudes and spike frequencies were found to be higher in BALB mice than C57 mice. With regard to EEG power spectrum, absolute power of investigated bands was not different between the two strains. Interestingly, the relative power of all investigated bands differed significantly between two strains. The relative power of delta and theta was lower whereas relative power of alpha, beta and gamma was higher in C57 mice compared to BALB mice. In conclusion, our findings showed that BALB mice are more sensitive to penicillin induced epileptiform activity when compared to C57 strain.

Penicillin induced epileptiform activity and EEG spectrum analysis of BDNF heterozygous mice: an in vivo electrophysiological study.

Brain-derived neurotrophic factor (BDNF) heterozygous mice (BDNF (+/-)) kindle slowly and have a higher seizure threshold. However, BDNF (+/-) mice exhibit reduced cortical inhibition and disrupted balance of excitation/inhibition synaptic transmission. We investigated penicillin-induced focal cortical epileptiform activity and electroencephalogram (EEG) spectral power of BDNF (+/-) mice, by using electrocorticogram (ECoG) recordings. BDNF (+/-) mice (n=10) and wild type littermates (n=9) were anesthetized with i.p. urethane (1.750g/kg). The recordings of ECoG were carried out by using a data acquisition system and 100IU penicillin was administered intracortically to induce epileptiform activity. The latencies for the onset of spikes and the amplitude of the spikes showed no differences. However the frequency of the spikes was significantly lower in BDNF (+/-) mice at 40th and 45th min following penicillin injection. Additionally, the EEG power for both BDNF (+/-) and wild type mice reduced after penicillin injection and enhanced during epileptiform activity. The spectral power analysis also revealed that the absolute Gamma power of BDNF (+/-) was significantly smaller than wild types. The results of the present study provide the first in vivo electrophysiological evidence that BDNF heterozygous mice exhibited suppressed epileptiform activity. Moreover, reduced levels of BDNF led to a reduction of absolute Gamma band power.

θ burst and conventional low-frequency rTMS differentially affect GABAergic neurotransmission in the rat cortex.

Modified cortical excitability following repetitive transcranial magnetic stimulation (rTMS) may be related to short- or long-term synaptic plasticity of neuronal excitation but could also affect cortical inhibition. Therefore, in the rat we tested how three different rTMS protocols, intermittent and continuous theta-burst (iTBS, cTBS), and low-frequency 1 Hz stimulation, change the expression of GAD65, GAD67 and GAT-1 which are expressed in cortical inhibitory interneurons in an activity-dependent manner. Acutely (2 h), all protocols reduced the expression of GAD67 in frontal, motor, somatosensory and visual cortex but increased that of GAD65 and GAT-1 to different degree, with iTBS having the strongest acute effect. The initial decrease in GAD67 reversed after 1 day, leading to a strong increase in GAD67 expression for up to 7 days primarily in the frontal cortex in case of iTBS, cTBS and in all studied areas following 1 Hz rTMS. While also GAD65 and GAT-1 expression reversed after 1 day in case of iTBS and cTBS, 1 Hz rTMS induced a steady increase in GAD65 and GAT-1 expression during the 7 days investigated. Our data demonstrate that rTMS affects the expression of activity-dependent proteins of the cortical inhibitory interneurons. Besides common effects of low- (1 Hz) and high-frequency (TBS) stimulation on protein expression, differences in quantity and time course of changes point to differences in the contribution of possible neuronal subsystems. Further studies are needed to distinguish cell-type specific effects.

Locus coeruleus activation facilitates memory encoding and induces hippocampal LTD that depends on beta-adrenergic receptor activation.

Spatial memory formation is enabled through synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. It is, however, unclear how relevant spatial information is selected for encoding, in preference to less pertinent information. As the noradrenergic locus coeruleus (LC) becomes active in response to novel experiences, we hypothesized that the LC may provide the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Test pulse stimulation evoked stable basal synaptic transmission at Schaffer collateral (SC)-CA1 stratum radiatum synapses in freely behaving adult rats. Coupling of these test pulses with electrical stimulation of the LC induced long-term depression (LTD) at SC-CA1 synapses and induced a transient suppression of theta-frequency oscillations. Effects were N-methyl-D-aspartate and beta-adrenergic receptor dependent. Activation of the LC also increased CA1 noradrenalin levels and facilitated the encoding of spatial memory for a single episode via a beta-adrenoceptor-dependent mechanism. Our results demonstrate that the LC plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This LC-hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing.

High- and low-frequency repetitive transcranial magnetic stimulation differentially activates c-Fos and zif268 protein expression in the rat brain.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability depending on the stimulus-frequency used, with high frequency (5 Hz and higher) increasing it but low frequency (usually 1 Hz or lower) reducing it. To determine the efficiency of different rTMS protocols in inducing cortical network activity, we tested the acute effect of one low-frequency rTMS protocol (1 Hz) and two different high-frequency protocols (10 Hz and intermittent theta-burst stimulation, iTBS) on the expression of the two immediate early gene (IEG) proteins c-Fos and zif268 in the rat brain. The cortical expression of both IEGs was specifically changed in an rTMS-dependent manner. One and 10 Hz rTMS enhanced c-Fos protein expression in all cortical areas tested, while iTBS was effective only in limbic cortices. Zif268 expression was increased in almost all cortical areas after iTBS, while 10 Hz rTMS was effective only in the primary motor and sensory cortices. One Hertz rTMS had no effect on cortical zif268 expression. Furthermore, sham-rTMS had no effect on zif268 expression but increased c-Fos in limbic cortices. This is the first study demonstrating that cortical zif268 and c-Fos expression can be specifically modulated by acute rTMS depending on the pattern of stimulation applied.

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.