Synaptic depression in visual cortex tissue slices: an in vitro model for cortical neuron adaptation

Synaptic depression was assessed from intracellular recordings in cortical tissue slices. Evoked postsynaptic potentials exhibited synaptic depression with an exponential or double exponential decrease (time constants: <1–30 s) in amplitude during repetitive afferent stimulation by short trains of suprathreshold stimuli. Depressed synaptic responses recovered with an exponential time course (time constants: 10 s-8 min) during presentation of similar short trains of stimuli every 5 or 10 s. Cortical cells recorded extracellularly in cat visual cortex show similar time constants of response decrement during adaptation to moving stripes. Postsynaptic voltage- or ion-regulated conductances and chloride conductances do not appear to be involved in synaptic depression. Input resistance changes and effects of injection of chloride indicate a lack of GABA_A receptor-mediated effects. Hyperpolarizing or depolarizing neurons, and pairing polarization with afferent stimulation, also did not affect synaptic depression. This distinguishes these processes from long-term depression and long-term potentiation. Our results suggest that the most likely mechanisms of synaptic depression and adaptation in cortical cells are presynaptic decrease in transmitter release and/or receptor desensitization. Short-term postsynaptic changes may also occur after synaptic depression.     

Long-term depression induced by sensory deprivation during cortical map plasticity in vivo

Cortical map plasticity is thought to involve long-term depression (LTD) of cortical synapses, but direct evidence for LTD during plasticity or learning in vivo is lacking. One putative role for LTD is in the reduction of cortical responsiveness to behaviorally irrelevant or unused sensory stimuli, a common feature of map plasticity. Here we show that whisker deprivation, a manipulation that drives map plasticity in rat somatosensory cortex (S1), induces detectable LTD-like depression at intracortical excitatory synapses between cortical layer 4 (L4) and L2/3 pyramidal neurons. This synaptic depression occluded further LTD, enhanced LTP, was column specific, and was driven in part by competition between active and inactive whiskers. The synaptic locus of LTD and these properties suggest that LTD underlies the reduction of cortical responses to deprived whiskers, a major component of S1 map plasticity.     

Cellular mechanisms of long-term depression induced by noradrenaline in rat prefrontal neurons

Noradrenaline (NA) is released in the prefrontal cortex (PFC) during salient behavioral phases and thought to modulate PFC-mediated cognitive functions. However, cellular actions of NA in PFC neurons are still not well understood. In the present study, we investigated long-term effects of bath-applied NA (12.5 min) on glutamatergic synaptic transmission in rat PFC pyramidal neurons maintained in vitro. We found that NA concentration-dependently (5 μM≤[NA]≤20 μM) induces long-term depression (LTD) of layer I–II to layer V pyramidal neuron glutamatergic synapses. NA acts through α1- and α2-adrenoceptors, but not β-adrenoceptors, to induce LTD. This NA-induced LTD depends on concurrent single synaptic activations of N-methyl-d-aspartate (NMDA) receptors and requires the activation of protein kinase C and postsynaptic Extracellular signal-Regulated Kinases (ERK1/2). Western blot analyses showed that NA (20 μM for 12.5 min) indeed induces transient increases of ERK1/2 phosphorylation in PFC neurons, which is dependent at least in part on the activation of NMDA receptors and α1-adrenoceptors. Together, these results demonstrate that NA can lastingly depress glutamatergic synapses in rat PFC neurons through mechanisms involving α-adrenoceptors, NMDA receptors, and the activation of postsynaptic ERK1/2.     

Long-term increases in neuronal activity in the motor cortex evoked by simultaneous stimulation of the thalamus and somatosensory cortex in cats

Experiments on anesthetized cats were used to study the activity of motor cortex neurons (field 4γ) in response to separate and simultaneous stimulation of the ventrolateral nucleus of the thalamus and the somatosensory cortex (field 2) of the brain. Long-term potentiation of motor cortex neuron activity in response to simultaneous stimulation of the ventrolateral nucleus and somatosensory cortex arose only in regions receiving corticocortical projections from the stimulation site in the somatosensory cortex of the brain, while regions lacking corticocortical projections from the somatosensory cortex showed no such effect. Experiments demonstrated that the duration of increased motor cortex neuron activity following stimulation of the ventrolateral nucleus of the thalamus and somatosensory cortex was greater than one hour after recording was started. These data led to the conclusion that simultaneous stimulation of corticocortical and thalamocortical afferents can alter the level of neuronal activity in the motor cortex only in regions with convergent sensory inputs from the thalamus and somatosensory cortex of the brain. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 84, No. 5–6, pp. 460–468, May–June, 1998.     

Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex

By means of a semi-automatic image analyzer plugged into an Apple II computer and suitable computer programs it is possible to analyze transmitter-identified nerve terminals. Thus, a densitometric approach is applied on the original photograph followed by systematic sampling which is carried out by means of a grating of circles. This procedure allows the study quantitatively of density and intensities of different types of densely packed tyrosine hydroxylase (TH) immunoreactive nerve terminals of the nuc. caudatus putamen. It is shown that the islandic TH immunoreactive nerve terminals have a higher density, but a TH content similar to the diffuse types of TH immunoreactive nerve terminals in the nuc. caudatus putamen.     

Behavioral recovery from unilateral photothrombotic infarcts of the forelimb sensorimotor cortex in rats: role of the contralateral cortex

During sensorimotor recovery following stroke ipsi- and contralesional alterations in brain function have been characterized in patients as well as animal models of focal ischemia, but the contribution of these bilateral processes to the functional improvement is only poorly understood. Here we examined the role of the homotopic contralateral cortex for sensorimotor recovery after focal ischemic infarcts at different time periods after the insult. One group of animals received a unilateral single photothrombotic infarct in the forelimb sensorimotor cortex, while four additional groups received a second lesion in the contralateral homotopic cortex either immediately or 2 days, 7 days, or 10 days after the first infarct. The time course of functional recovery of the impaired forelimbs was assessed using different sensorimotor scores: forelimb-activity during exploratory behavior and frequency of forelimb-sliding in the glass cylinder as well as forelimb misplacement during grid walking. Focal infarcts in the forelimb sensorimotor cortex area significantly impaired the function of the contralateral forelimb in these different behavioral tests. The subsequent damage of the contralateral homotopic forelimb sensorimotor cortex only affected the forelimb opposite to the new lesion but did not reinstate the original deficit. The time course of sensorimotor recovery after bilateral sequential cortical infarcts did not significantly differ from animals with unilateral single lesions. These data indicate that following small ischemic cortical infarcts in the forelimb sensorimotor cortex the contralateral cortex homotopic to the lesion plays only a minor role for functional recovery.     

A repetitive intracortical microstimulation pattern induces long-lasting synaptic depression in brain slices of the rat primary somatosensory cortex

Repetitive intracortical microstimulation (ICMS) applied to the rat primary somatosensory cortex (SI) in vivo was reported to induce reorganization of receptive fields and cortical maps. The present study was designed to examine the effect of such an ICMS pattern applied to layer IV of brain slices containing SI on the efficacy of synaptic input to layer II/III. Effects of ICMS on the synaptic strength was quantified for the first synaptic component (s1) of cortical field potentials (FPs) recorded from layer II/III of SI. FPs were evoked by stimulation in layer IV. The pattern of ICMS was identical to that used in vivo. However, stimulation intensity had to be raised to induce an alteration of synaptic strength. In brain slices superfused with standard ACSF, repetitive ICMS induced a short-lasting (60 min) reduction of the amplitude (-37%) and the slope (-61%) of s1 evoked from the ICMS site, while the amplitude and the slope of s1 evoked from a control stimulation site in cortical layer IV underwent a slow onset increase (13% and 50%, respectively). In brain slices superfused with ACSF containing 1.25 microM bicuculline, ICMS induced an initial strong reduction of the amplitude (-50%) and the slope (-79%) of s1 evoked from the ICMS site. These effects decayed to a sustained level of depression by -30% (amplitude) and -60% (slope). In contrast to experiments using standard ACSF, s1 evoked from the control site was not affected by ICMS. The presynaptic volley was not affected in either of the two groups of experiments. A conventional high frequency stimulation (HFS) protocol induced input-specific long-term potentiation (LTP) of the amplitude and slope of s1 (25% and 76%, respectively). Low frequency stimulation (LFS) induced input-specific long-term depression (LTD) of the amplitude and slope of s1 (24% and 30%, respectively). Application of common forms of conditioning stimulation (HFS and LFS) resulted in LTP or LTD of s1, indicating normal susceptibility of the brain slices studied to the induction of common forms of synaptic plasticity. Therefore, the effects of repetitive ICMS on synaptic FP components were considered ICMS-specific forms of short-lasting (standard ACSF) or long-lasting synaptic depression (ACSF containing bicuculline), the latter resembling neocortical LTD. Results of this study suggest that synaptic depression of excitatory mechanisms are involved in the cortical reorganization induced by repetitive ICMS in vivo. An additional contribution of an ICMS-induced modification of inhibitory mechanisms to cortical reorganization is discussed.     

Extracellular calcium activity changes in cat sensorimotor cortex induced by iontophoretic application of aminoacids

Summary Extracellular Ca²⁺ activity (a_Ca) changes were measured with Ca²⁺-sensitive microelectrodes in the cat cerebral cortex during iontophoretic administration of excitatory and inhibitory aminoacids. Glutamate, aspartate and DL homcysteate usually decreased a_Ca from a baseline of 1.3 mM to as low as 0.1 mM. The amplitude of the changes was largest at depths between 100 and 300 m beneath the cortical surface. The a_Ca decreases could be deminished or blocked by Co²⁺, Mn²⁺ or La³⁺ as well as by GABA. These data suggest that large Ca²⁺ conductances that may be voltage-sensitive are present in apical dendrites of neocortical neurones.     

Stellate cells differentiate successively in the cat sensorimotor cortex during early postnatal ontogeny

Golgi and Golgi-Kopsch techniques were used to investigate maturation of stellate and pyramidal cells and development of stellate-pyramidal connections in kittens of the following ages: 2, 7, 14, 21, 28 and 34 days. By two weeks, stellate cells in layer V have become mature. Layer III stellate cells with vertical axon ramifications are differentiated by 2–3 weeks of life and in 3-week-olds the horizontal spread of axon collaterals amounts to 1300 μm. Layer II stellate cells which are poorly developed in newborns acquire the greatest number of collaterals and a complex axon branching pattern by 4 weeks of age.     

The sliding threshold of modification hypothesis: application to the effect of hypothyroidism or chronic psychosocial stress and nicotine on synaptic plasticity

The Bienenstock, Cooper, and Munro (BCM) theory or the sliding threshold model can be used to explain the changes in synaptic plasticity related to learning and memory, namely long-term potentiation (LTP) and depression (LTD). In this study, we applied synaptic plasticity changes induced by either chronic psychosocial stress or hypothyroidism, and their restoration by chronic nicotine treatment, to the sliding threshold model. Psychosocial stress- or hypothyroidism-induced changes in synaptic plasticity generated a shift in the sliding threshold of modification (θ_m) toward LTD. In addition, chronic nicotine treatment restored the θ_m to the normal position by normalizing psychosocial stress- or hypothyroidism-induced impairment of LTP and enhancement of LTD. The data correlate with our previous findings: a shift in the balance of kinase/phosphatase toward phosphatase during psychosocial stress or hypothyroidism, which is restored by chronic nicotine treatment.     

N-methyl-D-aspartate receptor-independent long-term depression and depotentiation in the sensorimotor cortex of the freely moving rat

Bidirectional modifications in synaptic efficacy are central components in recent models of cortical learning and memory, and we previously demonstrated both long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD) in the neocortex of the unanaesthetized adult rat. Here, we have examined the effects of N-methyl-D-aspartate receptor (NMDAR) blockade on the induction of LTD, LTP, and depotentiation of field potentials evoked in sensorimotor cortex by stimulation of the white matter in the adult, freely moving rat. High frequency (300 Hz) stimulation (HFS) was used to induce LTP and prolonged, low-frequency (1 Hz) stimulation was used to induce either depotentiation or LTD. LTD was expressed as a reduction in the amplitude of the short and long-latency field potential components, while depotentiation was expressed as a decrease in the amplitude of a previously enhanced late component. Under NMDAR blockade, HFS failed to induce LTP and instead produced a depression effect similar to LTD. Following washout of the drug, HFS induced a normal LTP effect. Unlike LTP, LTD and depotentiation were found to be NMDAR-independent in the neocortex of the freely moving rat.     

腹外侧眶皮层中miR-200对慢性应激所致大鼠抑郁行为调控作用研究

目的:观察慢性不可预知温和应激(CUMS)模型大鼠腹外侧眶皮层(VLO)内miR-200和双特异性磷酸酶1(DUSP1)表达变化,并探讨VLO内注射miR-200模拟物对抑郁行为的调控作用及机制。方法:大鼠建立CUMS抑郁模型后分为5组:CUMS+miR-200模拟物组(VLO内注射20 pmol miR-200 mimic);CUMS+阴性对照组(VLO内注射20 pmol阴性对照siRNA);无应激+阴性对照组;无应激+miR-200模拟物组;CUMS+氟西汀(10 mg/kg/d)组。依次进行蔗糖偏爱测试、旷场实验、高架十字迷宫实验。Western Blot检测VLO内DUSP1、细胞外调节蛋白激酶(ERK)、pERK蛋白表达。结果:与无应激组比较,CUMS组大鼠体重降低(P0.0001)、蔗糖偏爱下降(P=0.008),VLO中miR-200表达减少(P0.0001),DUSP1表达增高(P=0.0054);与CUMS+阴性对照组比较,CUMS+miR-200模拟物组大鼠蔗糖偏爱率(P=0.028),开放臂进入时间(P=0.031)和进入次数(P0.0001)均升高,总活动距离不受影响;与CUMS+阴性对照组比较,CUMS+miR-200模拟物组VLO中DUSP1(P=0.046)和pERK(P=0.042)蛋白水平显著升高。结论:慢性应激性环境所致抑郁样行为与VLO内pERK下调有关,miR-200可直接下调VLO内DUSP1表达,提高pERK表达并最终改善抑郁症状。     

糖皮质激素注射建立小鼠行为抑郁症模型

目的研究糖皮质激素注射小鼠抑郁症样情感行为变化。方法C57/B6雄性小鼠18只随机分为3组,模型组以20 mg/kg剂量每日1次注射皮质酮,持续21 d,另有生理盐水对照组每日注射等剂量生理盐水21 d,空白对照组不做任何处置,观察小鼠体重变化,用敞箱实验及糖水消耗试验测定动物行为。结果抑郁模型组小鼠代表焦虑行为的敞箱试验得分明显降低、反应快感行为的奖赏糖水消耗百分比明显降低。结论糖皮质激素持续注射法可用于制作行为小鼠抑郁模型,以及探究抑郁症行为变化发病机制以及寻找更适合治疗抑郁症的药物。     

Complex structure of quisqualate-sensitive glutamate receptors in rat cortex

Multiplicity of excitatory amino acid receptors has previously been demonstrated. The functional size of the quisqualate-type receptors was investigated by high energy radiation inactivation analysis of the binding of [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) to rat cortical membranes. The AMPA binding site is coupled to a high molecular weight modulatory unit, which down-regulates the affinity of the binding site for quisqualate, glutamate and AMPA. The estimated molecular target size of the AMPA binding site is different from the reported molecular weight of the glutamate binding site isolated from bovine brain. Furthermore, enhanced [3H]AMPA binding induced by chaotropic ions seems not to be a consequence of removal of the modulatory unit.     

Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses

Cholinergic innervation of hippocampus and cortex is required for some forms of learning and memory. Several reports have shown that activation of muscarinic m1 receptors induces a long-term depression (mLTD) at glutamate synapses in hippocampus and in several areas of cortex, including perirhinal and visual cortices. This plasticity likely contributes to cognitive function dependent upon the cholinergic system. In rodent models, degeneration of hippocampal cholinergic innervation following lesion of the medial septum stimulates sprouting of adrenergic sympathetic axons, originating from the superior cervical ganglia (SCG), into denervated hippocampal subfields. We previously reported that this adrenergic sympathetic sprouting occurs simultaneously with a reappearance of cholinergic fibers in hippocampus and rescue of mLTD at CA3-CA1 synapses. Because cholinergic neurons throughout basal forebrain degenerate in aging and Alzheimer's disease, it is critical to determine if this compensatory sprouting occurs in other regions impacted by cholinergic cell loss. To this end, we investigated whether lesion of the nucleus basalis magnocellularis (NbM) to cholinergically denervate cortex stimulates adrenergic sympathetic sprouting and the accompanying increase in cholinergic innervation. Further, we assessed whether the presence of sprouting positively correlates with the ability of glutamate synapses in acute visual cortex slices to express mLTD and low frequency stimulation induced LTD (LFS LTD), another cholinergic dependent form of plasticity in visual cortex. We found that both mLTD and LFS LTD are absent in animals when NbM lesion is combined with bilateral removal of the SCG to prevent possible compensatory sprouting. In contrast, when the SCG remain intact to permit sprouting in animals with NbM lesion, cholinergic fiber density is increased concurrently with adrenergic sympathetic sprouting, and mLTD and LFS LTD are preserved. Our findings suggest that autonomic compensation for central cholinergic degeneration is not specific to hippocampus, but is a general repair mechanism occurring in other brain regions important for normal cognitive function.     

EGCG对16Hz,155dB次声诱导的大鼠小胶质细胞过度激活的影响

目的:研究表没食子儿茶素没食子酸酯(epigallocatechin gallate,EGCG)对次声诱导的大鼠小胶质细胞过度激活的抑制作用,探讨EGCG潜在的次声对脑损伤的防护作用。方法:16 Hz,155 dB次声刺激原代培养的小胶质细胞,通过细胞因子表达量和免疫荧光染色,观察不同浓度(1μmol/L、10μmol/L、100μmol/L)的EGCG在不同时程(12 h和24 h)对次声激活的小胶质细胞的抑制作用。结果:1μmol/L或10μmol/L EGCG预孵可显著抑制次声后大鼠小胶质细胞IL-1β、IL-6、IL-18、TNF-α表达的上调,且10μmol/L组的作用最强(P<0.01)。10μmol/L EGCG可以减少次声诱导的小胶质细胞过度激活的形态变化。结论:EGCG对次声诱导的大鼠小胶质细胞过度激活具有显著的抑制作用。     

Movement induced modulation of afferent transmission to single neurons in the ventroposterior thalamus and somatosensory cortex in rat

Summary Single neurons were simultaneously recorded in the forepaw areas of the primary somatosensory (SI) cortex and ventroposterolateral (VPL) thalamus of awake rats during rest and running behaviors. Movement dependent changes in somatic sensory transmission were tested by generating post-stimulus histograms of these neurons' responses to stimulation through electrodes chronically implanted under the skin of the forepaw, while the aminal ran on a timed treadmill. As viewed in post-paw-stimulus histograms, the evoked unit responses (EURs) could be differentiated into short (4.5 ± 0.1−10.9 ± 0.2 ms) and longer (12.9 ± 0.4 31.3 ± ± 0.9 ms) latency components (“SEURs” and “LEURs”, respectively). The magnitudes of firing during these responses were measured and normalized as percent increases over background firing. By comparison with resting behavior, treadmill movement suppressed both SEURs and LEURs in the thalamus, as well as the cortex. The SEURs, however, were much more strongly suppressed in the SI cortex (−48.3 ± 2.7%) than in the VPL thalamus (−28.1 ± 6.7%). By contrast, similar magnitudes of suppression of LEURs were found in the SI (−25.8 ± 8.6%) and VPL (−26.5 ± 11.1%). These results suggest that the suppression of LEURs observed in the SI cortex may result from modulatory actions on subcortical circuits. Major suppression of SEURs, on the other hand, may occur intracortically, with a minor component ocurring subcortically. Thus, VPL thalamus and SI cortex in the rat appear to be differentially subject to movement related modulation of sensory transmission.     

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats

Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30 mg/kg) on methamphetamine (METH, 2.5 mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30 mg/kg) on repeated METH (2.5 mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30 mg/kg) blocked the METH (2.5 mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30 mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5 mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia.