Continuous Theta Burst Stimulation over the Left Dorsolateral Prefrontal Cortex Decreases Medium Load Working Memory Performance in Healthy Humans

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load.     

Mapping the After-effects of Theta Burst Stimulation on the Human Auditory Cortex with Functional Imaging

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing¹. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function ². An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions ³. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated ⁴. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity.Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS ^5-7. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex ^8,9, premotor cortex ¹⁰, primary somatosensory cortex ^11,12 and language-related areas ¹³, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task ². We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.     

The Predictive Nature of Pseudoneglect for Visual Neglect: Evidence from Parietal Theta Burst Stimulation

Following parietal damage most patients with visual neglect bisect horizontal lines significantly away from the true centre. Neurologically intact individuals also misbisect lines; a phenomenon referred to as ‘pseudoneglect’. In this study we examined the relationship between neglect and pseudoneglect by testing how patterns of pre-existing visuospatial asymmetry predict asymmetry caused by parietal interference. Twenty-four participants completed line bisection and Landmark tasks before receiving continuous theta burst stimulation to the left or right angular gyrus. Results showed that a pre-existing pattern of left pseudoneglect (i.e. right bias), but not right pseudoneglect, predicts left neglect-like behaviour during line bisection following right parietal cTBS. This correlation is consistent with the view that neglect and pseudoneglect arise via a common or linked neural mechanism.     

Theta Burst Stimulation of the Cerebellum Modifies the TMS-Evoked N100 Potential,a Marker of GABA Inhibition

Theta burst stimulation (TBS) of the cerebellum, a potential therapy for neurological disease, can modulate corticospinal excitability via the dentato-thalamo-cortical pathway, but it is uncertain whether its effects are mediated via inhibitory or facilitatory networks. The aim of this study was to investigate the effects of 30Hz cerebellar TBS on the N100 waveform of the TMS-evoked potential (TEP), a marker of intracortical GABA_B-mediated inhibition. 16 healthy participants (aged 18–30 years; 13 right handed and 3 left handed) received 30Hz intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation over the right cerebellum, in three separate sessions. The first 8 participants received TBS at a stimulus intensity of 80% of active motor threshold (AMT), while the remainder received 90% of AMT. Motor evoked potentials (MEP) and TEP were recorded before and after each treatment, by stimulating the first dorsal interosseus area of the left motor cortex. Analysis of the 13 right handed participants showed that iTBS at 90% of AMT increased the N100 amplitude compared to sham and cTBS, without significantly altering MEP amplitude. cTBS at 80% of active motor threshold decreased the N100 amplitude and cTBS overall reduced resting MEP amplitude. The study demonstrates effects of 30Hz cerebellar TBS on inhibitory cortical networks that may be useful for treatment of neurological conditions associated with dysfunctional intracortical inhibition.     

Influence of Anodal Transcranial Direct Current Stimulation (tDCS) over the Right Angular Gyrus on Brain Activity during Rest

Although numerous studies examined resting-state networks (RSN) in the human brain, so far little is known about how activity within RSN might be modulated by non-invasive brain stimulation applied over parietal cortex. Investigating changes in RSN in response to parietal cortex stimulation might tell us more about how non-invasive techniques such as transcranial direct current stimulation (tDCS) modulate intrinsic brain activity, and further elaborate our understanding of how the resting brain responds to external stimulation. Here we examined how activity within the canonical RSN changed in response to anodal tDCS applied over the right angular gyrus (AG). We hypothesized that changes in resting-state activity can be induced by a single tDCS session and detected with functional magnetic resonance imaging (fMRI). Significant differences between two fMRI sessions (pre-tDCS and post-tDCS) were found in several RSN, including the cerebellar, medial visual, sensorimotor, right frontoparietal, and executive control RSN as well as the default mode and the task positive network. The present results revealed decreased and increased RSN activity following tDCS. Decreased RSN activity following tDCS was found in bilateral primary and secondary visual areas, and in the right putamen. Increased RSN activity following tDCS was widely distributed across the brain, covering thalamic, frontal, parietal and occipital regions. From these exploratory results we conclude that a single session of anodal tDCS over the right AG is sufficient to induce large-scale changes in resting-state activity. These changes were localized in sensory and cognitive areas, covering regions close to and distant from the stimulation site.     

Theta Burst Stimulation Applied over Primary Motor and Somatosensory Cortices Produces Analgesia Unrelated to the Changes in Nociceptive Event-Related Potentials

Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO₂ laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.     

间歇性θ节律经颅磁刺激改善大鼠工作记忆的海马与前额叶跨脑区神经网络效应研究

目的 间歇性θ节律刺激（iTBS）作为一种新型的经颅磁刺激模式，已经广泛应用于探索大脑认知功能和神经调控等方面，但其电生理调控机制尚不清晰，探索iTBS对大脑认知功能的影响及其电生理机制，对脑疾病的治疗和磁刺激的临床应用具有重要意义。方法 本文利用iTBS制备磁刺激大鼠模型，采集记录大鼠在执行工作记忆（WM）任务过程中腹侧海马（vHPC）和内侧前额叶皮层（mPFC）的局部场电位（LFPs）信号，应用格兰杰因果网络分析方法，研究了iTBS对大鼠WM过程中vHPC与mPFC跨脑区神经网络协同和信息交互的影响。结果 iTBS增强了大鼠的学习记忆能力，使其完成工作记忆任务所需时长减少（2.67±1.63）d（P<0.05），iTBS显著改善了大鼠的行为学表现；同时iTBS增强了大鼠在WM期间vHPC与mPFC脑区的自因果网络连接，增加了网络连接强度、连接密度和全局效率（P<0.05）；并且iTBS增强了vHPC与mPFC脑区的跨脑区网络连接，增加了vHPC-mPFC跨脑区的节点度和因果流向（P<0.05）。结论 iTBS磁刺激对大鼠工作记忆行为学及相关脑区神经网络均有显著的积极作用，iTBS可以促进大鼠认知能力，提高大脑神经网络的信息交互和传递效率，iTBS的神经调控机制可能是通过增强大脑vHPC与mPFC之间的网络连接和信息交互来提高工作记忆能力。     

Interaction of Motor Training and Intermittent Theta Burst Stimulation in Modulating Motor Cortical Plasticity: Influence of BDNF Val66Met Polymorphism

Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities.     

Artificial Theta Stimulation Impairs Encoding of Contextual Fear Memory

Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4–12 Hz) and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.     

Discrete Pattern of Burst Stimulation in the Ventrobasal Thalamus for Anti-Nociception

The thalamus has been proposed to play a role in sensory modulation via switching between tonic and burst dual firing of individual neurons. Of the two firing modes, altered burst firing has been repeatedly implicated with pathological pain conditions, which suggests that maintaining a certain form of thalamic burst could be crucial for controlling pain. However, specific elements of burst firing that may contribute to pain control have not yet been actively investigated. Utilizing the deep brain stimulation (DBS) technique, we explored the effects of bursting properties in pain control by electrically stimulating the ventrobasal (VB) thalamus in forms of burst patterned to test different aspects of bursts during the formalin induced nociception in mice. Our results demonstrated that electrical stimulations mimicking specific burst firing properties are important in producing an anti-nociceptive effect and found that the ≤3 ms interval between burst pluses (intra-burst-interval: IntraBI) and ≥3 pulses per burst were required to reliably reduce formalin induced nociceptive responses in mice. Periodicity of IntraBI was also suggested to contribute to anti-nociception to a limited extent.     

Down-Regulation of AMPA Glutamate Receptors Reduces Cerebrocortical Metabolic Response to Stimulation

We tested the hypothesis that chronic stimulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) glutamate receptors with an agonist causes down-regulation of the receptor protein and a decrement in basal and/or stimulated cerebral O2 consumption. Male Wistar rats were intradurally infused with 10 microM AMPA by an osmotic pump at a rate of 1 microl/h for 6 days. As a result, the specific binding of (S)-[3H]-5-fluorowillardiine to AMPA receptors in the cerebral cortex decreased 46% from 2.7 +/- 0.3 to 1.5 +/- 0.6 (density units). Under isoflurane anesthesia and after topical stimulation to the right cerebral cortex with 10(-3) M AMPA, cerebral blood flow (14C-iodoantipyrine method) and O2 consumption (cryomicrospectrophotometrically determined) were determined in control and down-regulated rats. Down-regulation of AMPA receptors did not alter basal O2 consumption. In control, after agonist stimulation, the O2 consumption in the ipsilateral cortex increased by 34%, (4.7 +/- 0.5 ml O2 x min(-1) x 100 g(-1) compared to 3.5 +/- 0.4 in the contralateral cortex). In the down-regulated rats, the O2 consumption did not significantly increase (4.0 +/- 1.5 ml O2 x min(-1) x 100 g(-1) compared to 3.3 +/- 1.7 in the contralateral cortex) after AMPA. In conclusion, following chronic simulation, AMPA receptors underwent down-regulation, but such down-regulation did not alter basal cerebrocortical blood flow or O2 consumption. AMPA down-regulation reduced the agonist stimulated increase in cortical O2 consumption.     

Stimulation in the Dorsolateral Prefrontal Cortex Changes Subjective Evaluation of Percepts

Nelson and Narens have proposed a metacognition model that dissociates the objective processing of information (object-level) and the subjective evaluation of the performance (i.e., the metalevel). Neurophysiological evidence also indicates that the prefrontal cortices (PFC) are the brain areas which perform the metalevel function [1]–[3]. A corresponding neural mechanism of Nelson and Narens’s model, called dynamic filtering theory [4], [5], indicates that object-level processing is distributed in the posterior cortices and regulated by the prefrontal cortices with a filtering or gating mechanism to select appropriate signals and suppress inappropriate signals and noise. Based on this model, a hypothesis can be developed that, in the case of uncertainty or overloading of object-level processing, the prefrontal cortices will become more active in order to modulate signals and noise. This hypothesis is supported by a recent fMRI study [6] showing that the PFC (Brodmann area 9, BA9) was activated when subjects were overloaded in a bimodal attentional task, compared to a unimodal task. Here, we report a study showing that applying repetitive transmagnetic stimulation (rTMS) over the BA9 in order to interfere with its functional activity resulted in significant increas in guessed responses, compared to three other control conditions (i.e., no-TMS, sham TMS on BA9, and rTMS on Cz). The results are compatible with the dynamic filtering theory and suggest that a malfunction of the PFC would weaken the quality of meta-cognitive percepts and increase the number of guessed responses.     

Cytoarchitecture of the Ferret Suprasylvian Gyrus Correlated with Areas Containing Multiunit Responses Elicited by Stimulation of the Face

The cytoarchitecture was studied in a segment of the ferret suprasylvian gyrus containing at least two and possibly four somesthetic representations of the face that were observed in the primary somatosensory cortex. These representations were restricted to the crown of the gyrus and were surrounded by somesthetically unresponsive cortex that extended down both sides to the base of adjacent sulci. Numerous cytoarchitectonic subdivisions were found on a qualitative basis, and were confirmed quantitatively by cluster analyses and relevant statistical tests of 10 prominent features from layers III, IV, and V. Four distinct cytoarchitectonic subdivisions, each with a well-developed and homogeneous granular layer IV, were found distributed from anterior to posterior along the crown of the gyrus at sites corresponding to the locations of the four facial representations. The surrounding unresponsive cortex had a fragmented cytoarchitecture, especially along the medial bank and base of the coronal sulcus. This unresponsive cortex separated the facial representations from the body representations, which were located on the adjacent posterior cruciate gyrus. Most of the unresponsive subdivisions had a heterogeneous or agranular layer IV and fairly well-developed sublamination in layer III, which may be indicative of extensive corticocortical connections. One set of unresponsive subdivisions had comparable cytoarchitectures that directly bordered the facial representations. Another set of unresponsive subdivisions with comparable architectures occupied most of the lateral bank of the gyrus. The implications of multiple representations and cytoarchitectonic fragmentation of the ferret primary somatosensory cortex are discussed in relation to the organization of the primary somatosensory cortex in other species.     

Cutaneous Magnetic Stimulation Reduces Rat Chronic Pain via Activation of the Supra-Spinal Descending Pathway

Recent studies have demonstrated that magnetic stimulation (MS) can induce cellular responses such as Ca²⁺ influx into the cultured neurons and glia, leading to increased intracellular phosphorylation. We have demonstrated previously that MS reduces rat neuropathic pain associated with the prevention of neuronal degeneration. Thus, we aimed to elucidate the actions of MS in relation to modulation of spinal neuron–glia and the descending inhibitory system in chronic pain. The male SD rats intrathecally implanted with catheters were subjected to sciatic nerve ligation (CCI). MS is a low power apparatus characterized by two different frequencies, 2 KHz and 83 MHz. Rats were given MS to the skin (injured sciatic nerve) for 10 min from the seventh day after CCI. The paw withdrawal latency (PWL) evoked by thermal stimuli was measured for 14 days after CCI. Immunohistochemistry for Iba-1 or GFAP was performed after 4% paraformaldehyde fixation (microscopic analysis). We employed microdialysis for measuring CSF 5-HIAA as a reflection of 5-HT release by MS stimulation. Following CCI, rats showed a decrease in PWL after CCI, and the decrease continued until the 14th day. With MS treatment, the decrease in PWL was reduced during the 10–14 day after CCI. Injection of JNK-1 inhibitors on the 14th day antagonized the analgesic effect of MS. MS also eliminated the CCI-induced decrease in GFAP immunoreactivity. Moreover, MS evoked spinal 5-HT release reflected by increase in spinal 5-HIAA level. Thus, we demonstrate that a novel magnetic stimulator used cutaneously can ameliorate chronic pain by not only preventing abnormal spinal neuron–glia interaction, but also through the activation of the supra-spinal descending inhibitory system.     

The Saccharomyces cerevisiae RAD9 Checkpoint Reduces the DNA Damage-Associated Stimulation of Directed Translocations

Genetic instability in the Saccharomyces cerevisiae rad9 mutant correlates with failure to arrest the cell cycle in response to DNA damage. We quantitated the DNA damage-associated stimulation of directed translocations in RAD9⁺ and rad9 mutants. Directed translocations were generated by selecting for His⁺ prototrophs that result from homologous, mitotic recombination between two truncated his3 genes, GAL1::his3-Δ5′ and trp1::his3-Δ3′::HOcs. Compared to RAD9⁺ strains, the rad9 mutant exhibits a 5-fold higher rate of spontaneous, mitotic recombination and a greater than 10-fold increase in the number of UV- and X-ray-stimulated His⁺ recombinants that contain translocations. The higher level of recombination in rad9 mutants correlated with the appearance of nonreciprocal translocations and additional karyotypic changes, indicating that genomic instability also occurred among non-his3 sequences. Both enhanced spontaneous recombination and DNA damage-associated recombination are dependent on RAD1, a gene involved in DNA excision repair. The hyperrecombinational phenotype of the rad9 mutant was correlated with a deficiency in cell cycle arrest at the G₂-M checkpoint by demonstrating that if rad9 mutants were arrested in G₂ before irradiation, the numbers both of UV- and γ-ray-stimulated recombinants were reduced. The importance of G₂ arrest in DNA damage-induced sister chromatid exchange (SCE) was evident by a 10-fold reduction in HO endonuclease-induced SCE and no detectable X-ray stimulation of SCE in a rad9 mutant. We suggest that one mechanism by which the RAD9-mediated G₂-M checkpoint may reduce the frequency of DNA damage-induced translocations is by channeling the repair of double-strand breaks into SCE.     

Cyclosporine A Reduces Dendritic Outgrowth of Neuroblasts in the Subgranular Zone of the Dentate Gyrus in C57BL/6 Mice

In the present study, we observed the effects of cyclosporine A (CsA), an efficient immunosuppressant, on cell proliferation and neuroblast differentiation in the subgranular zone of the dentate gyrus (SZDG) in normal C57BL/6 mice using Ki67 and doublecortin (DCX) immunohistochemical staining, respectively. At 8 weeks of age, vehicle (physiological saline) or CsA was daily administered (40 mg/kg, i.p.) for 1 week. Animals were sacrificed at 2 weeks after last administration. CsA treatment did not show any influences in neurons, astrocytes and microglia based on immunohistochemistry for its markers, respectively. However, in the CsA-treated group, Fluoro-Jade B, a marker for neurodegeneration, positive cells were found in the SZDG, not in the vehicle-treated group. In the vehicle-treated group, Ki67 immunoreactive (⁺) nuclei were clustered in the SZDG, whereas in the CsA-treated group Ki67⁺ nuclei were scattered in the SZDG, showing no difference in cell numbers. Numbers of DCX⁺ neuroblasts with well-developed processes (tertiary dendrites) were much lower in the CsA-treated group than those in the vehicle-treated group; however, numbers of DCX⁺ neuroblasts with secondary dendrites were similar in both the groups. These results suggest that CsA significantly reduces dendritic outgrowth and complexity from neuroblasts in the SZDG without any affecting in neurons, astrocytes and microglia in normal mice.     

Stimulation of the Sigma-1 Receptor by DHEA Enhances Synaptic Efficacy and Neurogenesis in the Hippocampal Dentate Gyrus of Olfactory Bulbectomized Mice

Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX) mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831) phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473), Akt (Ser-308) and ERK in the DG. Furthermore, GSK-3β (Ser-9) phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.     

Diminished Noradrenergic Stimulation Reduces the Activity of Rolipram-Sensitive, High-Affinity Cyclic AMP Phosphodiesterase in Rat Cerebral Cortex

Abstract: The present study examined the in vivo regulation of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase (PDE4) in rat cerebral cortex. The hydrolysis of cyclic AMP, formed by stimulation of β-adrenergic receptors, was measured in cerebral cortical slices. Hydrolysis of cyclic AMP formed under these conditions was inhibited by the PDE4-selective inhibitor rolipram but not by selective inhibitors of other PDE families. Intraventricular infusion of 6-hydroxydopamine (6-OHDA; 200 µg) decreased the rate constant of cyclic AMP hydrolysis and increased the cyclic AMP half-life 17 days, but not 1 or 7 days, following the treatment. A reduction in norepinephrine (NE) content occurred first; the NE level was reduced to 42, 24, and 6% of control at 1, 7, and 17 days after 6-OHDA infusion, respectively. This was followed by the development of supersensitivity of β-adrenergic receptor-linked adenylyl cyclase, which occurred 7 days after the infusion. The reduction in PDE4 activity occurred last. When a higher dose of 6-OHDA (300 µg) was used, the reduction in the rate constant of cyclic AMP hydrolysis occurred by 7 days; at this time NE content was depleted to 6% of control. Similar to 6-OHDA treatment, continuous blockade of β-adrenergic receptors, produced by chronic propranolol infusion, decreased the rate constant of cyclic AMP hydrolysis. Therefore, the current results indicate that diminished stimulation of β-adrenergic receptors, either by loss of noradrenergic innervation or by receptor blockade, reduces the activity of PDE4. This suggests that PDE4 regulation may contribute in the homeostasis of the noradrenergic receptor-effector system in the brain.     

间歇性θ脉冲刺激联合有氧运动训练对老年2型糖尿病合并轻度认知功能障碍患者糖脂代谢、认知功能和听觉诱发电位P300的影响

摘要 目的：探讨间歇性θ脉冲刺激（iTBS）联合有氧运动训练对老年2型糖尿病（T2DM）合并轻度认知功能障碍（MCI）患者糖脂代谢、认知功能和听觉诱发电位P300的影响。方法：选取2020年3月~2021年11月期间来我院接受治疗的老年T2DM合并MCI患者117例。按照随机数字表法分为对照组（有氧运动训练,58例）和观察组（iTBS联合有氧运动训练,59例）。观察两组干预前后糖脂代谢、认知功能和听觉诱发电位P300的变化情况。结果：观察组干预后空腹血糖（FBG）、糖化血红蛋白（HbA1c）低于对照组（P<0.05）。两组干预后总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）组间对比,统计学无差异（P>0.05）。观察组干预后蒙特利尔量表（MoCA）各维度及总分高于对照组（P<0.05）。观察组干预后中央区（Cz）潜伏期、组顶区（Pz）潜伏期短于对照组,Cz波幅、Pz波幅高于对照组（P<0.05）。结论：iTBS联合有氧运动训练用于老年T2DM合并MCI患者,可有效降低血糖,改善机体认知功能和听觉诱发电位P300。