Transient plasticity response is regulated by histone deacetylase inhibitor in oxygen-glucose deprivation condition.

BACKGROUND: The pathological form of synaptic plasticity, ischemic long-term potentiation (iLTP), induced by oxygen and glucose deprivation (OGD), is implicated in the acute phase of stroke with the potentiation of N-methyl-D-aspartate receptor (NMDAR). While there has been widespread attention on the excitatory system, a recent study reported that γ-aminobutyric acid (GABA)ergic system is also involved in iLTP. Valproic acid (VPA), a histone deacetylase inhibitor, protects against ischemic damage. However, whether VPA regulates early phase plasticity in ischemic stroke remains unknown. The present study aims to investigate the potential role and mechanism of VPA in ischemic stroke. METHODS: A brief exposure of OGD on the hippocampal slices and the induction of photothrombotic ischemia (PTI) were used as ex vivo and in vivo models of ischemic stroke, respectively. RESULTS: Using extracellular recordings, iLTP was induced in the hippocampal Schaffer collateral pathway following OGD exposure. VPA treatment abolished hippocampal iLTP via GABAA receptor enhancement and extracellular signal-regulated kinase (ERK) phosphorylation. Administration of VPA reduced brain infarct volume and motor dysfunction in mice with PTI. Moreover, VPA protected against ischemic injury by upregulating the GABAergic system and ERK phosphorylation, as well as by reducing of matrix metalloproteinase in a PTI-induced ischemic stroke model. CONCLUSIONS: Together, this study revealed the protection of VPA in ex vivo OGD-induced pathological form of neuroplasticity and in vivo PTI-induced brain damage and motor dysfunction through rescuing GABAergic deficiency and the pathological hallmarks of ischemia.

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study.

BACKGROUND: Prolonged intermittent theta-burst stimulation (iTBS) is effective for major depressive disorder (MDD). However, whether longer piTBS treatment in a single session could have antidepressant efficacy remains elusive. Therefore, this double-blind, randomized, sham-controlled study aimed to investigate the antidepressant efficacy of 2 daily piTBS sessions for treating MDD patients with a history of poor responses to at least 1 adequate antidepressant trial in the current episode. METHODS: All patients received 2 uninterrupted sessions per day for 10 weekdays (i.e., 2 weeks; a total of 20 sessions). Seventy-two patients were recruited and 1:1:1 randomly assigned to one of three groups: piTBS (piTBSx2), 10-Hz rTMS (rTMSx2), or sham treatment (shamx2, randomly assigned to piTBS or rTMS). 10-Hz rTMS group was included as an active comparison group to enhance assay sensitivity. RESULTS: piTBSx2 group had significantly more responders at week 2 than shamx2 group, but it did not yield better antidepressant effects regarding the %depression changes. The changes of antidepressant scores were not different among the three groups at week 1 (-26.2% vs. -23.3% vs. -22.%) or at week 2 (-34.1% vs. -37.1% vs. -30.1%). Longer treatment duration did not result in stronger placebo effects [sham(piTBS)x2: - 31.7% vs. sham(rTMS)x2: - 26.7%]. CONCLUSION: The present sham-controlled study confirmed that piTBS is an effective antidepressant option, but found no evidence to support that longer piTBS treatment duration resulted in more rapid or better antidepressant effects. A high placebo effect was observed, but longer treatment duration of brain stimulation was not linearly associated with stronger placebo effects.

Fracture Characteristics of Commercial PEEK Dental Crowns: Combining the Effects of Aging Time and TiO2 Content.

Polyetheretherketone (PEEK) is an emerging thermoplastic polymer with good mechanical properties and an elastic modulus similar to that of alveolar bone. PEEK dental prostheses for computer-aided design/computer-aided manufacturing (CAD/CAM) systems on the market often have additives of titanium dioxide (TiO2) to strengthen their mechanical properties. However, the effects of combining aging, simulating a long-term intraoral environment, and TiO2 content on the fracture characteristics of PEEK dental prostheses have rarely been investigated. In this study, two types of commercially available PEEK blocks, containing 20% and 30% TiO2, were used to fabricate dental crowns by CAD/CAM systems and were aged for 5 and 10 h based on the ISO 13356 specifications. The compressive fracture load values of PEEK dental crowns were measured using a universal test machine. The morphology and crystallinity of the fracture surface were analyzed by scanning electron microscopy and an X-ray diffractometer, respectively. Statistical analysis was performed using the paired t-test (α = 0.05). Results showed no significant difference in the fracture load value of the test PEEK crowns with 20% and 30% TiO2 after 5 or 10 h of aging treatment; all test PEEK crowns have satisfactory fracture properties for clinical applications. Fracture surface analysis revealed that all test crowns fractured from the lingual side of the occlusal surface, with the fracture extending along the lingual sulcus to the lingual edge, showing a feather shape at the middle part of the fracture extension path and a coral shape at the end of the fracture. Crystalline analysis showed that PEEK crowns, regardless of aging time and TiO2 content, remained predominantly PEEK matrix and rutile phase TiO2. We would conclude that adding 20% or 30% TiO2 to PEEK crowns may have been sufficient to improve the fracture properties of PEEK crowns after 5 or 10 h of aging. Aging times below 10 h may still be safe for reducing the fracture properties of TiO2-containing PEEK crowns.

An efficient cellular image-based platform for high-content screening of neuroprotective agents against chemotherapy-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect, with no approved therapy for prevention or treatment. Here, we aimed to establish a high-content image platform based on the neurite outgrowth of dorsal root ganglia (DRG)-derived neuron cells for the discovery of neuroprotective agents against paclitaxel-induced CIPN. ND7/23 cells, an immortalized hybrid DRG cell line, were maturely differentiated by induction with nerve growth factor and upregulation of intracellular cAMP levels. High-content image analyses of the neurofilament-stained neurite network showed that paclitaxel disrupted the neurite outgrowth of well-differentiated ND7/23 DRG neuron cells, recapitulating characteristic effects of paclitaxel on primary cultured DRG neurons. This process coincided with the upregulated activity of store-operated Ca2+ entry, similar to those found in rodent models of paclitaxel-induced CIPN. The previously identified neuroprotective agents, minoxidil and 8-Br-cyclic adenosine monophosphate ribose (8-Br-cADPR), attenuated the reduction in total neurite outgrowth in paclitaxel-damaged ND7/23 cells. Additionally, the total neurite outgrowth of well-differentiated ND7/23 cells was concentration-dependently reduced by the neurotoxic chemotherapeutic agents, oxaliplatin and bortezomib, but not the less neurotoxic 5-fluorouracil. We demonstrated that high-content analyses of neurite morphology in well-differentiated DRG neuron-derived cells provide an effective, reproducible, and high-throughput strategy for developing therapeutics against CIPN.

Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model.

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC.

Influence of Aging on the Fracture Characteristics of Polyetheretherketone Dental Crowns: A Preliminary Study.

Although polyetheretherketone (PEEK) is becoming more widely used in dentistry applications, little is known about how aging will affect this material. Therefore, this study aimed to investigate the influence of an aging treatment on fracture characteristics of PEEK dental crowns. Additionally, the impact of the addition of titanium dioxide (TiO2) into PEEK was examined. Two types of commercial PEEK discs were used in this study, including TiO2-free and 20% TiO2-containing PEEK. The PEEK dental crowns were fabricated and aging-treated at 134 °C and 0.2 MPa for 5 h in accordance with the ISO 13356 specification before being cemented on artificial tooth abutments. The fracture loads of all crown samples were measured under compression tests. Results demonstrated that adding TiO2 enhanced the fracture load of PEEK crowns compared to TiO2-free PEEK crowns before the aging treatment. However, the aging treatment decreased the fracture load of TiO2-containing PEEK crowns while increasing the fracture load of TiO2-free PEEK crowns. The fracture morphology of TiO2-containing PEEK crowns revealed finer feather shapes than that of the TiO2-free PEEK crowns. We concluded that adding TiO2 increased the fracture load of PEEK crowns without aging treatment. Still, the aging treatment influenced the fracture load and microscopic fracture morphology of PEEK crowns, depending on the addition of TiO2.

Generational synaptic functions of GABAA receptor ß3 subunit deteriorations in an animal model of social deficit.

BACKGROUND: Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. METHODS: The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. RESULTS: Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. CONCLUSIONS: Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus.

BACKGROUND: Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. METHODS: Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. RESULTS: LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. CONCLUSIONS: These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.

Cortical excitatory and inhibitory correlates of the fronto-limbic circuit in major depression and differential effects of left frontal brain stimulation in a randomized sham-controlled trial.

BACKGROUND: Major depressive disorder (MDD), particularly treatment-resistant ones, is associated with abnormal fronto-limbic glucose metabolism. 10-Hz repetitive transcranial magnetic stimulation (rTMS) over left prefrontal cortex (PFC) is believed to normalize the abnormal metabolism to treat depression. However, the exact molecular mechanisms underlying the mood circuit of depressed brains and whether brain stimulation techniques regulate the underlying molecules remain elusive. METHODS: Whole-brain glucose metabolism and cortical excitatory and inhibitory markers including P30, N45, P60, N100, and LICI (long-interval cortical inhibition) of TMS-evoked potentials from left DLPFC were measured in 40 subjects with MDD patients. The neurophysiological markers were repeated immediately after 1st session of left PFC rTMS, intermittent theta-burst stimulation (iTBS), and sham (randomly assigned). RESULTS: Brain glucose metabolism in the limbic structures significantly correlated with left PFC P30 (mainly GABA-A and glutamate receptor mediated) and with LICI (mainly GABA-B receptor mediated inhibition) (FWE-corrected p < 0.001). Correlations between other neurophysiological markers (left PFC N45, P60, and N100) and posterior cingulate cortex, a key region in the default mode network, were also noted. One session of rTMS significantly decreased left PFC P60 (mainly glutamate receptor mediated), while a significant group effect was found for LICI (iTBS < sham). CONCLUSION: The first study showed that the underlying molecular mechanisms of fronto-limbic circuit of MDD brains involved glutamatergic excitation and GABAergic inhibition at specific time points. In addition, one session of rTMS mainly modulated glutamatergic neurotransmission at left PFC, while the mechanisms of iTBS might involve GABA-B receptor mediated inhibition. CLINICAL TRIALS REGISTRY NUMBER: UMIN000044951.

Predictive roles of brain-derived neurotrophic factor Val66Met polymorphism on antidepressant efficacy of different forms of prefrontal brain stimulation monotherapy: A randomized, double-blind, sham-controlled study.

BACKGROUND: Although repetitive transcranial magnetic stimulation (rTMS) and prolonged intermittent theta-burst stimulation (piTBS) can induce changes in synaptic plasticity, the influence of brain-derived neurotrophic factor (BDNF) genotypes on their antidepressant effects remain unknown. Hence, we investigated the BDNF polymorphism contribution to the antidepressant effect of different forms left-sided prefrontal stimulations in a randomized, sham-controlled study METHODS: Seventy-five patients with medication-resistant depression were randomly assigned into three monotherapy groups: piTBS, high-frequency(HF) rTMS, or sham. The acute treatment period was two weeks. 17-item Hamilton Depression Rating scale (HDRS-17) were applied at baseline, week-1, and week-2. The primary outcome was percentage changes of HDRS-17 (%HDRS-17 changes) analyzed by generalized estimating equation (GEE) model. RESULTS: The GEE analysis revealed a significant interaction between group, time, and BDNF genotypes effects on %HDRS-17 changes over time.  In patients carrying Val homozygotes, piTBS and HF-rTMS both exhibited significantly greater %HDRS reduction than sham at week-2. In Met carriers, only piTBS showed better efficacy than sham at week-2 (piTBS vs. sham, -41.1% vs.-18.9%, p=0.004). Regarding the influence of different BDNF genotypes on antidepressant efficacy in each intervention, only HF-rTMS exhibited significantly different degrees of %HDRS-17 changes between Val homozygotes and Met carriers (-68.5% vs. -26.4%, p=0.012, respectively), but piTBS delivered the consistent efficacy regardless of the BDNF polymorphism. CONCLUSIONS: This is the first study to confirm the different impacts of BDNF genotypes on the effect of different left-sided prefrontal brain stimulation. BDNF Val66Met polymorphism may play a role in the antidepressant response of piTBS and HF-rTMS. (Trial Registration Number UMIN-CTR:UMIN000020892: Registration date: Feb.4, 2016).

Production of Lactobacillus brevis ProGA28 attenuates stress-related sleep disturbance and modulates the autonomic nervous system and the motor response in anxiety/depression behavioral tests in Wistar-Kyoto rats.

AIMS: Many studies have reported that the production of Lactobacillus brevis is beneficial for sleep, but the underlying mechanism remains unclear. Other known beneficial effects of Lactobacillus brevis include improvement of anxious or depressive symptoms and better modulation of the autonomic nervous system, both of which impact sleep. In this study, we investigated whether the sleep benefit of Lactobacillus brevis was associated with the modulating effects on the autonomic nervous system and anxious/depressive symptoms. MAIN METHODS: Wistar-Kyoto rats were fed the production of Lactobacillus brevis (ProGA28) for the last 2 weeks of treatment before being exposed to case exchange (stress-induced insomnia paradigm). Waking, quiet sleep, and paradoxical sleep states were defined based on polysomnographic measurements. Autonomic functioning was assessed by heart rate variability (HRV). A combined behavioral test was used to evaluate anxiety-like or depressive-like behaviors after the following 2 days. KEY FINDINGS: In exposure to the dirty cage, the control group had significant prolongation of sleep latency, sleep loss during the first 2 h, and decreased parasympathetic activity and increased sympathetic activity during quiet sleep, which were significantly mitigated in the ProGA28 group. In behavioral tests, the ProGA28 group exhibited significantly less anxiety/depression-like motor responses in the elevated plus maze test, the forced swimming test, and the three-chamber social interaction test. Less initial sleep loss in the ProGA28 group was related to higher parasympathetic activity during quiet sleep, and shorter sleep latency in both groups was associated with longer time staying in the open arm in the elevated plus maze test. SIGNIFICANCE: These findings suggest that L. brevis ProGA28 can attenuate stress-related sleep disturbance, which may be associated with increased parasympathetic activity and decreased anxiety-like behaviors.

Differential mechanisms of synaptic plasticity for susceptibility and resilience to chronic social defeat stress in male mice.

Mood dysregulation refers to the inability of a person to control their negative emotions, and it is linked to various stressful experiences. Dysregulated neural synaptic plasticity and actin-filament dynamics are important regulators of stress response in animal models. However, until now, there is no evidence to differential the mechanisms of synaptic plasticity and actin-filament dynamics in stress susceptibility and stress-resistant. Here we found that depression-like behaviour was observed in the susceptible group following chronic social defeat stress (CSDS) exposure, but not in stress-resistant mice. High-frequency stimulation-induced long-term potentiation (LTP) was impaired in the CSDS-induced depression-susceptible group. Further, the levels of pro-brain derived neurotrophic factor (BDNF), mature BDNF, PSD-95, phosphorylated CaMKII, and phosphorylated Cofilin, an actin-filament dynamics regulator, were reduced in CSDS-induced depression-susceptible mice unlike in stress-resistant mice. These results demonstrate that synaptic plasticity-related molecules, such as BDNF and phosphorylated Cofilin, are important for maintaining synaptic functions and structure in mice that experience more stress.

Photon-induced deactivations of multiple traps in CH3NH3PbI3 perovskite films by different photon energies.

Photon-induced trap deactivation is commonly observed in organometal halide perovskites. Trap deactivation is characterized by an obvious photoluminescence (PL) enhancement. In this work, the properties of traps in CH3NH3PbI3 perovskite films were studied based on the PL enhancement excited by lasers of different wavelengths (633 nm and 405 nm). Two types of electron traps were identified; one can be deactivated by both 633 nm and 405 nm illuminations, whereas the other one can only be deactivated by 405 nm illumination. The energy levels of both types of traps were beneath the conduction band minimum. The expressions of the PL enhancement kinetics due to the trap deactivations by lasers of different wavelengths were derived. The ratio of the constants of the radiative recombination rate and the initial capture rates for both traps was determined from the PL enhancement. The trap deactivation was a photon-related process rather than a photocarrier-related process, and the deactivation time was inversely proportional to the photon flux density.

Studies on the substrate-dependent photocatalytic properties of Cu2O heterojunctions.

Cu2O is a promising material for photocatalysis because of its absorption ability in the ultraviolet (UV)-visible light range. Cu2O deposited on conductive Ti and fluorine-doped tin oxide (FTO) substrates behaves as a photocathode. Cu2O deposited on an n-type semiconductor such as TiO2 nanotube arrays (TNA)/Ti behaves as a photoanode and has demonstrated better photocatalytic activity than that of TNA/Ti. The substrate-dependent photocatalytic properties of Cu2O heterojunctions are not well studied. In this work, the photocatalytic properties of a Cu2O/TNA/Ti junction as a photoanode and of Cu2O/Ti and Cu2O/FTO junctions as photocathodes without bias were systematically studied to understand their performance. The Cu2O/TNA/Ti photoanode exhibited higher photocurrent spectral responses than those of Cu2O/Ti and Cu2O/FTO photocathodes. The photoanodic/photocathodic properties of those junctions were depicted in their energy band diagrams. Time-resolved photoluminescence indicated that Cu2O/TNA/Ti, Cu2O/Ti, and Cu2O/FTO junctions did not enhance the separation of photogenerated charges. The improved photocatalytic properties of Cu2O/TNA/Ti compared with TNA/Ti were mainly attributed to the UV-visible light absorption of Cu2O.

Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Glucosamine Enhancement of BDNF Expression and Animal Cognitive Function.

Brain-derived neurotrophic factor (BDNF) is an important factor for memory consolidation and cognitive function. Protein kinase A (PKA) signaling interacts significantly with BDNF-provoked downstream signaling. Glucosamine (GLN), a common dietary supplement, has been demonstrated to perform a variety of beneficial physiological functions. In the current study, an in vivo model of 7-week-old C57BL/6 mice receiving daily intraperitoneal injection of GLN (0, 3, 10 and 30 mg/animal) was subjected to the novel object recognition test in order to determine cognitive performance. GLN significantly increased cognitive function. In the hippocampus GLN elevated tissue cAMP concentrations and CREB phosphorylation, and upregulated the expression of BDNF, CREB5 and the BDNF receptor TrkB, but it reduced PDE4B expression. With the in vitro model in the HT22 hippocampal cell line, GLN exposure significantly increased protein and mRNA levels of BDNF and CREB5 and induced cAMP responsive element (CRE) reporter activity; the GLN-mediated BDNF expression and CRE reporter induction were suppressed by PKA inhibitor H89. Our current findings suggest that GLN can exert a cognition-enhancing function and this may act at least in part by upregulating the BDNF levels via a cAMP/PKA/CREB-dependent pathway.

The gastroprotective effect of the foxtail millet and adlay processing product against stress-induced gastric mucosal lesions in rats.

Foxtail millet (Setaria italica (L.) P. Beauv.) and adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) seeds have substantial benefits possesses remarkable edible and nutritive values, and ease of processing and food manufacturing. They have nutraceutical properties in the form of antioxidants which prevent deterioration of human health and have long been used in traditional Chinese medicine as a remedy for many diseases. The present study is designed to investigate the gastroprotective effect of foxtail millet and adlay processing product (APP) diet on water immersion restraint stress (WIRS) induced ulceration in rats. We examined the effects of intake of AIN-93G diet containing either foxtail millet (10, 20 and 40%, 4 weeks) or APP (15 and 30%, 5 weeks) on macroscopic ulcer index (UI), plasma calcium level, lipid peroxidation products (estimated by the thiobarbituric acid reactive substances; TBARS), non-protein sulfhydryl (NPSH), digestive enzyme activities, and histopathology were determined. The results showed that pretreatment with millet and adlay diets significantly prevented the gastric mucosal lesion development. In addition, ulcerated rats showed depletion of NPSH levels whereas treatment with millet and adlay reverted this decline in stress-induced rats. Histological studies confirmed the results. The finding suggests that millet and adlay diets promote ulcer protection by the decrease in ulcer index, TBARS values and increase NPSH concentrations. Millet and adlay diets retain the advantage of being a natural product which may protect the gastric mucosa against ulceration.

Uncovering the Modulatory Interactions of Brain Networks in Cognition with Central Thalamic Deep Brain Stimulation Using Functional Magnetic Resonance Imaging.

Deep brain stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. It acts by altering brain networks and facilitating synaptic plasticity. For enhancing cognitive functions, the central thalamus (CT) has been shown to be a potential DBS target. The network-level mechanisms contributing to the effect exerted by DBS on the CT (CT-DBS) remain unknown. Combining CT-DBS with functional magnetic resonance imaging (fMRI), this study explored brain areas activated while applying CT-DBS in rats, using a newly developed neural probe that was compatible with MRI and could minimize the image distortion and resolve safety issues. Results showed activation of the anterior cingulate cortex, motor cortex, primary and secondary somatosensory cortices, caudate putamen, hypothalamus, thalamus, and hippocampus, suggesting that the corticostriatal, corticolimbic, and thalamocortical brain networks were affected. Behaviorally, the CT-DBS group required a shorter time than sham controls to learn a water-reward lever-pressing task and made more correct choices in a T-maze task. Concurrent with enhanced learning performance, bilateral CT-DBS resulted in alteration in the functional connectivity of brain networks determined by resting-state fMRI. Western blot analyses showed that the protein level of both dopamine D1 and α4-nicotinic acetylcholine receptors was increased, and dopamine D2 receptor was decreased. These data suggest that CT-DBS can enhance cognitive performance as well as brain connectivity through the modulation of synaptic plasticity, such that CT is a target providing high potential for the remediation of acquired cognitive learning and memory disabilities.