Control Of Brain Functions Research Articles

Impact of KDM6B mosaic brain knockout on synaptic function and behavior

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.

Scalp Acupuncture Synchronizing Dual Task Gait for Enhancing Prefrontal Cortex Response.

Studies have shown that motor-cognitive dual task can greatly improve motor/cognitive function. However, the therapeutic effect of motor-cognitive dual task is still limited. How to improve dual-task performance is the key to solving this problem. Scalp acupuncture is a non-drug intervention method of traditional Chinese medicine to treat brain-derived diseases by acupuncturing the corresponding projection area of cerebral cortex function on the scalp. Studies have shown that scalp acupuncture helps improve neuronal damage and cognitive dysfunction and plays a neuroprotective function in central nervous system diseases. However, no relevant studies have discussed the synergistic gain effect of motor-cognitive dual task and scalp acupuncture. Therefore, this protocol aims to demonstrate the standardized operation of scalp acupuncture synchronizing motor-cognitive dual task and motor-cognitive dual task and compares the differences between these two tasks in healthy subjects through a randomized cross-over trial. This protocol initially revealed the possible influence mechanism of scalp acupuncture synchronizing motor-cognitive dual task on cognitive performance, gait control, and cortical brain function, which can provide new ideas and a theoretical basis for clinical exploration of new and effective non-drug treatment of integrated Chinese and Western medicine.

The associations among glycemic control, heart variability, and autonomic brain function in healthy individuals: Age- and sex-related differences

IntroductionThe purpose of this study was to clarify the relationships between glycemia and function of the autonomic nervous system (ANS), assessed via resting-state functional connectivity (FC) and heart-rate variability (HRV). MethodsData for this study were extracted from the Leipzig Study for Mind-Body-Emotion Interactions, including 146 healthy adults (114 young, 32 older). Variables of interest were glycated hemoglobin (HbA1c), resting-state FC in the salience aspect of the central-autonomic (S-CAN) and salience network (SN) and HRV (RMSSD and high-frequency HRV (HF-HRV)). ResultsHbA1c was inversely correlated with FC in the S-CAN but not SN. HbA1c was inversely correlated with HRV. Both RMSSD and log(HF-HRV) were correlated with FC in the S-CAN and SN. Age- (not sex-related) differences were observed in the Hb1Ac-FC associations (stronger in older adults) while sex- (not age-related) differences were observed in the HRV-FC (stronger in females). ConclusionsThese findings extend the diabetes literature to healthy adults in relating glycemia and brain function. The age- and sex-related differences in these relationships highlight the need to account for the potential effects of age and sex in future investigations.

The Effect of Mindset Interventions on Stress and Academic Motivation in College Students

Stress levels are high among college students in the United States. Growth mindset and stress-is-enhancing mindset interventions offer ways to reduce stress, but minimal research has examined them. This study’s aim was to examine the effect of mindset interventions on mindsets, stress, academic motivation, and responses to hypothetical academic scenarios. Participants included 210 college students who were randomized to one of four groups: growth mindset (intelligence is malleable), stress mindset (stress is beneficial), synergistic (intelligence is malleable, and stress is beneficial), or control (brain functions). The growth mindset and the synergistic mindset group increased in growth mindset, and the growth mindset group had higher growth mindset than the stress mindset and control group post-intervention. The stress mindset and the synergistic group increased in stress-is-enhancing mindset, and both groups had higher stress-is-enhancing mindsets than the growth mindset and control group post-intervention. All groups decreased in stress and increased in academic motivation. The synergistic group was the only group to improve on all the main outcomes, and students in this group were less likely to want to withdraw from a course in both negative hypothetical academic scenarios (if they failed an assignment or were faced with a professor with a fixed mindset). Our findings suggest that students would benefit from increased access to mindset interventions.

Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice

Intestinal γδ T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for γδ T cells (γδ-/-) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with γδ-/- microbiota induced R/C behavior whereas colonization of γδ-/- mice with WT microbiota abolished the R/C behavior. Moreover, γδ-/- mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal γδ T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.

Machine learning-based high-frequency neuronal spike reconstruction from low-frequency and low-sampling-rate recordings

Recording neuronal activity using multiple electrodes has been widely used to understand the functional mechanisms of the brain. Increasing the number of electrodes allows us to decode more variety of functionalities. However, handling massive amounts of multichannel electrophysiological data is still challenging due to the limited hardware resources and unavoidable thermal tissue damage. Here, we present machine learning (ML)-based reconstruction of high-frequency neuronal spikes from subsampled low-frequency band signals. Inspired by the equivalence between high-frequency restoration and super-resolution in image processing, we applied a transformer ML model to neuronal data recorded from both in vitro cultures and in vivo male mouse brains. Even with the x8 downsampled datasets, our trained model reasonably estimated high-frequency information of spiking activity, including spike timing, waveform, and network connectivity. With our ML-based data reduction applicable to existing multichannel recording hardware while achieving neuronal signals of broad bandwidths, we expect to enable more comprehensive analysis and control of brain functions.

Microglia at the Tripartite Synapse during Postnatal Development: Implications for Autism Spectrum Disorders and Schizophrenia.

Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation, and elimination mainly during postnatal development via a complex interplay with neighboring astrocytes and microglia that, by shaping neural connectivity, may have a crucial role in the strengthening and weakening of synaptic functions, that is, the functional plasticity of synapses. Indeed, an increasing number of studies have unveiled the roles of microglia and astrocytes in synapse formation, maturation, and elimination as well as in regulating synaptic function. Over the past 15 years, the mechanisms underlying the microglia- and astrocytes-dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of these glial cells in early postnatal development may underlie the cause of synaptic dysfunction that leads to neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia.

Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis

The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. Invitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. Invivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

CGP7930 - An allosteric modulator of GABABRs, GABAARs and inwardly-rectifying potassium channels

Type-A and -B GABA receptors (GABAARs/GABABRs) control brain function and behaviour by fine tuning neurotransmission. Over-time these receptors have become important therapeutic targets for treating neurodevelopmental and neuropsychiatric disorders. Several positive allosteric modulators (PAMs) of GABARs have reached the clinic and selective targeting of receptor subtypes is crucial. For GABABRs, CGP7930 is a widely used PAM for in vivo studies, but its full pharmacological profile has not yet been established. Here, we reveal that CGP7930 has multiple effects not only on GABABRs but also GABAARs, which for the latter involves potentiation of GABA currents, direct receptor activation, and also inhibition. Furthermore, at higher concentrations, CGP7930 also blocks G protein-coupled inwardly-rectifying K+ (GIRK) channels diminishing GABABR signalling in HEK 293 cells. In male and female rat hippocampal neuron cultures, CGP7930 allosteric effects on GABAARs caused prolonged rise and decay times and reduced the frequency of inhibitory postsynaptic currents and potentiated GABAAR-mediated tonic inhibition. Additional comparison between predominant synaptic- and extrasynaptic-isoforms of GABAAR indicated no evident subtype selectivity for CGP7930.In conclusion, our study of CGP7930 modulation of GABAARs, GABABRs and GIRK channels, indicates this compound is unsuitable for use as a specific GABABR PAM.

Tamm plasmon-based dopamine detection by using a chitosan-polyaniline-gold nanostructure

Dopamine is a biomolecule that plays an important role in controlling brain function. The concentration of dopamine is a critical parameter in biotechnology. In the present research, a novel methodology for synthesis of a chitosan/polyaniline-gold-nanoparticle nanostructure layer by using the laser ablation technique is developed. The novel polyaniline nanostructure composite layer was coated on the surface of the photonic crystal with 28 alternating layers of SiO2 and TiO2 by an electron gun deposition machine. By implementing the reflectance set-up, a photonic crystal/chitosan/polyaniline-gold-nanoparticle was used to measure the low concentration of dopamine by the lowest concentration of dopamine set to 1 ppm. The results propose a new approach and future directions in sensor-based techniques.

Hippocampal, Whole Midbrain, Red Nucleus, and Ventral Tegmental Area Volumes Are Increased by Selective Breeding for High Voluntary Wheel-Running Behavior.

Uncovering relationships between neuroanatomy, behavior, and evolution are important for understanding the factors that control brain function. Voluntary exercise is one key behavior that both affects, and may be affected by, neuroanatomical variation. Moreover, recent studies suggest an important role for physical activity in brain evolution. We used a unique and ongoing artificial selection model in which mice are bred for high voluntary wheel-running behavior, yielding four replicate lines of high runner (HR) mice that run ∼3-fold more revolutions per day than four replicate nonselected control (C) lines. Previous studies reported that, with body mass as a covariate, HR mice had heavier whole brains, non-cerebellar brains, and larger midbrains than C mice. We sampled mice from generation 66 and used high-resolution microscopy to test the hypothesis that HR mice have greater volumes and/or cell densities in nine key regions from either the midbrain or limbic system. In addition, half of the mice were given 10 weeks of wheel access from weaning, and we predicted that chronic exercise would increase the volumes of the examined brain regions via phenotypic plasticity. We replicated findings that both selective breeding and wheel access increased total brain mass, with no significant interaction between the two factors. In HR compared to C mice, adjusting for body mass, both the red nucleus (RN) of the midbrain and the hippocampus (HPC) were significantly larger, and the whole midbrain tended to be larger, with no effect of wheel access nor any interactions. Linetype and wheel access had an interactive effect on the volume of the periaqueductal gray (PAG), such that wheel access increased PAG volume in C mice but decreased volume in HR mice. Neither linetype nor wheel access affected volumes of the substantia nigra, ventral tegmental area, nucleus accumbens, ventral pallidum (VP), or basolateral amygdala. We found no main effect of either linetype or wheel access on neuronal densities (numbers of cells per unit area) for any of the regions examined. Taken together, our results suggest that the increased exercise phenotype of HR mice is related to increased RN and hippocampal volumes, but that chronic exercise alone does not produce such phenotypes.

Neuroimmune signaling at the brain borders.

The central nervous system (CNS) has been viewed as an immunologically privileged site, but emerging works are uncovering a large array of neuroimmune interactions primarily occurring at its borders. CNS barriers sites host diverse population of both innate and adaptive immune cells capable of, directly and indirectly, influence the function of the residing cells of the brain parenchyma. These structures are only starting to reveal their role in controlling brain function under normal and pathological conditions and represent an underexplored therapeutic target for the treatment of brain disorders. This review will highlight the development of the CNS barriers to host neuro-immune interactions and emphasize their newly described roles in neurodevelopmental, neurological, and neurodegenerative disorders, particularly for the meninges.

Multimodal detection of dopamine by sniffer cells expressing genetically encoded fluorescent sensors

Dopamine supports locomotor control and higher brain functions such as motivation and learning. Consistently, dopaminergic dysfunction is involved in a spectrum of neurological and neuropsychiatric diseases. Detailed data on dopamine dynamics is needed to understand how dopamine signals translate into cellular and behavioral responses, and to uncover pathological disturbances in dopamine-related diseases. Genetically encoded fluorescent dopamine sensors have recently enabled unprecedented monitoring of dopamine dynamics in vivo. However, these sensors’ utility for in vitro and ex vivo assays remains unexplored. Here, we present a blueprint for making dopamine sniffer cells for multimodal dopamine detection. We generated sniffer cell lines with inducible expression of seven different dopamine sensors and perform a head-to-head comparison of sensor properties to guide users in sensor selection. In proof-of-principle experiments, we apply the sniffer cells to record endogenous dopamine release from cultured neurons and striatal slices, and for determining tissue dopamine content. Furthermore, we use the sniffer cells to measure dopamine uptake and release via the dopamine transporter as a radiotracer free, high-throughput alternative to electrochemical- and radiotracer-based assays. Importantly, the sniffer cell framework can readily be applied to the growing list of genetically encoded fluorescent neurotransmitter sensors.

AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.

AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named “early infantile epileptic encephalopathy 39” (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior.

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain, but the mechanisms involved in the regulation of this process are ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglia-synapse contacts and an elevated amount of microglial phagocytic inclusions. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and a concurrent increase in expression of uncoupling protein 2 (Ucp2), a regulator of mitochondrial ROS generation. Conditional ablation of Ucp2 from microglia hindered phasic elimination of spine synapses with consequent accumulations of ROS and lysosome-lipid droplet complexes, which resulted in hippocampal neuronal circuit dysfunctions assessed by electrophysiology, and altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in the control of brain functions.

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress.

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.

Gut Microbiota Approach-A New Strategy to Treat Parkinson's Disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by neuronal loss and dysfunction of dopaminergic neurons located in the substantia nigra, which contain a variety of misfolded α-synuclein (α-syn). Medications that increase or substitute for dopamine can be used for the treatment of PD. Recently, numerous studies have shown gut microbiota plays a crucial role in regulating and maintaining multiple aspects of host physiology including host metabolism and neurodevelopment. In this review article, the role of gut microbiota in the etiological mechanism of PD will be reviewed. Furthermore, we discussed current pharmaceutical medicine-based methods to prevent and treat PD, followed by describing specific strains that affect the host brain function through the gut-brain axis. We explained in detail how gut microbiota directly produces neurotransmitters or regulate the host biosynthesis of neurotransmitters. The neurotransmitters secreted by the intestinal lumen bacteria may induce epithelial cells to release molecules that, in turn, can regulate neural signaling in the enteric nervous system and subsequently control brain function and behavior through the brain-gut axis. Finally, we proved that the microbial regulation of the host neuronal system. Endogenous α-syn can be transmitted long distance and bidirectional between ENS and brain through the circulatory system which gives us a new option that the possibility of altering the community of gut microbiota in completely new medication option for treating PD.

Melatonin Prevents Brain Damage and Neurocognitive Impairment Induced by Plasmodium Berghei ANKA Infection in Murine Model of Cerebral Malaria.

Cerebral malaria is characterized by permanent cognitive impairments in Plasmodium-infected children. Antimalarial therapies show little effectiveness to avoid neurological deficits and brain tissue alterations elicited by severe malaria. Melatonin is a well-recognized endogenous hormone involved in the control of brain functions and maintenance of blood–brain barrier integrity. The current study has evaluated the effect of melatonin on the histological alterations, blood–brain barrier leakage, and neurocognitive impairments in mice developing cerebral malaria. Swiss mice infected with Plasmodium berghei ANKA strain was used as cerebral malaria model. Melatonin treatment (5 and 10 mg/kg) was performed for four consecutive days after the infection, and data have shown an increased survival rate in infected mice treated with melatonin. It was also observed that melatonin treatment blocked brain edema and prevented the breakdown of blood–brain barrier induced by the Plasmodium infection. Furthermore, hematoxylin and eosin staining revealed that melatonin mitigates the histological alterations in Plasmodium-infected animals. Melatonin was also able to prevent motor and cognitive impairments in infected mice. Taken together, these results show for the first time that melatonin treatment prevents histological brain damages and neurocognitive alterations induced by cerebral malaria.

The COMT rs4680 polymorphism, family functioning and preschoolers' attentional control indexed by intraindividual reaction time variability.

Trial-to-trial intraindividual reaction time variability (IIRTV) serves as an index of attentional control and related endogenous brain function. What determinants contribute to preschoolers' attentional control indexed by IIRTV remains unknown. The present study examined how catechol-o-methyltransferase (COMT) rs4680 polymorphism interacted with family functioning (cohesion and adaptability) to impact on preschoolers' attentional control indexed by IIRTV. One hundred forty-four preschool children (Mage =4.19, SD=0.63) completed the flanker task to assess their IIRTV. Their parents were asked to fill out the Family Adaptability and Cohesion Evaluation Scale II to assess family functioning. After controlling for age, socioeconomic status (SES) and mean reaction time, results showed that the COMT rs4680 polymorphism was positively associated with preschoolers' IIRTV at the 5% significance level (p=.02) but not after multiple testing adjustment (p=.08). Moreover the COMT rs4680 polymorphism significantly interacted with family functioning to impact on preschoolers' IIRTV and the interaction effects remained significant after correction for multiple testing (p=.01, ΔR2 =0.06 in congruent conditions; p=.04, ΔR2 =0.04 in combined conditions). In addition, the significant interaction between SES and COMT rs4680 polymorphism was also found in the present study (p=.01, ΔR2 =0.05 in congruent conditions; p=.05, ΔR2 =0.03 in combined conditions). No sex differences were found in the present sample. The findings of the present study expand our knowledge about the gene×environment underpinnings of children's attentional control and endogenous brain function, and provide evidence for the Vantage Sensitivity model on children's development.

Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice

Ethnopharmacological relevanceGreen tea has been used as a traditional medicine to control brain function and digestion. Recent works suggest that drinking green tea could prevent cognitive function impairment. During tea manufacturing processes, such as brewing and sterilization, green tea catechins are epimerized. However, the effects of heat-epimerized catechins on cognitive function are still unknown. To take this advantage, we developed a new green tea extract, high temperature processed-green tea extract (HTP-GTE), which has a similar catechin composition to green tea beverages. Aim of the studyThis study aimed to investigate the effect of HTP-GTE on scopolamine-induced cognitive dysfunction and neuronal differentiation, and to elucidate its underlying mechanisms of action. Materials and methodsThe neuronal differentiation promoting effects of HTP-GTE in SH-SY5Y cells was assessed by evaluating neurite length and the expression level of synaptophysin. The DNA methylation status at the synaptophysin promoter was determined in differentiated SH-SY5Y cells and in the hippocampi of mice. HTP-GTE was administered for 10 days at doses of 30, 100 and 300 mg/kg (p.o.) to mice, and its effects on cognitive functions were measured by Y-maze and passive avoidance tests under scopolamine-induced cholinergic blockade state. ResultsHTP-GTE induced neuronal differentiation and neurite outgrowth via the upregulation of synaptophysin gene expression. These beneficial effects of HTP-GTE resulted from reducing DNA methylation levels at the synaptophysin promoter via the suppression of DNMT1 activity. The administration of HTP-GTE ameliorated cognitive impairments in a scopolamine-treated mouse model. ConclusionsThese results suggest that HTP-GTE could alleviate cognitive impairment by regulating synaptophysin expression and DNA methylation levels. Taken together, HTP-GTE would be a promising treatment for the cognitive impairment observed in dysfunction of the cholinergic neurotransmitter system.