[Show abstract][Hide abstract] ABSTRACT: Paracrine signals produced from stem cells influence tissue regeneration by inducing the differentiation of endogenous stem or progenitor cells. However, many recent studies that have investigated paracrine signaling of stem cells have relied on either two-dimensional transwell systems or conditioned medium culture, neither of which provide optimal culture microenvironments for elucidating the effects of paracrine signals in vivo. In this study, we recapitulated in vivo-like paracrine signaling of human mesenchymal stem cells (hMSCs) to enhance functional neuronal differentiation of human neural stem cells (hNSCs) in three-dimensional (3D) extracellular matrices (ECMs) within a microfluidic array platform. In order to amplify paracrine signaling, hMSCs were genetically engineered using cationic polymer nanoparticles to overexpress glial cell-derived neurotrophic factor (GDNF). hNSCs were cultured in 3D ECM hydrogel used to fill central channels of the microfluidic device, while GDNF-overexpressing hMSCs (GDNF-hMSCs) were cultured in channels located on both sides of the central channel. This setup allowed for mimicking of paracrine signaling between genetically engineered hMSCs and endogenous hNSCs in the brain. Co-culture of hNSCs with GDNF-hMSCs in the 3D microfluidic system yielded reduced glial differentiation of hNSCs while significantly enhancing differentiation into neuronal cells including dopaminergic neurons. Neuronal cells produced from hNSCs differentiating in the presence of GDNF-hMSCs exhibited functional neuron-like electrophysiological features. The enhanced paracrine ability of GDNF-hMSCs was finally confirmed using an animal model of hypoxic-ischemic brain injury. This study demonstrates the presented 3D microfluidic array device can provide an efficient co-culture platform and provide an environment for paracrine signals from transplanted stem cells to control endogenous neuronal behaviors in vivo.
[Show abstract][Hide abstract] ABSTRACT: To investigate immediate changes in hyolaryngeal movement and swallowing function after a cycle of neuromuscular electrical stimulation (NMES) on both submental and throat regions and submental placement alone in patients with dysphagia.
Fifteen patients with dysphagia were recruited. First, videofluoroscopic swallowing study (VFSS) was performed before NMES. All patients thereafter received a cycle of NMES by 2 methods of electrode placement: 1) both submental and throat regions and 2) submental placement alone concomitant with VFSS. The Penetration-Aspiration Score (PAS) and the NIH-Swallowing Safety Scale (NIH-SSS) were measured for swallowing function.
During swallowing, hyolaryngeal descent significantly occurred by NMES on both submental and throat regions, and anterior displacement of hyolaryngeal complex was significant on submental placement alone. NMES on submental placement alone did not change the PAS and NIH-SSS. However, NMES on both submental and throat regions significantly reduced the NIH-SSS, although it did not change the PAS. Patients with no brainstem lesion and with dysphagia duration of <3 months showed significantly improved the NIH-SSS.
Immediate hyolaryngeal movement was paradoxically depressed after NMES on both submental and throat regions with significant reductions in the NIH-SSS but not the PAS, suggesting improvement in pharyngeal peristalsis and cricopharyngeal functions at the esophageal entry rather than decreased aspiration and penetration. The results also suggested that patients with dysphagia should be carefully screened when determining motor-level NMES.
Annals of Rehabilitation Medicine 04/2015; 39(2):199-209. DOI:10.5535/arm.2015.39.2.199
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of treadmill walking exercise as a treatment method to improve gait efficiency in adults with cerebral palsy (CP) and to determine gait efficiency during overground walking after the treadmill walking exercise.
Fourteen adults with CP were recruited in the experimental group of treadmill walking exercise. A control group of 7 adults with CP who attended conventional physical therapy were also recruited. The treadmill walking exercise protocol consisted of 3-5 training sessions per week for 1-2 months (total 20 sessions). Gait distance, velocity, VO2, VCO2, O2 rate (mL/kg·min), and O2 cost (mL/kg·m) were assessed at the beginning and at the end of the treadmill walking exercise. The parameters were measured by KB1-C oximeter.
After the treadmill walking exercise, gait distance during overground walking up to 6 minutes significantly increased from 151.29±91.79 to 193.93±79.01 m, and gait velocity increased from 28.09±14.29 to 33.49±12.69 m/min (p<0.05). Energy efficiency evaluated by O2 cost during overground walking significantly improved from 0.56±0.36 to 0.41±0.18 mL/kg·m (p<0.05), whereas O2 rate did not improve significantly after the treadmill walking exercise. On the other hand, gait velocity and O2 cost during overground walking were not significantly changed in the control group.
Treadmill walking exercise improved the gait efficiency by decreased energy expenditure during overground walking in adults with CP. Therefore, treadmill walking exercise can be an important method for gait training in adults with CP who have higher energy expenditure.
Annals of Rehabilitation Medicine 02/2015; 39(1):25-31. DOI:10.5535/arm.2015.39.1.25
[Show abstract][Hide abstract] ABSTRACT: Adults with cerebral palsy (CP) are known to have low bone mass with an increased risk of fragility fracture. CP is classified into two major types: spastic (pyramidal) and dyskinetic (extrapyramidal). Spastic CP is the most common and is characterized by muscle hypertonicity and impaired neuromuscular control. By contrast, dyskinetic CP is characterized by mixed muscle tone with involuntary movements. The aim of this study was to elucidate the relationship between bone metabolism and subtype of CP. Fifty-eight adults with CP (aged 18 to 49years, mean age 33.2years; 32 men, 26 women) were included in this cross-sectional analysis. Lumbar spine and femoral bone mineral density (BMD) Z-scores were measured. Bone markers, including C-telopeptide of type I collagen (CTx) and osteocalcin (OCN), were also analyzed. Among these participants, 30 had spastic CP and 28 had dyskinetic CP. The Z-scores of lumbar spine BMD did not differ between the two types. However, the Z-scores of femur trochanteric BMD were significantly lower in participants with spastic CP than in those with dyskinetic CP (-1.6±1.2 vs. -0.9±1.1, p<0.05). Seventy-four percent of participants with either type of CP had abnormally elevated CTx, while about 90% of participants showed normal OCN levels. When participants were subclassified into nonambulatory and ambulatory groups, the nonambulatory group had significantly lower BMD in the femur, including the trochanteric and total regions, whether they were spastic or dyskinetic (p<0.05). Because the type of CP affects bone mass, nonambulatory spastic CP participants showed the lowest total hip region BMD among the four groups. These results reveal that reduced weight bearing and immobility related to CP causes a negative bone balance because of increased bone resorption, which leads to a lower bone mass. In addition, hypertonicity of the affected limbs in participants with spastic CP resulted in lower bone mass than in those with dyskinetic CP. Type of CP and degree of ambulatory function in adults with CP should be regarded as important factors affecting bone metabolism.
Bone 10/2014; 71. DOI:10.1016/j.bone.2014.10.003 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, cell-based therapy has been highlighted as an alternative to treating ischemic brain damage in stroke patients. The present study addresses the therapeutic potential of polysialic acid-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (NPC(PSA-NCAM+)) derived from human embryonic stem cells (hESCs) in a rat stroke model with permanent middle cerebral artery occlusion. Data showed that rats transplanted with NPC(PSA-NCAM+) are superior to those treated with phosphate buffered saline (PBS) or mesenchymal stem cells (MSCs) in behavioral performance throughout time points. In order to investigate its underlying events, immunohistochemical analysis was performed on rat ischemic brains treated with PBS, MSCs, and NPC(PSA-NCAM+). Unlike MSCs, NPC(PSA-NCAM+) demonstrated a potent immunoreactivity against human specific nuclei, doublecortin, and Tuj1 at day 26 post-transplantation, implying their survival, differentiation, and integration in the host brain. Significantly, NPC(PSA-NCAM+) evidently lowered the positivity of microglial ED-1 and astrocytic GFAP, suggesting a suppression of adverse glial activation in the host brain. In addition, NPC(PSA-NCAM+) elevated α-SMA(+) immunoreactivity and the expression of angiopoietin-1 indicating angiogenic stimulation in the host brain. Taken together, the current data demonstrate that transplanted NPC(PSA-NCAM+) preserve brain tissue with reduced infarct size and improve behavioral performance through actions encompassing anti-reactive glial activation and pro-angiogenic activity in a rat stroke model. In conclusion, the present findings support the potentiality of NPC(PSA-NCAM+) as the promising source in the development of cell-based therapy for neurological diseases including ischemic stroke.
[Show abstract][Hide abstract] ABSTRACT: Hemophilia A, one of the most common genetic bleeding disorders, is caused by various mutations in the blood coagulation factor VIII (F8) gene. Among the genotypes that result in hemophilia A, two different types of chromosomal inversions that involve a portion of the F8 gene are most frequent, accounting for almost half of all severe hemophilia A cases. In this study, we used a transcription activator-like effector nuclease (TALEN) pair to invert a 140-kbp chromosomal segment that spans the portion of the F8 gene in human induced pluripotent stem cells (iPSCs) to create a hemophilia A model cell line. In addition, we reverted the inverted segment back to its normal orientation in the hemophilia model iPSCs using the same TALEN pair. Importantly, we detected the F8 mRNA in cells derived from the reverted iPSCs lines, but not in those derived from the clones with the inverted segment. Thus, we showed that TALENs can be used both for creating disease models associated with chromosomal rearrangements in iPSCs and for correcting genetic defects caused by chromosomal inversions. This strategy provides an iPSC-based novel therapeutic option for the treatment of hemophilia A and other genetic diseases caused by chromosomal inversions.
Proceedings of the National Academy of Sciences 06/2014; 111(25). DOI:10.1073/pnas.1323941111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate the effect of deep brain stimulation (DBS) on reducing dystonia and disability in adults with cerebral palsy (CP) and to compare the therapeutic outcomes between primary dystonia patients and CP patients over two years after bilateral pallidal DBS.
Five patients with primary dystonia and seven CP patients with dystonia were recruited. All subjects received DBS surgery in both globus pallidus. Burke-Fahn-Marsden dystonia rating scale consisting of dystonia movement score and disability score and subjective satisfaction scale were assessed after 1 month and every 6 months over two years following DBS treatment.
On the dystonia movement scale, both groups of primary dystonia patients and CP patients showed a significant decrease over time following DBS. On the disability scale, patients with primary dystonia showed a significant decrease over time, whereas the disability score of CP patients did not change over the two years. Comparing the dystonia movement and disability scores of CP patients at each assessment, patients with primary dystonia showed a significant reduction after 6 months. Comparing the satisfaction scores of CP patients after DBS, patients with primary dystonia showed significantly higher subjective satisfaction.
Whereas dystonia can be significantly reduced in patients with primary dystonia, CP patients showed a modest improvement on the dystonia movement scale, but not on the disability scale. Therefore, DBS may be considered with caution as a treatment modality of CP patients with dystonia.
Annals of Rehabilitation Medicine 04/2014; 38(2):209-17. DOI:10.5535/arm.2014.38.2.209
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells (MSCs) have been derived from different sources including adipose tissue (AT), bone marrow (BM), and umbilical cord blood (UCB). We investigated that human MSCs may differentiate into neurons that produce gamma-aminobutyric acid ((GABA)ergic neurons) in response to brain-derived neurotrophic factor (BDNF). This potential for GABAergic neuronal differentiation was also evaluated in MSCs derived from different sources of AT, BM, and UCB. For this purpose, the AT-, BM-, and UCB-MSCs were plated onto poly-D-lysine/laminin with BDNF, and were compared with control MSCs cultured without BDNF. To compare various neuronal differentiation potential among BM-, UCB-, and AT-MSCs, reverse transcription polymerase chain reaction was performed with nestin, a neural stem cell marker, ChAT, a cholinergic neuronal marker, TH, a dopaminergic neuronal marker, and GAD67, a GABAergic neuronal marker. Immunocytochemistry was also assessed as the expression of beta III-tubulin and GABA. As a result, the BDNF-treated groups of BM-, UCB-, and AT-MSCs expressed nestin at higher levels than control MSCs. In addition, the BDNF-treated groups of BM- and UCB-MSCs expressed GAD67 at higher levels than control MSCs, whereas GAD67 was not increased in the BDNF-treated group of AT-MSCs. In immunocytochemistry, exposure to BDNF promoted GABAergic neuronal differentiation, as demonstrated by the increased percentages of GABA(+)/GABA+ /4 ',6-diamidino-2-phenylindole (DAPI)(+) cells compared with the control cultures of AT-, BM-, and UCB-MSCs. In particular, after the BDNF-induced GABAergic neuronal differentiation, GABA(+)/DAPI(+) cells (%) were significantly increased in BM-MSCs compared with the other groups. In conclusion, BM-MSC is the most ideal cell source for human MSCs into GABAergic neuronal differentiation.
Animal cells and systems the official publication of the Zoological Society of Korea 02/2014; 18(1):17-24. DOI:10.1080/19768354.2013.877076 · 0.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin (EPO) and granulocyte colonystimulating factor (G-CSF) are likely to play broad roles in the brain. We investigated the effects of combination therapy with EPO and G-CSF in hypoxic-ischemic brain injury during the acute, subacute, and chronic phases. A total of 79 C57BL/6 mice with hypoxic-ischemic brain injury were randomly assigned acute (days 1-5), subacute (days 11-15) and chronic (days 28-32) groups. All of them were treated with G-CSF (250 μg/kg) and EPO (5 000 U/kg) or saline daily for 5 consecutive days. Behavioral assessments and immunohistochemistry for angiogenesis, neurogenesis, and astrogliosis were performed with an 8-week follow-up. Hypoxia-inducible factor-1 (HIF-1) was also measured by Western blot analysis. The results showed that the combination therapy with EPO and G-CSF in the acute phase significantly improved rotarod performance and forelimb-use symmetry compared to the other groups, while subacute EPO and G-CSF therapy exhibited a modest improvement compared with the chronic saline controls. The acute treatment significantly increased the density of CD31(+) (PECAM-1) and α-smooth muscle actin(+) vessels in the frontal cortex and striatum, increased BrdU(+)/PSANCAM(+) neurogenesis in the subventricular zone, and decreased astroglial density in the striatum. Furthermore, acute treatment significantly increased the HIF-1 expression in the cytosol and nucleus, whereas chronic treatment did not change the HIF-1 expression, consistent with the behavioral outcomes. These results indicate that the induction of HIF-1 expression by combination therapy with EPO and G-CSF synergistically enhances not only behavioral function but also neurogenesis and angiogenesis while decreasing the astroglial response in a timedependent manner.
[Show abstract][Hide abstract] ABSTRACT: Objective:
Cerebral palsy (CP) is a disabling condition characterized by the motor impairment, which is difficult to be ameliorated. In the brain of infants with CP, there are persistent pathomechanisms including accentuated neuroinflammation. Since erythropoietin was demonstrated to have neuroprotective effect via anti-inflammatory and anti-apoptotic properties, we hypothesized that the administration of recombinant human EPO (rhEPO) could help children with CP, especially young infants.
Materials and method:
We investigated the therapeutic efficacy of rhEPO for infants with CP, who had been undergoing active rehabilitation in hospitalized setting to eliminate treatment bias. Twenty infants with CP were randomly divided into EPO or control group equally. We compared the changes in the Gross Motor Function Measure (GMFM) and the Bayley Scales of Infant Development-II (BSID-II) scores during one month of hospitalization between two groups.
The improvements after 1 month on the GMFM A and GMFM total scores differed significantly between the groups (p = 0.003, p = 0.04, respectively). However, the changes after 6 months were not different between the two groups. The scores of BSID-II did not show any differences at 1-month and 6-months post-treatment.
These results indicated that rhEPO could have therapeutic efficacy for infants with CP during the active rehabilitation and anti-inflammation was suggested to be one of its therapeutic mechanisms.
Brain & development 12/2013; 36(9). DOI:10.1016/j.braindev.2013.11.002 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As a sequential, programmed movement of fingers, keyboard playing is a promising technique for inducing execution and a high level of coordination during finger movements. Also, keyboard playing can be physically and emotionally rewarding for adolescents in rehabilitation settings and thereby motivate continued involvement in treatment.
The purpose of this study is to evaluate the effects of keyboard playing using Musical Instrument Digital Interface (MIDI) on finger movement for adolescents with brain damage.
Eight adolescents with brain damage, ages 9 to 18 years (M = 13 years, SD = 2.78), in physical rehabilitation settings participated in this study. Measurements included MIDI keyboard playing for pressing force of the fingers and hand function tests (Grip and Pinch Power Test, Box and Block Test of Manual Dexterity [BBT], and the Jebsen Taylor Hand Function Test).
Results showed increased velocity of all fingers on the MIDI-based test, and statistical significance was found in the velocity of F2 (index finger), F3 (middle finger), and F5 (little finger) between pre- and post-training tests. Correlation analysis between the pressing force of the finger and hand function tests showed a strong positive correlation between the measure of grip power and the pressing force of F2 and F5 on the Grip and Pinch Strength Test. All fingers showed strong correlation between MIDI results and BBT. For the Jebsen Taylor Hand Function Test, only the moving light objects task at post-training yielded strong correlation with MIDI results of all fingers.
The results support using keyboard playing for hand rehabilitation, especially in the pressing force of individual finger sequential movements. Further investigation is needed to define the feasibility of the MIDI program for valid hand rehabilitation for people with brain damage.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate the effects of enriched environment (EE) on promoting angiogenesis and neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in seven day-old CD-1® mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At six weeks of age, the mice were randomly assigned to either EE or standard cages (SC) for two months. Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. In order to identify angiogenic growth factors regulated by EE, an array-based multiplex ELISA assay was used to measure the expression in frontal cortex, striatum, and cerebellum. Among the growth factors, the expression of fibroblast growth factor-2 (FGF-2) was confirmed using western blotting. Platelet endothelial cell adhesion molecule-1 (PECAM-1) and α-smooth muscle actin (α-SMA) were also evaluated using immunohistochemistry. As a result, mice exposed to EE showed significant improvements in rotarod and ladder walking performances compared to SC controls. The level of FGF-2 was significantly higher in the frontal cortex of EE mice at 8 weeks after treatment in multiplex ELISA and western blot. On the other hand, FGF-2 in the striatum significantly increased at 2 weeks after exposure to EE earlier than in the frontal cortex. Expression of activin A was similarly upregulated as FGF-2 expression pattern. Particularly, all animals treated with FGF-2 neutralizing antibody abolished the beneficial effect of EE on motor performance relative to mice not given anti-FGF-2. Immunohistochemistry showed that densities of α-SMA(+) and PECAM-1(+) cells in frontal cortex, striatum, and hippocampus were significantly increased following EE, suggesting the histological findings exhibit a similar pattern to the upregulation of FGF-2 in the brain. In conclusion, EE enhances endogenous angiogenesis and neurobehavioral functions mediated by upregulation of FGF-2 in chronic hypoxic-ischemic brain injury.
PLoS ONE 09/2013; 8(9):e74405. DOI:10.1371/journal.pone.0074405 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is used to treat neurological diseases such as stroke and Parkinson's disease (PD). Although rTMS has been used clinically, its underlying therapeutic mechanism remains unclear. The objective of the present study was to clarify the neuroprotective effect and therapeutic mechanism of rTMS in an animal model of PD. Adult Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine (6-OHDA) into the right striatum. Rats with PD were then treated with rTMS (circular coil, 10Hz, 100% of motor threshold, 20min/day) daily for 4 weeks. Behavioral assessments such as amphetamine-induced rotational test and treadmill locomotion test were performed, and the dopaminergic (DA) neurons of substantia nigra pas compacta (SNc) were histologically examined. Expression of neurotrophic/growth factors was also investigated by multiplex ELISA and western blotting analysis 4 weeks after rTMS application. Among the results, the number of amphetamine-induced rotations was significantly lower in the rTMS group than in the control group at 4 weeks post-treatment. Treadmill locomotion was also significantly improved in the rTMS-treated rats. Tyrosine hydroxylase-positive DA neurons and DA fibers in rTMS group rats were greater than those in untreated group in both ipsilateral SNc and striatum, respectively. The expression levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, and vascular endothelial growth factor were elevated in both the 6-OHDA-injected hemisphere and the SNc of the rTMS-treated rats. In conclusion, rTMS treatment improved motor functions and survival of DA neurons, suggesting that the neuroprotective effect of rTMS treatment might be induced by upregulation of neurotrophic/growth factors in the PD animal model.
Brain research 08/2013; 1537. DOI:10.1016/j.brainres.2013.08.051 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to examine the effects of Therapeutic Instrument Music Performance (TIMP) for fine motor exercises in adults with cerebral palsy (CP). Individuals with CP (n = 5) received a total of twelve, 30-min TIMP sessions, two days per week for six to nine weeks. Pre- and post-Music Instrument Digital Interface (MIDI) data were used as a measure of hand function. Pre-velocity was significantly different from the normative data obtained from typical adults (n = 20); however, post-velocity did not yield significance, specifically in the second and fifth fingers, indicating improvement in hand function for the adults with cerebral palsy. The finding implies that TIMP using keyboard playing may effectively improve manual dexterity and velocity of finger movement. Based on these results, future program development of instrumental playing for adults with CP is called for to enhance both their independent living skills and quality of life.
[Show abstract][Hide abstract] ABSTRACT: After spinal cord injury (SCI), functional and structural reorganization occurs at multiple levels of brain including motor cortex. However, the underlying mechanism still remains unclear. The current study was performed to investigate the alterations in the expression of the main regulators of neuronal development, survival and death, in the brain following thoracic contusive SCI in a mouse model.
Eight-week-old female imprinting control region mice (n=60; 30-35 g) were used in this study. We analyzed the expression levels of regulators such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and histone deacetylase (HDAC) 1 in the brain following thoracic contusive SCI.
The expression of BDNF levels were elevated significantly compared with control group at 2 weeks after injury (p<0.05). The expression of NGF levels were elevated at 2, 4 weeks compared with control group, but these difference were not significant (p>0.05). The GDNF levels were elevated at 2 week compared with control group, but these differences were not significant (p>0.05). The difference of HDAC1 levels were not significant at 2, 4 and 8 weeks compared with control group (p>0.05).
These results demonstrate that the upregulation of BDNF may play on important role in brain reorganization after SCI.
Journal of Korean Neurosurgical Society 06/2013; 53(6):337-41. DOI:10.3340/jkns.2013.53.6.337 · 0.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to define the acoustic voice and speech characteristics of patients with Parkinson disease (PD). Seven female patients with PD and seven female healthy controls participated in this study. Each subject was instructed to vocalize extended corner vowels (/a/, /e/, /i/, /u/) three times for at least 5 seconds at a comfortable voice loudness and tone. The voice was analyzed using the Praat program. As a result, female patients with PD showed a significant increase in jitter and noise-to-harmonics ratio (NHR). In addition, F1 and F2 among the PD patients demonstrated asymmetric centralization of unrounded vowels (/a/, /e/, /i/) in high/low/front/back positions of the tongue, consequently leading to a significant decrease in vowel space area, compared to healthy controls. This study showed the acoustic characteristics of vowel sounds not only by laryngeal variables such as abnormal jitter and NHR, but also by articulatory variables such as asymmetric centralization and reduced vowel space area in female patients with PD. Therefore, it is important to use these objective and sensitive variables to evaluate the status or severity of hypokinetic dysarthria in patients with PD.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: . Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated. OBJECTIVES: . We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns. METHODS: . We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA). RESULTS: . In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na(+)/Cl(-)-dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner. CONCLUSION: . An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of environmental enrichment (EE) on the function of transplanted adipose stem cells (ASCs) and the combined effect of EE and ASC transplantation on neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O₂ for 90 min). At 6 weeks of age, the mice were randomly injected with either ASCs or PBS into the striatum and were randomly assigned to either EE or standard cages (SC), comprising ASC-EE (n=18), ASCSC (n=19), PBS-EE (n=12), PBS-SC (n=17), and untreated controls (n=23). Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and βIII-tubulin⁺ neurons derived from the transplanted ASCs were significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increasedBrdU⁺βIII-tubulin⁺ neurons, GFAP⁺ astrocytic density and fibroblast growth factor-2 (FGF2) level but not the level of CS-56⁺ glial scarring in the striatum. In conclusion, EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2.