Kyoon Huh

Dynamics of Population Code for Working Memory in the Prefrontal Cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.

Autologous Mesenchymal Stem Cell Therapy Delays the Progression of Neurological Deficits in Patients With Multiple System Atrophy

We evaluated the feasibility and safety of therapy with mesenchymal stem cells (MSCs) through consecutively intra‐arterial and three repeated intravenous injections and compared the long‐term prognosis between MSC‐treated (n=11) and control multiple system atrophy (MSA) patients (n=18). The MSC‐treated patients showed significantly greater improvement on the unified MSA rating scale (UMSARS) than the control patients at all visits throughout the 12‐month study period. Orthostasis in UMSARS I items and cerebellar dysfunction‐related items of UMSARS II items were significantly different in favor of MSC treatment compared to controls. Serial positron emission tomography scan in the MSC‐treated group showed that increased fluorodeoxyglucose uptake from baseline was noted in cerebellum and frontal white matters. No serious adverse effects related to MSC therapy occurred. This study demonstrated that MSC therapy in patients with MSA was safe and delayed the progression of neurological deficits with achievement of functional improvement in the follow‐up period.

The plasma alpha-synuclein levels in patients with Parkinson's disease and multiple system atrophy.

Summary.α-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson’s disease (PD). In this study, we measured the plasma α-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The α-synuclein level was significantly elevated in patients with PD (79.9 ± 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9 pg/ml). The α-synuclein level was higher in patients with PD than in those with MSA (79.9 ± 4.0 vs 78.1 ± 3.5, p = 0.016). Our study demonstrated that the α-synuclein level in plasma is elevated in patients with PD and MSA.

Association of the metabolic syndrome with intracranial atherosclerotic stroke

To investigate the impact of metabolic syndrome (MetSD) on the development of intracranial atherosclerotic stroke, the authors evaluated the components of the MetSD in 512 patients with stroke. The MetSD was observed most frequently in patients with intracranial atherosclerosis (p = 0.007). In multiple regression analysis, the MetSD, but not conventional risk factors, was independently associated with intracranial atherosclerosis (p = 0.005). The results suggest that treatment of metabolic abnormalities may be an important prevention strategy for intracranial atherosclerosis.

Ginsenoside Rb1 and Rg1 Improve Spatial Learning and Increase Hippocampal Synaptophysin Level in Mice

We investigated the cognition enhancing effects of ginsenoside Rb1 and Rg1. Mice were trained in a Morris water maze following injection (i.p.) of Rb1 (1 mg/kg) or Rg1 (1 mg/kg) for 4 days. Both Rb1‐ and Rg1‐injected mice showed enhanced spatial learning compared to control animals. The hippocampus, but not the frontal cortex, of treated mice contained higher density of a synaptic marker protein, synaptophysin, compared to control mice. Electrophysiological recordings in hippocampal slices revealed that Rb1 or Rg1 injection did not change the magnitude of paired‐pulse facilitation or long‐term potentiation. Our results suggest that Rb1 and Rg1 enhance spatial learning ability by increasing hippocampal synaptic density without changing plasticity of individual synapses. J. Neurosci. Res. 63:509–515, 2001.

Frequency and mechanisms of stroke recurrence after cryptogenic stroke

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow‐up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003

Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.

Asiaticoside (AS) derivatives were tested for potential protective effects against Aβ‐induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Aβ‐induced death of B103 cells at 1 μM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H2O2‐induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine‐induced apoptosis. These results suggest that the three AS derivatives block Aβ toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n‐methyl‐D‐aspartic acid (NMDA) or non‐NMDA receptor‐mediated synaptic transmission, paired‐pulse facilitation or induction of long‐term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Aβ‐induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimers disease drug that protects neurons from Aβ toxicity. J. Neurosci. Res. 58:417–425, 1999.

Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity.

Estrogen is beneficial to patients with Alzheimers disease (AD) but has a limited clinical use due to its proliferative and oncogenic effects on non-neuronal cells responsive to estrogen. In an attempt to find an estrogen substitute that retains the beneficial effects of estrogen with minimal side effects, we compared the neuroprotective and proliferative effects of genistein, a selective estrogen receptor (ER) beta-agonist, with those of estrogen. Genistein and 17beta-estradiol showed comparable levels of protection against Abeta-induced deaths of cultured SH-SY5Y human neuroblastoma cells, which were blocked by an estrogen receptor antagonist, ICI 182,780. On the other hand, 17beta-estradiol, but not genistein, induced proliferation of uterine endometrial cells. Our results suggest that genistein is a potential alternative to estrogen in the treatment of Alzheimers disease.

Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand.

Abstract: Peripheral neuropathy following cisplatin treatment is a major limiting factor in cisplatin chemotherapy of cancer patients. We investigated the pathomechanism underlying cisplatin neuropathy using a mouse dorsal root ganglion neuron‐neuroblastoma hybrid cell line (N18D3) developed in our laboratory. DNA fragmentation, a characteristic feature of apoptosis, was induced in hybrid neurons following treatment with cisplatin. Accumulation of p53, Fas, and Fas ligand (Fas‐L) was also demonstrated in these neurons. Preincubation with N‐acetylcysteine (NAC), a precursor of glutathione, blocked cisplatin‐induced apoptosis completely, whereas Trolox, a vitamin E analogue, blocked it partially. Cisplatin‐induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In contrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin‐induced Fas/Fas‐L accumulation. These results suggest that the neuroprotective effects of antioxidants against cisplatin‐induced neurotoxicity in hybrid neurons are mediated mainly through the inhibition of p53 accumulation but not of Fas/Fas‐L accumulation by these antioxidants.

IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes.

β‐Site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of β amyloid. Since we found that injection of interferon‐γ (IFN‐γ) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN‐γ in a region specific manner and down‐regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN‐γ treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN‐γ treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen‐activated or extracellular signal‐regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN‐γ‐induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN‐γ‐induced STAT1 signaling cascade. Taken together, our results suggest that IFN‐γ activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes.