investigating-long-term-synaptic-plasticity-interlamellar-hippocampus

Investigating Long-term Synaptic Plasticity in Interlamellar Hippocampus CA1 by Electrophysiological Field Recording

The study of synaptic plasticity in the hippocampus has focused on the use of the CA3-CA1 lamellar network. Less attention has been given to the ...

Incheon National University

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1(-/-) mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action. 

AgRP Neurons Regulate Bone Mass.

Various pathophysiologic mechanisms leading to sickness behaviors have been proposed. For example, an inflammatory process in the hypothalamus has been implicated, but the signaling modalities that involve inflammatory mechanisms and neuronal circuit functions are ill-defined. Here, we show that toll-like receptor 2 (TLR2) activation by intracerebroventricular injection of its ligand, Pam3CSK4, triggered hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in altered input organization and increased activity of proopiomelanocortin (POMC) neurons. These animals developed sickness behavior symptoms, including anorexia, hypoactivity, and hyperthermia. Antagonists of nuclear factor kappa B (NF-κB), cyclooxygenase pathway and melanocortin receptors 3/4 reversed the anorexia and body weight loss induced by TLR2 activation. These results unmask an important role of TLR2 in the development of sickness behaviors via stimulation of hypothalamic microglia to promote POMC neuronal activation in association with hypothalamic inflammation.

Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis.

Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation, short-term postsynaptic plasticity (STPP), has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain.

A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines.

A brain-enriched secreting signal peptide, NELL2, has been suggested to play multiple roles in the development, survival, and activity of neurons in mammal. We investigated here a possible involvement of central NELL2 in regulating feeding behavior and metabolism.  hybridization and an im-munohistochemical approach were used to determine expression of NELL2 as well as its colocalization with proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the rat hypothalamus. To investigate the effect of NELL2 on feeding behavior, 2 nmole of antisense NELL2 oligodeoxynucleotide was administered into the lateral ventricle of adult male rat brains for 6 consecutive days, and changes in daily body weight, food, and water intake were monitored. Metabolic state-dependent NELL2 expression in the hypothalamus was tested  using a fasting model. NELL2 was noticeably expressed in the hypothalamic nuclei controlling feeding behavior. Furthermore, all arcuatic POMC and NPY positive neurons produced NELL2. The NELL2 gene expression in the hypothalamus was up-regulated by fasting. However, NELL2 did not affect POMC and NPY gene expression in the hypothalamus. A blockade of NELL2 production in the hypothalamus led to a reduction in daily food intake, followed by a loss in body weight without a change in daily water intake in normal diet condition. NELL2 did not affect short-term hunger dependent appetite behavior. Our data suggests that hypothalamic NELL2 is associated with appetite behavior, and thus central NELL2 could be a new therapeutic target for obesity.

A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats.

Heparin-binding EGF-like growth factor (HB-EGF) is a potent growth factor involved in wound healing and tumorigenesis. Despite the sequence similarity between HB-EGF and EGF, HB-EGF induces cellular proliferation and migration more potently than EGF. However, the differential regulation by HB-EGF and EGF has not been thoroughly elucidated. In this study, we compared signaling pathways activated by HB-EGF and EGF to understand the details of the molecular mechanism of the high potency induced by HB-EGF. HB-EGF specifically induced the phosphorylation of EGFR-Y1045 and activated Stat5, which is responsible for promoting cell proliferation, and migration. The competition of phosphorylated EGFR-Y1045 inhibited Stat5 activation and consequently lowered the effect of HB-EGF on cell proliferation, suggesting that the phosphorylation of EGFR-Y1045 is essential for the activation of Stat5. The phosphorylation of EGFR-Y1045 and Stat5 induced by HB-EGF was prevented by sequestering the heparin-binding domain, suggesting that the heparin-binding domain is critical for HB-EGF-mediated signaling and cellular responses. In conclusion, the heparin-binding domain of HB-EGF was responsible for EGFR-mediated Stat5 activation, resulting in a more potent cellular proliferation, and migration than that mediated by EGF. This molecular mechanism is useful for understanding ligand-specific EGFR signaling and developing biomedicines for wound healing or cancer therapy.

Stat5 phosphorylation is responsible for the excessive potency of HB-EGF.

Here, we report thyroid transcription factor 1 (TTF-1) as an important transcription factor for the expression of heme oxygenase-1 (HO-1). HO-1 is a well-known cytoprotective enzyme against inflammation. We observed that HO-1 co-expressed with TTF-1 in mouse hypothalamic cells. Results from luciferase and chromatin immunoprecipitation assays revealed that TTF-1 directly activated HO-1 transcription by binding to binding domains in the 5'-flanking region of the HO-1 gene. A proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), induced nuclear translocation of TTF-1 and increased binding affinity of TTF-1 to its binding sites on the HO-1 gene. HO-1 mRNA increased with TTF-1 overexpression but decreased with RNA interference of TTF-1 expression in rat astroglial C6 cells. Together with results showing involvement of TTF-1 in the TNF-α-induced increase in interleukin 1 beta and monocyte chemotactic protein 1 production, this study suggests that TTF-1 plays an important role in the mouse hypothalamus TNF-α-induced inflammatory response for regulating HO-1 gene expression.

Role of thyroid transcription factor-1 in transcriptional regulation of heme oxygenase-1.

Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus.

Visfatin Triggers Anorexia and Body Weight Loss through Regulating the Inflammatory Response in the Hypothalamic Microglia.

Bluetongue is a re-emergent arthropod-transmitted viral disease that affects all wild and domestic ruminant species, reducing herd productivity. The epidemiology of bluetongue virus (BTV) infection is poorly defined in much of the world, including extensive portions of Asia and the Middle East. In the Republic of Korea (ROK), scarce information is available on the status of BTV infection. Despite evidence of BTV in neighboring countries, such as the People's Republic of China and Japan, and the presence of Culicoides species that have recently been reported as possible vectors for BTV transmission, no serological data on BTV infection or circulation have been reported in the ROK. The objective of this study was to investigate the seroprevalence of BTV antibodies in the domestic goat population to glean further insights into BTV epidemiology in ROK. The results of this study indicate that in 2012-2013, on a countrywide level, the estimated seroprevalence rate of BTV antibodies was 15.7% (50/318) in domestic goat flocks and 11.7% (94/802) in individual animals. To our knowledge, this is the first serological evidence of antibodies against circulating BTV in the domestic goat population in the ROK.

Bluetongue Virus Antibodies in Domestic Goats: A Countrywide and Retrospective Study in the Republic of Korea.

Here, we report that Forkhead Box O1 (FOXO1) protein, a tumor suppressor, regulates expression of nicotinamide phosphoribosyltransferase (Nampt) in human breast cancer MCF-7 cells. Nampt plays an important role in the regulation of cell growth, survival, DNA replication and repair, and angiogenesis in tumorigenesis. We revealed that FOXO1 directly inhibits Nampt expression via binding to FOXO1 binding domains in the 5'-flanking region of the nampt gene. Nampt expression was increased by insulin and downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which was inhibited by FOXO1 overexpression. Accordingly, we showed that FOXO1 is also involved in insulin signaling-induced cell survival and proliferation in MCF-7 cells. These results suggest that FOXO1 plays an important role in human breast cancer cells by regulating nampt gene expression.

FOXO1 functions in the regulation of nicotinamide phosphoribosyltransferase (Nampt) expression.

Bluetongue, which is caused by bluetongue virus (BTV), is a vector-borne viral disease that affects wild and domestic ruminants. Trade restrictions can have a devastating impact in areas where BTV is endemic, regardless of the incidence of clinical disease. Currently, little is known about the prevalence of BTV infection in the Republic of Korea (ROK), and limited data on the BTV situation in the ROK are available. In this study, an epidemiological survey of BTV infection in farmed and free-ranging cervids from the ROK was conducted by a countrywide retrospective cross-sectional study. In total, BTV infection was widespread in the ROK, as 74 of 790 (9.4%, 95% confidence interval = 7.5-11.6%) cervid sera samples collected from 318 herds contained antibodies to BTV. Additionally, 42 herds evaluated in this study contained BTV seropositive cervids (13.2%). Serological evidence of bluetongue virus infection was observed in 17 of 158 free-ranging cervid animals, which accounts for the prevalence rate of approximately 10.8% (17/158; 95% CI = 6.8-16.6). Neutralizing antibodies to BTV-1, -2, -4, -7, and -15 serotypes were identified and RNAs of the BTV-1, -7, and -15 serotypes were detected, indicating that BTV was circulating in the cervids in ROK. These results suggest that cervids were actively exposed to BTV in the ROK and these species might serve as an important reservoir for the transmission of BTV. This is the first report on the evidence of circulating antibodies against BTV and serotype distribution in cervids in the ROK.

Evidence of bluetongue virus circulation in farmed and free-ranging cervids from the Republic of Korea: A retrospective cross-sectional study.

Dodamssal rice (Oryza sativa L.) includes high levels of resistant starch (RS), which is a source of dietary fiber. Recently, there has been an increase in the prevalence of obesity in canines; however, the information regarding diet treatments for such a condition is inadequate.

Trial data of the anti-obesity potential of a high resistant starch diet for canines using Dodamssal rice and the identification of discriminating markers in feces for metabolic profiling.

Elevated saturated free fatty acid levels during over-nutrition lead to hypothalamic inflammation, which perturbs energy homeostasis. Whether brain-derived metabolites are coupled to the development of obesity pathogenesis during the early over-nutrition period has not been thoroughly investigated. In this study, we found increased linoleic acid, an unsaturated fatty acid, in both the whole brain and hypothalamus of mice fed a high-fat diet for 4 weeks. Furthermore, we observed that linoleic acid effectively reversed the inflammatory responses induced by palmitic acid treatment in microglial cells. Collectively, this study suggests the reversible function of linoleic acid on brain inflammation in association with microglial activation during short-term exposure to a high-fat diet.

Linoleic acid rescues microglia inflammation triggered by saturated fatty acid.

Bluetongue is a vector-borne viral disease, and bluetongue virus (BTV) outbreaks can cause substantial economic losses. Even subclinical infection may carry significant associated costs, including a loss of condition, reduced milk yield, and infertility and abortion, and indirect costs, largely due to the export restrictions and surveillance requirements imposed to limit the spread of the virus. However, the BTV epidemiology in the Far East remains incompletely understood, especially in the cattle population in South Korea. In this study, the seroprevalence of BTV antibodies and distribution of BTV serotypes in dairy cattle in South Korea were evaluated to improve the understanding of the BTV epidemiological situation in the Asia-Pacific region.

Article	Year
AgRP Neurons Regulate Bone Mass. Cell reports\| PubMed ID: 26411686	2015
Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Scientific reports\| PubMed ID: 27405276	2016
A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines. Frontiers in cellular neuroscience\| PubMed ID: 27746721	2016
A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats. Molecules and cells\| PubMed ID: 28301916	2017
Stat5 phosphorylation is responsible for the excessive potency of HB-EGF. Journal of cellular biochemistry\| PubMed ID: 29274275	2018
Role of thyroid transcription factor-1 in transcriptional regulation of heme oxygenase-1. Biochemical and biophysical research communications\| PubMed ID: 29305861	2018
Visfatin Triggers Anorexia and Body Weight Loss through Regulating the Inflammatory Response in the Hypothalamic Microglia. Mediators of inflammation\| PubMed ID: 29362519	2017
Bluetongue Virus Antibodies in Domestic Goats: A Countrywide and Retrospective Study in the Republic of Korea. Vector borne and zoonotic diseases (Larchmont, N.Y.)\| PubMed ID: 29688829	2018
FOXO1 functions in the regulation of nicotinamide phosphoribosyltransferase (Nampt) expression. Biochemical and biophysical research communications\| PubMed ID: 30799084	2019
Evidence of bluetongue virus circulation in farmed and free-ranging cervids from the Republic of Korea: A retrospective cross-sectional study. Veterinary microbiology\| PubMed ID: 30827381	2019
Trial data of the anti-obesity potential of a high resistant starch diet for canines using Dodamssal rice and the identification of discriminating markers in feces for metabolic profiling. Metabolomics : Official journal of the Metabolomic Society\| PubMed ID: 30830428	2019
Linoleic acid rescues microglia inflammation triggered by saturated fatty acid. Biochemical and biophysical research communications\| PubMed ID: 30952426	2019
Serological evidence of bluetongue virus infection and serotype distribution in dairy cattle in South Korea. BMC veterinary research\| PubMed ID: 31337392	2019

Jae Geun Kim

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