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1.  Yy1 Gene Dosage Effect and Bi-Allelic Expression of Peg3 
PLoS ONE  2015;10(3):e0119493.
In the current study, we tested the in vivo effects of Yy1 gene dosage on the Peg3 imprinted domain with various breeding schemes utilizing two sets of mutant alleles. The results indicated that a half dosage of Yy1 coincides with the up-regulation of Peg3 and Zim1, suggesting a repressor role of Yy1 in this imprinted domain. This repressor role of Yy1 is consistent with the observations derived from previous in vitro studies. The current study also provided an unexpected observation that the maternal allele of Peg3 is also normally expressed, and thus the expression of Peg3 is bi-allelic in the specific areas of the brain, including the choroid plexus, the PVN (Paraventricular Nucleus) and the SON (Supraoptic Nucleus) of the hypothalamus. The exact roles of the maternal allele of Peg3 in these cell types are currently unknown, but this new finding confirms the previous prediction that the maternal allele may be functional in specific cell types based on the lethality associated with the homozygotes for several mutant alleles of the Peg3 locus. Overall, these results confirm the repressor role of Yy1 in the Peg3 domain and also provide a new insight regarding the bi-allelic expression of Peg3 in mouse brain.
PMCID: PMC4361396  PMID: 25774914
2.  Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension 
Despite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. The role of the brain in the initiation and progression of all forms of hypertension is well established, but the role of brain TLR4 in progression of hypertension has never been explored. Therefore, we investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals.
Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were administered either a specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide in their PVN for 14 days. MAP was recorded continuously by radiotelemetry. PVN and blood were collected for the measurement of pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β), anti-inflammatory cytokine IL-10, inducible nitric oxide synthase (iNOS), TLR4, nuclear factor (NF) κB activity and plasma norepinephrine (NE) and high mobility group box (HMGB)1 expression, respectively.
Hypertensive rats exhibited significantly higher levels of TLR4 in the PVN. TLR4 inhibition within the PVN attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, iNOS levels, and NFκB activity in SHR but not in WKY rats. These results were associated with a reduction in plasma NE and HMGB1 levels and an increase in IL-10 levels in SHR.
This study demonstrates that TLR4 upregulation in PVN plays an important role in hypertensive response. Our results provide mechanistic evidence that hypertensive response in SHR are mediated, at least in part, by TLR4 in the PVN and that inhibition of TLR4 within the PVN attenuates blood pressure and improves inflammation, possibly via reduction in sympathetic activity.
PMCID: PMC4337244  PMID: 25879545
Paraventricular nucleus; Hypertension; TLR4; Cytokines; IL-10; NFκB
3.  Correction: Peg3 Mutational Effects on Reproduction and Placenta-Specific Gene Families 
PLoS ONE  2014;9(1):10.1371/annotation/8de03ec5-e62c-4135-87ee-4928475090a8.
PMCID: PMC3894177
4.  Peg3 Mutational Effects on Reproduction and Placenta-Specific Gene Families 
PLoS ONE  2013;8(12):e83359.
Peg3 (paternally expressed gene 3) is an imprinted gene encoding a DNA-binding protein. This gene plays important roles in controlling fetal growth rates and nurturing behaviors. In the current study, a new mutant mouse model has been generated to further characterize the functions of this DNA-binding protein. Besides known phenotypes, this new mutant model also revealed potential roles of Peg3 in mammalian reproduction. Female heterozygotes produce a much smaller number of mature oocytes than the wild-type littermates, resulting in reduced litter sizes. According to genome-wide expression analyses, several placenta-specific gene families are de-repressed in the brain of Peg3 heterozygous embryos, including prolactin, cathepsin and carcinoembryonic antigen cell adhesion molecule (Ceacam) families. The observed de-repression is more pronounced in females than in males. The de-repression of several members of these gene families is observed even in the adult brain, suggesting potential defects in epigenetic setting of the placenta-specific gene families in the Peg3 mutants. Overall, these results indicate that Peg3 likely controls the transcription of several placenta-specific gene families, and further suggest that this predicted transcriptional control by Peg3 might be mediated through unknown epigenetic mechanisms.
PMCID: PMC3877027  PMID: 24391757
5.  GABA Is Excitatory in Adult Vasopressinergic Neuroendocrine Cells 
Neuronal excitability in the adult brain is controlled by a balance between synaptic excitation and inhibition mediated by glutamate and GABA, respectively. While generally inhibitory in the adult brain, GABAA receptor activation is excitatory under certain conditions in which the GABA reversal potential is shifted positive due to intracellular Cl− accumulation, such as during early postnatal development and brain injury. However, the conditions under which GABA is excitatory are generally either transitory or pathological. Here, we reveal GABAergic synaptic inputs to be uniformly excitatory in vasopressin (VP)-secreting magnocellular neurons in the adult hypothalamus under normal conditions. The GABA reversal potential (EGABA) was positive to resting potential and spike threshold in VP neurons, but not in oxytocin (OT)-secreting neurons. The VP neurons lacked expression of the K+-Cl− co-transporter 2 (KCC2), the predominant Cl− exporter in the adult brain. The EGABA was unaffected by inhibition of KCC2 in VP neurons, but was shifted positive in OT neurons, which express KCC2. Alternatively, inhibition of the Na+-K+-Cl− co-transporter 1 (NKCC1), a Cl− importer expressed in most cell types mainly during postnatal development, caused a negative shift in EGABA in VP neurons, but had no effect on GABA currents in OT neurons. GABAA receptor blockade caused a decrease in the firing rate of VP neurons, but an increase in firing in OT neurons. Our findings demonstrate that GABA is excitatory in adult VP neurons, suggesting that the classical excitation/inhibition paradigm of synaptic glutamate and GABA control of neuronal excitability does not apply to VP neurons.
PMCID: PMC3561926  PMID: 22238092
6.  Synaptically Activated Burst-Generating Conductances Underlie a Group-Pacemaker Mechanism for Respiratory Rhythm Generation in Mammals 
Progress in Brain Research  2010;187:111-136.
Breathing, chewing and walking are critical life-sustaining behaviors in mammals that consist essentially of simple rhythmic movements. Breathing movements in particular involve the diaphragm, thorax, and airways but emanate from a network in the lower brain stem. This network can be studied in reduced preparations in vitro and using simplified mathematical models that make testable predictions. An iterative approach that employs both in vitro and in silico models has ruled out canonical mechanisms for respiratory rhythm that involve reciprocal inhibition and pacemaker properties. We present an alternative model in which emergent network properties play the key rhythmogenic role. Specifically, we show evidence that synaptically activated burst-generating conductances – which are only available in the context of network activity – engender robust periodic bursts in respiratory neurons. Because the cellular burst-generating mechanism is linked to network synaptic drive we dub this type of system a group pacemaker.
PMCID: PMC3370336  PMID: 21111204
preBötzinger Complex; pre-Bötzinger Complex; central pattern generator (CPG); metabotropic glutamate receptors; calcium-activated nonspecific cation current; mathematical models; emergent network properties; breathing
7.  Performance, properties, and plasticity of identified oxytocin and vasopressin neurones in vitro 
Journal of neuroendocrinology  2010;22(5):330-342.
The neurohypophysial hormones oxytocin (OT) and vasopressin (VP) originate from hypothalamic neurosecretory cells in the paraventricular and supraoptic (SON) nuclei. The firing rate and pattern of action potentials arising from these neurones determine the timing and quantity of peripheral hormone release. We have used immunochemical identification of biocytin-filled SON neurones in hypothalamic slices in vitro to uncover differences between OT and VP neurones in membrane and synaptic properties, firing patterns, and plasticity during pregnancy and lactation. In this review we summarise some recent findings from this approach: 1) VP neuronal excitability is influenced by slow (sDAP) and fast (fDAP) depolarising afterpotentials that underlie phasic bursting activity. The fDAP may relate to a transient receptor potential (TRP) channel, type melastatin (TRPM4 and/or TRPM5), both of which are immunochemically localised more to VP neurones, and especially, to their dendrites. Both TRPM4 and TRPM5 mRNAs are found in the SON, but single cell RT-PCR suggestsTRPM4 might be the more prominent channel. Phasic bursting in VP neurones is little influenced by spontaneous synaptic activity in slices, being shaped largely by intrinsic currents. 2) The firing pattern of OT neurones ranges from irregular to continuous, with the coefficient of variation determined by randomly distributed, spontaneous GABAergic, inhibitory synaptic currents (sIPSCs). These sIPSCs are 4–5 fold more frequent in OT vs. VP neurones, and much more frequent than spontaneous excitatory synaptic currents. 3) Both cell types express Ca++-dependent afterhyperpolarisations (AHPs), including an apamin-sensitive, medium duration AHP and a slower, apamin-insensitive AHP (sAHP). In OT neurones, both AHPs are enhanced during pregnancy and lactation. During pregnancy, the plasticity of the sAHP is blocked by antagonism of central OT receptors. AHP enhancement is mimicked by exposing slices from Day 19 pregnant rats to OT and oestradiol, suggesting central OT and sex steroids program this plasticity during pregnancy by direct hypothalamic actions. In conclusion, the differences in VP and OT neuronal function are underlain by differences in both membrane and synaptic properties, and differentially modulated by reproductive state.
PMCID: PMC2910405  PMID: 20210845
afterhyperpolarisation; depolarising afterpotential; electrophysiology; pregnancy; lactation

Results 1-7 (7)