Calcium-dependent fast depolarizing afterpotentials in vasopressin neurons in the rat supraoptic nucleus

Oxytocin (OT) and vasopressin (VP) synthesizing magnocellular cells (MNCs) in the supraoptic nucleus (SON) display distinct firing patterns during the physiological demands for these hormones. Depolarizing afterpotentials (DAPs) in these neurons are involved in controlling phasic bursting in VP neurons. Our whole cell recordings demonstrated a Cs+-resistant fast DAP (fDAP; decay tau = ∼200 ms), which has not been previously reported, in addition to the well-known Cs+-sensitive slower DAP (sDAP; decay tau = ∼2 s). Immunoidentification of recorded neurons revealed that all VP neurons, but only 20% of OT neurons, expressed the fDAP. The activation of the fDAP required influx of Ca2+ through voltage-gated Ca2+ channels as it was strongly suppressed in Ca2+-free extracellular solution or by bath application of Cd2+. Additionally, the current underlying the fDAP (IfDAP) is a Ca2+-activated current rather than a Ca2+ current per se as it was abolished by strongly buffering intracellular Ca2+ with BAPTA. The I-V relationship of the I fDAP was linear at potentials less than -60 mV but showed pronounced outward rectification near -50 mV. IfDAP is sensitive to changes in extracellular Na+ and K+ but not Cl-. A blocker of Ca2+-activated nonselective cation (CAN) currents, flufenamic acid, blocked the fDAP, suggesting the involvement of a CAN current in the generation of fDAP in VP neurons. We speculate that the two DAPs have different roles in generating after burst discharges and could play important roles in determining the distinct firing properties of VP neurons in the SON neurons. Copyright © 2007 The American Physiological Society

The importance of financial market development on the relationship between loan guarantees for SMEs and local market employment rates

We empirically examine whether a major government intervention in the small-firm credit market yields significantly better results in markets that are less financially developed. The government intervention that we investigate is SBA-guaranteed lending. The literature on financing small and medium size enterprises (SMEs) suggests that small firms may be exposed to a particular type of market failure associated with credit rationing. And SMEs in markets that are less financially developed will likely face a greater degree of this market failure. To test our hypothesis, we use the level of bank deposits per capita as our relative measure of financial market development, and we use local market employment rates as our measure of economic performance. After controlling for the appropriate cross-sectional market characteristics, we find that SBA-guaranteed lending has a significantly more (less) positive impact on the average annual level of employment when the local market is relatively less (more) financially developed. This result has important implications for public policy directives concerning where SBA-guaranteed lending should be directed.Small Business Administration ; Financial markets ; Small business - Finance ; Employment

High-threshold, Kv3-like potassium currents in magnocellular neurosecretory neurons and their role in spike repolarization

We identified Kv3-like high-threshold K+ currents in hypothalamic supraoptic neurons using whole cell recordings in hypothalamic slices and in acutely dissociated neurons. Tetraethylammonium (TEA)-sensitive currents (TEA) evoked from -50 I/V were characterized by a large component that inactivated in 10-30 ms, and a smaller, persistent component that inactivated in 1-2 s. UV relations in dissociated neurons revealed TEA-subtracted currents with a slope and voltage dependency consistent with the presence of Kv3-like channels. In slices, tests with 0.01-0.7 mM TEA produced an IC50 of 200-300 nM for both fast and persistent currents. The fast transient current was similar to currents associated with the expression of Kv3.4 subunits, given that it was sensitive to BDS-I (100 nM). The persistent TEA-sensitive current appeared similar to those attributed to Kv3.1/3.2 subunits. Although qualitatively similar, oxytocin (OT) and vasopressin (VP) neurons in slices differed in the stronger presence of persistent current in VP neurons. In both cell types, the IC50 for TEA-induced spike broadening was similar to that observed for current suppression in voltage clamp. However, TEA had a greater effect on the spike width of VP neurons than of OT neurons. Immunochemical studies revealed a stronger expression of the Kv3.1b α-subunit in VP neurons, which may be related to the greater importance of this current type in VP spike repolarization. Because OT and VP neurons are not considered fast firing, but do exhibit frequency- and calcium-dependent spike broadening, Kv3-like currents may be important for maintaining spike width and calcium influx within acceptable limits during repetitive firing. Copyright © 2004 The American Physiological Society

Variation in sodium current amplitude between vasopressin and oxytocin hypothalamic supraoptic neurons

Biophysical characteristics of tetrodotoxin-sensitive sodium (Na+) currents were studied in vasopressin (VP) and oxytocin (OT) supraoptic neurons acutely isolated from rat hypothalamus. Na+ current density (pA/pF) was significantly greater in VP neurons than in OT neurons. No significant difference between VP and OT neurons was detected regarding the voltage dependence of activation and steady-state inactivation, or rate of recovery from inactivation of Na+ currents. In both VP and OT neurons, the macroscopic inactivation of the Na+ currents was best fitted with a double-exponential expression suggesting two rates of inactivation. Also in both types, the time course of recovery from inactivation proceeded with fast and slow time constants averaging around 8 and 350 ms, respectively, suggesting the presence of multiple pathways of recovery from inactivation. The slower time constant of recovery of inactivation may be involved in the decrease in action potential (AP) amplitude that occurs after the first spike during burst firing in both neuronal types. The larger amplitude of Na+ currents in VP vs. OT neurons may explain the previous observations that VP neurons exhibit a lower AP threshold and greater AP amplitude than OT neurons, and may serve to differently tune the firing properties and responses to neuromodulators of the respective neuronal types. © 2013 the American Physiological Society

Dietary protein intake and renal function

Recent trends in weight loss diets have led to a substantial increase in protein intake by individuals. As a result, the safety of habitually consuming dietary protein in excess of recommended intakes has been questioned. In particular, there is concern that high protein intake may promote renal damage by chronically increasing glomerular pressure and hyperfiltration. There is, however, a serious question as to whether there is significant evidence to support this relationship in healthy individuals. In fact, some studies suggest that hyperfiltration, the purported mechanism for renal damage, is a normal adaptative mechanism that occurs in response to several physiological conditions. This paper reviews the available evidence that increased dietary protein intake is a health concern in terms of the potential to initiate or promote renal disease. While protein restriction may be appropriate for treatment of existing kidney disease, we find no significant evidence for a detrimental effect of high protein intakes on kidney function in healthy persons after centuries of a high protein Western diet

Performance, properties and plasticity of identified oxytocin and vasopressin neurones in vitro

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: (i) 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 reverse transcriptase-polymerisation suggests that TRPM4 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. (ii) 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 four- to five-fold more frequent in OT versus VP neurones, and much more frequent than spontaneous excitatory synaptic currents. (iii) Both cell types express Ca 2+-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 that central OT and sex steroids programme 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. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd

Sex-Specific Modulation of Gene Expression Networks in Murine Hypothalamus

The hypothalamus contains nuclei and cell populations that are critical in reproduction and that differ significantly between the sexes in structure and function. To examine the molecular and genetic basis for these differences, we quantified gene expression in the hypothalamus of 39 pairs of adult male and female mice belonging to the BXD strains. This experimental design enabled us to define hypothalamic gene coexpression networks and provided robust estimates of absolute expression differences. As expected, sex has the strongest effect on the expression of genes on the X and Y chromosomes (e.g., Uty, Xist, Kdm6a). Transcripts associated with the endocrine system and neuropeptide signaling also differ significantly. Sex-differentiated transcripts often have well delimited expression within specific hypothalamic nuclei that have roles in reproduction. For instance, the estrogen receptor (Esr1) and neurokinin B (Tac2) genes have intense expression in the medial preoptic and arcuate nuclei and comparatively high expression in females. Despite the strong effect of sex on single transcripts, the global pattern of covariance among transcripts is well preserved, and consequently, males and females have well matched coexpression modules. However, there are sex-specific hub genes in functionally equivalent modules. For example, only in males is the Y-linked gene, Uty, a highly connected transcript in a network that regulates chromatin modification and gene transcription. In females, the X chromosome paralog, Kdm6a, takes the place of Uty in the same network. We also find significant effect of sex on genetic regulation and the same network in males and females can be associated with markedly different regulatory loci. With the exception of a few sex-specific modules, our analysis reveals a system in which sets of functionally related transcripts are organized into stable sex-independent networks that are controlled at a higher level by sex-specific modulators

On Nearly Strategic Measures

1 online resource (PDF, 17 pages

Locally Coherent Rates of Exchange

1 online resource (PDF, 33 pages

On Nearly Strategic Measures

1 online resource (PDF, 17 pages