The purpose of this study was to identify a potentiation effect on 30 meter (m) fly sprint performance in collegiate sprinters and jumpers (M=21, W=5) following an acute bout of whole-body vibration. The WBV protocol consisted of one 30 second bout at 50 Hz, ~3 mm amplitude, and 60 seconds rest before a 30m fly sprint. Sprint times were measured using timing gates, and characteristics of strength and power were measured using a force plate. Analysis included measures of jump height, peak power, peak force, and rate of force development. Each subject participated in 3 separate trials using randomized treatment sessions over 3 months of preparation training. The control condition consisted of no vibration and WBV treatment 1 and 2 incorporated vibration. Statistics comparing the average sprint times showed no treatment effects. The results of this study indicate that WBV at 50 Hz and ~3 mm amplitude has no effect on sprint times.

Endocannabinoids (eCBs) are small molecules that are capable of modulating synaptic plasticity of both excitatory and inhibitory synapses in the brain. While eCBs bind to transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1) in the central nervous system, we recently identified a form of non-CB1, non-TRPV1 mediated long term depression activated by the eCB anandamide at CA1 hippocampal stratum radiatum interneurons. GPR55, an orphan G-protein receptor, has been identified in the hippocampus and is capable of activation by eCBs, making it a good candidate for mediating this non-CB1, non-TRPV1 form of synaptic plasticity. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of GPR55 agonist O-1602 on excitatory synapses. We also performed field recordings from CA1 pyramidal cells in rats and GPR55 knockout mice and littermate controls to investigate the effect of GPR55 agonists O-1602 and lysophosphatidylinositol (LPI) on both basal output and electrically induced long-term depression and long-term potentiation in the hippocampus. Application of O-1602 in rats depressed long-term potentiation in CA1 pyramidal cells, and depressed excitatory glutamatergic transmission onto some interneurons. O-1602 had no effect on long-term depression of CA1 pyramidal cells. GPR55 +/+ mice showed an increase in long-term potentiation in the presence of LPI compared to GPR55-/- littermates. GPR55-/-mice had no change in long-term potentiation when exposed to O-1602, though there was an increase in post-tetanic potentiation with O-1602. In order to examine whether GPR55 has a role in formation of spatial memory, GPR55 -/- mice were compared to littermate controls during a Morris water maze behavioral task, with a reversal task after 7 days of training. GPR55-/-mice did not perform in a different manner on either the training task or the reversal, though there may be a trend of difference in training worth investigating further. This study illustrates a novel pathway for synaptic plasticity modulation through GPR55 in the hippocampus, and may therefore provide valuable insight into both the effects of synthetic and endogenous cannabinoids on the brain and the processes underlying learning and memory.

Contemporary cellular models of learning and memory are articulated around the idea that synapses undergo activity-dependent weight changes. However, conventional forms of Hebbian plasticity do not adequately address certain features inherent to behavioral learning. First, associative learning driven by delayed behavioral outcomes introduces a temporal credit assignment problem, whereby one must remember which action corresponds to which outcome. Yet, current models of associative synaptic plasticity, such as spike-timing-dependent plasticity, require near coincident activation of pre- and postsynaptic neurons (i.e., within ~ 10 ms), a time delay that is orders of magnitude smaller than that required for behavioral associations. For individual neurons to associate two cues, a biological mechanism capable of potentiating synaptic weights must be able to bind events that are separated in time. Theoretical work has suggested that a synaptic eligibility trace, a time-limited process that momentarily renders synapses eligible for weight updates via delayed instructive signals, can solve this problem. However, no material substrate of eligibility traces has been identified in the brain. Second, under certain conditions, neurons need to swiftly update their weights to reflect rapid learning. Current plasticity experiments require the repetition of multiple pairings to induce long-term synaptic plasticity. In this thesis, I addressed these problems using a combination of whole-cell recordings, two-photon uncaging, calcium imaging, and mechanistic modeling. I uncovered a form of synaptic plasticity known as behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons in the prefrontal cortex of mice. BTSP induced synaptic potentiation by pairing temporally separated pre- and postsynaptic events (0.5 s - 1 s), regardless of their order. The temporal window for BTSP induction offers a line of solution to the temporal credit assignment problem by highlighting the presence of a synaptic mechanism that expands the time for the induction of activity-dependent long-term synaptic plasticity, spanning hundreds of milliseconds. We further found that BTSP can be induced following a single pairing, enabling rapid weight updates required for one-shot learning. Using two-photon calcium imaging in apical oblique dendrites, I discovered a novel short-term and associative plasticity of calcium dynamics (STAPCD) that exhibited temporal characteristics mirroring the induction rules of BTSP. I identified a core set of molecular components crucial for both STAPCD and BTSP and developed a computational simulation that models the calcium dynamics as a latent memory trace of neural activity (i.e., eligibility traces). Together, we find that calcium handling by the endoplasmic reticulum enables synaptic weight updates upon receipt of delayed instructive signals, obeys rules of burst-dependent one-shot learning, and thus provides a mechanism that satisfies the requirements anticipated of eligibility traces. Collectively, these findings offer a neural mechanism for the binding of cellular events occurring in single shot and separated by behaviorally relevant temporal delays to induce potentiation at synapses, providing a cellular model of associative learning.

No description available.

No description available.

Experimentelle Modelle und aktuelle Studien legen nahe, dass epileptische Anfälle mit Störungen des adrenergen Systems im Gehirns einhergehen. Noradrenalin, welches an beta-adrenerge Rezeptoren bindet, ist für hippokampale Plastizität sowie für das hippokampale Lernen und Gedächtnis von großer Bedeutung. Die vorliegende Arbeit untersucht epilepsieinduzierte Veränderungen der noradrenergen Steuerung von hippokampalen Ausgangssignalen. Gezielt werden die funktionellen Konsequenzen synaptischer Plastizität, hervorgerufen durch beta-adrenerge Rezeptoraktivierung an CA1-Subiculum Synapsen, für die neuronale Signaltransduktion zwischen Hippocampus und parahippokampal Regionen in einem Tiermodell für Epilepsie untersucht. Wir kombinieren elektrophysiologische Methoden (Single-Cell- und Multi-Elektroden-Array Ableitungen) um zu zeigen, dass die Aktivierung von beta-adrenergen Rezeptoren eine zellspezifische Form der Langzeit-Potenzierung in subiculären Pyramidenzellen induziert und eine Verstärkung der Konnektivität zwischen Subiculum und Presubiculum, beziehungsweise Subiculum und entorhinalen Cortex nach sich zieht. Bei Tieren, die mit dem Parasympathomimetikum Pilocarpin behandelten wurden, ist die beta-adrenerge Modulation zwischen dem Hippocampus und verschiedenen parahippokampal Zielstrukturen beeinträchtigt. Die gestörte polysynaptische Transmission zwischen CA1, dem Subiculum und parahippokampalen Zielstrukturen resultiert in einer Abnahme der Langzeit-Potenzierung im Presubiculum, wohingegen die Transmission zum medialen EC intakt bleibt. Diese Beeinträchtigung der beta-Adrenorezeptor abhängigen Modulation der Informationsübertragung vom Hippocampus zu seine Zielstrukturen können zu hippocampalen Defiziten, wie Gedächtnis- und Stimmungsstörungen beitragen, die häufig bei Patienten mit Temporallappen-Epilepsie beobachtet werden. / Experimental models and previous studies suggest that seizures are accompanied by disturbances in the beta-adrenergic (beta-AR) system of the brain. Norepinephrine acting via beta-ARs plays a major role in hippocampal plasticity and hippocampus-dependent learning and memory. To elucidate seizure-associated alterations in the norepinephrine-dependent encoding of hippocampal output, the present study investigates the functional consequences of the beta-AR mediated synaptic plasticity at CA1-subiculum synapses for the transduction of hippocampal output to the parahippocampal region in an animal model of epilepsy. Using combined electrophysiological (single-cell and multi-electrode array recordings) approaches, we show that activation of beta-AR induces a cell-specific form of long-term potentiation in subicular pyramidal cells that may allow a strengthening of target-specific connectivity to the presubiculum and entorhinal cortex (EC). In pilocarpine-treated animals, the beta-AR-mediated modulation of functional connectivity between the hippocampus and distinct parahippocampal target str uctures is disturbed. The attenuated long-term potentiation is associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. The impairment in the beta-AR-dependent modulation of information transfer from the hippocampus to its target structures may contribute to hippocampus-dependent deficits like memory impairments and mood disorders which are often observed in patients with temporal lobe epilepsy.

Pang Petti. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Repetitive stimulation of motor nerves causes an increase in the number of packets of transmitter ("quanta") that can be released in the ensuing period. This represents a type of conditioning, in which synaptic transmission may be enhanced by prior activity. Despite many studies of this phenomenon, there have been no investigations of the quantal mechanisms underlying these events, due to the rapid changes in transmitter output and the short time periods involved. To examine this problem, a method was developed in which estimates of the quantal release parameters could be obtained over very brief periods (3 s). Conventional microelectrode techniques were used to record miniature endplate potentials (MEPPs) from isolated frog (Rana pipiens) cutaneous pectoris muscles, before and after repetitive (40 sec at 80 Hz) nerve stimulation. Estimates were obtained of m (number of quanta released), n (number of functional release sites), p (mean probability of release) and var$\rm\sb{s}$p (spatial variance in p) using a method that employs counts of MEPPs per unit time. Fluctuations in the estimates were reduced using a moving bin technique (bin size = 3 s, $\Delta$bin = 1 s). Muscle contraction was prevented using low Ca$\sp{2+},$ high Mg$\sp{2+}$ Ringer or normal Ringer to which $\mu$-conotoxin GIIIA was added. These studies showed that: (1) the post-stimulation increase in transmitter release was dependent on stimulation frequency and not on the total number of stimulus impulses. When the total number of pulses was kept constant, the high frequency pattern produced a higher level of transmitter release than did the lower frequency patterns; (2) augmentation and potentiation were present in both low Ca$\sp{2+},$ high Mg$\sp{2+}$ and normal Ringer solutions, but potentiation, m, n, p and var$\rm\sb{s}$p were greater in normal Ringer solution than in low Ca$\sp{2+},$ high Mg$\sp{2+}$ solution. In low Ca$\sp{2+},$ high Mg$\sp{2+}$ solution, there was a larger decrease in n compared to p; (3) hypertonicity (addition of 100 mM sucrose) produced a marked increase in both basal and stimulation-induced values of m, n, and p. By contrast, there was a marked increase in the stimulation-induced but not the basal values of var$\rm\sb{s}$p; (4) hypertonicity produced a decrease in augmentation but had no effect on potentiation; (5) augmentation and potentiation appeared to involve mitochondrial uptake and efflux of cytoplasmic Ca$\sp{2+}.$ Tetraphenylphosphonium (which blocks mitochondrial Ca$\sp{2+}$ efflux and uptake) decreased augmentation and potentiation in low Ca$\sp{2+},$ high Mg$\sp{2+}$ solutions but increased potentiation in the same solution made hypertonic with 100 mM sucrose; (6) the overall findings suggest that this new method may be useful for investigating the subcellular dynamics of transmitter release following nerve stimulation.

The current investigation was an examination of the repetition-to-repetition magnitudes and changes in kinetic and kinematic characteristics of the back squat using accentuated eccentric loading (AEL) and cluster sets. Trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, back squat to body mass ratio = 1.8 ± 0.3) completed four load condition sessions, each consisting of three sets of five repetitions of either traditionally loaded straight sets (TL), traditionally loaded cluster sets (TLC), AEL cluster sets (AEC), and AEL straight sets where only the initial repetition had eccentric overload (AEL1). Eccentric overload was applied using weight releasers, creating a total eccentric load equivalent to 105% of concentric one repetition maximum (1RM). Concentric load was 80% 1RM for all load conditions. Using straight sets (TL and AEL1) tended to decrease peak power (PP) (d = −1.90 to −0.76), concentric rate of force development (RFDCON) (d = −1.59 to −0.27), and average velocity (MV) (d = −3.91 to −1.29), with moderate decreases in MV using cluster sets (d= −0.81 to −0.62). Greater magnitude eccentric rate of force development (RFDECC) was observed using AEC at repetition three (R3) and five (R5) compared to all load conditions (d = 0.21–0.65). Large within-condition changes in RFDECC from repetition one to repetition three (∆REP1–3) were present using AEL1 (d = 1.51), demonstrating that RFDECC remained elevated for at least three repetitions despite overload only present on the initial repetition. Overall, cluster sets appear to permit higher magnitude and improved maintenance of concentric outputs throughout a set. Eccentric overload with the loading protocol used in the current study does not appear to potentiate concentric output regardless of set configuration but may cause greater RFDECCcompared to traditional loading

Recently reported data demonstrate that Vav3, a Rho Guanine Nucleotide Exchange Factor (Rho GEF) is overexpressed in breast tumors, coexpressed with ER, necessary for proliferation in breast cancer cells, and predictive of response to neoadjuvant endocrine therapies in patients with ER+ tumors. Such data beg the question as to what roles Vav3 plays in modulation of steroid receptor activity in breast cancer and in resistance to current hormonal therapies. Using reporter assays, I provide novel evidence that Vav3 potentiates Estrogen Receptor activity and represses Androgen Receptor activity in breast cancer cells. Vav3 potentiates ligand-dependent estrogen receptor activity in the MCF-7. A truncated, constitutively active form of Vav3, caVav3 potentiates ligand dependent ER activity in both MCF-7 and T47D. Vav3 activates Rho GTPases through its GEF domain. ER potentiation by caVav3 is dependent upon GEF activity. A caVav3 mutant with defective GEF function represses basal and ligand-mediated ER activity in T47D. Although other studies have shown that Vav3 could activate various Rho GTPases, only constitutively active Rac1 mutants potentiated ER activity in both cell lines. Contrastingly, reporter assays were used to show that caVav3 inhibits ligand-mediated AR activity in the AR+ T47D cell line by both R1881 and DHT stimulation. caVav3-mediated repression of AR activity is GEF-dependent, as caVav3 GEF mutants potentiate AR activity. Constitutively active forms of Rho GTPases were found to repress AR activity to different extents, but R1881-mediated AR activity was only significantly repressed by caCdc42. My studies of the effect of androgens on AR protein by western blot show that androgens downregulate AR protein in the highly Vav3 positive T47D cell line. Previous studies have demonstrated that androgens stabilize AR protein in MCF-7, and I now provide evidence that overexpression of Vav3 or caVav3 reverses hormone-mediated AR protein stabilization in MCF-7. These data are especially relevant given recently published data that decreased AR protein levels contributed to failure of response to MPA in patients with metastatic breast cancer. Further breast cancer studies may prove Vav3 to be a potential drug target in hormone dependent, hormone independent, and metastatic disease.