Browsing by Subject "LTP"
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Item Regular treadmill exercise prevents sleep deprivation-induced impairment of hippocampal-dependent memory and synaptic plasticity(2012-04-19) Zagaar, Munder; Alkadhi, Karim; Eriksen, Jason; Salim, Samina; Grill, Raymond; Alcantara, AdrianaABSTRACT Study Objectives: Evidence suggests that regular exercise can protect against learning and memory impairment in the presence of insults such as stroke and neurodegeneration. The purpose of this study was to determine the effect of regular exercise on hippocampus-dependent learning and memory impairment associated with sleep deprivation. Experimental Design: We investigated the effects of 4 weeks of regular treadmill exercise on learning and memory impairment in 24 hour sleep-deprived rats. Sleep deprivation was accomplished using the columns-in-water model. We tested the effects of exercise and/or sleep deprivation using three approaches: the radial arm water maze (RAWM) task to test spatial learning and memory performance; electrophysiological recording in the Cornu Ammonis (CA1) and dentate gyrus (DG) areas of the hippocampus to measure synaptic plasticity; and western blot analysis to quantify the levels of key signaling molecules that are related to memory and synaptic plasticity. Results: In the RAWM, regular exercise prevented the sleep deprivation-induced impairment of spatial learning, short-term memory, and early-phase long-term potentiation (E-LTP) in both CA1 and DG areas. In correlation, exercise prevented the sleep deprivation-associated decrease in basal levels of phosphorylated and total calcium/calmodulin-dependent protein kinase II (P/total-CaMKII) and brain-derived neurotrophic factor (BDNF). High frequency stimulation (HFS), which increased the P-CaMKII and BDNF levels in normal animals, did not change these levels in sleep-deprived rats but did increase levels of the phosphatase calcineurin. In contrast, exercise increased BDNF and P-CaMKII levels in exercised/sleep-deprived rats, probably by preventing increases in calcineurin levels, thus maintaining appropriate P-CaMKII levels. Regular exercise also prevented the sleep deprivation-induced impairment of long-term memory and late-phase LTP. In correlation, exercise increased the basal levels of phosphorylated cAMP response element binding protein (P-CREB) and total-CREB as well as P/total- mitogen activated protein kinase (MAPK/ERK) in CA1 and DG areas of sleep-deprived rats. Also, exercise allowed multiple HFS to increase the levels of BDNF and P/total-CREB during L-LTP expression in sleep-deprived rats. Conclusions: These findings suggest that sleep deprivation impairs both the CA1 and DG areas whereas exercise prevents this impairment. Regular exercise exerts a protective effect against sleep deprivation-induced impairment probably by inducing BDNF expression, which can positively modulate basal and/or stimulated levels of P-CaMKII, P-CREB, P-MAPK/ERK and calcineurin. As a result, exercise-induced BDNF could contribute to the restoration of hippocampus-dependent learning and memory as well as LTP in both CA1 and DG areas.Item The role of amygdala group I mGluRs in synaptic plasticity and conditioned place preference in rodents(2007-07-17) Kady B. Schmidt; Patricia Shinnick-Gallagher; Joseph C. Holt; Joel P. GallagherCurrently, there are no approved medications for treating cocaine addiction, and cocaine addicts are highly prone to relapse. Cocaine cravings or seeking is difficult to control because of contextual cues and adequate treatment is not available. Previous studies found that group I metabotropic glutamate receptor (mGluR) antagonists can block the induction of conditioned place preference (CPP), a measure of cocaine seeking behavior, but their functions after clinically relevant withdrawal periods are not known. Our study showed that group I mGluR antagonists failed to block the expression of cocaine-induced CPP. Furthermore, the amygdala is known to be involved in the learned associations between cocaine and the cocaine-taking environment; changes in these associations are reflected in an in vitro model of plasticity, long-term potentiation, in amygdala pathways. Chronic cocaine withdrawal did not affect mGluR5-mediated LTP in the basolateral to central amygdala pathway. However, mGluR1-mediated LTP was reduced after cocaine administration and withdrawal and was partially due to GABA inhibition via endocannabinoids.Item Ultrastructural changes in synaptic and mitochondrial structure throughout postnatal development and long-term potentiation in rat hippocampus(2015-08) Smith, Heather Lynne; Harris, Kristen M.; Aldrich, Richard; Raab-Graham, Kimberly; Schallert, Timothy; Zemelman, BorisMitochondria, by providing the vast majority of ATP produced in neurons, fuel many steps of the synaptic vesicle cycle, but little is known about their role in synaptic vesicle clustering and mobilization during synaptic development and plasticity. Long-term potentiation (LTP), a cellular model for learning and memory, has a protein synthesis dependent late phase (L-LTP) that has been shown to recruit both pre- and postsynaptic mechanisms. In spite of their seeming importance in synaptic function, mitochondria are only found in roughly half of all mature presynaptic boutons, which implies that only a subset of boutons are capable of supporting increases in vesicle release. Preliminary exploration of CA1 boutons from perfusion- xed P15 rats, however, demonstrated that while smaller than boutons that contain mitochondria, boutons that are within three microns of mitochondria contain significantly more vesicles than those that are farther away from them, which raises the possibility that diffusion of ATP from nearby mitochondria could be sufficient to fuel LTP. To determine whether this was the case, I prepared 3D reconstructions from serial electron micrographs (3DEM) in order to quantify mitochondrial distance and vesicle counts in CA1 boutons following long-term potentiation in both P15 and adult Long-Evans rats. At both ages, mobilization of reserve pool vesicles following LTP required the presence of mitochondria. Mitochondria themselves also undergo structural changes following LTP. In adults, mitochondria become longer and less frequent along axons, implying that they undergo fusion. Although P15 mitochondria undergo no change in frequency, mitochondrial cristae become wider as mitochondrial matrix becomes more compact at both ages, which are both changes that correlate well with increased rates of respiration. To even further explore ultrastructural components required to support LTP, I used 3DEM to track changes in synaptic and subcellular structure from P8 to P12, during which animals undergo radical changes in their ability to support LTP. I found that spinogenesis may begin at P10 but increases sharply at P12, which coincides perfectly with the onset age of LTP. In conjunction with this increase in dendritic spines, axons built new single synaptic boutons from clusters of dense core and amorphous vesicles previously known to transport proteins and membrane to developing synapses. To fuel the creation of new boutons, mitochondrial division increased at P12, as evidenced by decreased mitochondrial size and increased mitochondrial frequency.Item Vesicle-free transition zones, dense core vesicles, and vesicle pool redistribution contribute to synapse growth(2012-05) Bell, Maria Elizabeth; Harris, Kristen M.; Aldrich, Richard; Benson, Deanna; Jones, Theresa; Nishiyama, HiroshiLong-term potentiation (LTP) is a widely studied cellular mechanism of learning and memory. LTP occurs at excitatory synapses on dendritic spines. Two hours after LTP induction in mature rat hippocampal slices, a reduction in spine number that is perfectly balanced by enlargement of the remaining synapses was previously observed. The sequence of events by which mature synapses enlarge is not well understood, but potential pre- and postsynaptic ultrastructural correlates of synapse growth have been identified. Vesicle-free transition zones (VFTZs) are postsynaptic thickenings contiguous with the PSD that have no apposing presynaptic vesicles perpendicular to the presynaptic membrane. VFTZs could be regions where synapses have expanded postsynaptically, but to which presynaptic vesicles have not yet been recruited. Presynaptic 80-nm dense core vesicles (DCVs) transport active zone proteins to the synapse during synaptogenesis, and may perform the same function during synaptic plasticity. 3-D reconstructions from ssTEM were used to investigate changes in VFTZs, DCVs, and presynaptic vesicles following LTP induction. By 30 minutes, VFTZ area and docked vesicle counts decreased, suggesting mobilization of additional vesicles to the synapse and enhanced release or delayed recycling. By two hours, VFTZs enlarged, suggesting VFTZ assembly contributes to synapse enlargement. DCV counts at 2 hours decreased relative to that at 30 minutes in both control and LTP conditions, suggesting DCVs were inserted at existing synapses to enlarge potentiated synapses in the LTP condition and to support ongoing spinogenesis in the control condition. The overall vesicle count in presynaptic boutons decreased at 2 hours following LTP induction, but docked vesicle count did not. Docked vesicle count was elevated at 2 hours relative to 30 minutes, suggesting that the depletion of docked vesicles observed at 30 minutes was followed by a replenishment and enhancement by 2 hours supplied by the non-docked vesicle pool. That the largest spines had more and larger VFTZs and recruited more DCVs and docked vesicles, and that the ratio of the sum of VFTZ area to the sum of PSD area is constant, provide further evidence that dendritic segments serve as functional units that manage resources in a coordinated and homeostatic way.