This thesis examines the rapid, non-genomic effects of estrogens on neural plasticity and learning. Estrogens are classically known to affect gene transcription events, however they have more recently been found to also rapidly activate second messenger systems within 1hr of administration. Therefore, we first examined the rapid effects of 17β-estradiol, and an estrogen receptor (ER) α and ERβ agonist on three different learning paradigms: object placement, object recognition, and social recognition. We found that both systemic injections and intrahippocampal delivery of 17β-estradiol and the ERα agonist improved performance on all 3 learning paradigms within 40min of hormone administration. However, the ERβ agonist administered systemically or intrahippocampally, improved performance only on the object placement learning paradigm, while having no effect on object recognition, and impairing social recognition at high doses. To elucidate how estrogens might rapidly affect learning, we examined how estrogens rapidly affect the neural plasticity of CA1 hippocampal neurons. We found that 17β-estradiol and the ERα agonist increased dendritic spine density in CA1 hippocampal neurons within 40min of administration, suggesting that estrogens rapidly increase the density of synapses within this brain region. Conversely, the ERβ agonist did not affect spine density, or decreased spine density. In addition, by using whole-cell patch clamp recordings of CA1 pyramidal neurons, we were able to determine that 17β-estradiol and the ERα agonist rapidly reduced AMPA receptor (but not NMDA receptor) mediated membrane depolarizations after 15min of hormone application. Similar to above, the ERβ agonist had no effect on AMPA or NMDA receptor mediated membrane depolarizations. These data suggest that estrogens rapidly promote the development of immature synapses (which contain low levels of synaptic AMPA receptors) within the CA1 hippocampus. Immature spines provide synaptic sites at which new memories can be stored and are thought of as “learning spines” (Kasai et al, 2003). Therefore, estrogens (through ERα) may rapidly induce the formation of hippocampal immature spines to promote learning. / Funded by NSERC

No description available.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

Le récepteur du glutamate de type N-méthyl-D-aspartate (NMDAR) est un transducteur clef dans la physiologie du système nerveux et dans nombre de ses pathologies, selon qu’il est localisé à la synapse ou en position extra-synaptique respectivement. Son activité est sous le contrôle étroit du ‘site-glycine’, dont l’activation est gouvernée par la disponibilité en coagoniste. Pourtant, on ignore encore largement les règles qui régissent cette étape limitante de l’activation des NMDARs in situ. Par ailleurs, l’ensemble des onnaissances actuelles suggère que les astrocytes pourraient contrôler les NMDARs dans le contexte des interactions entre cellules gliales et neurones, en particulier via la libération du gliotransmetteur D-sérine. Le principal objectif de ce travail de thèse a été de comprendre les modalités du contrôle endogène des NMDARs par leur site co-agoniste, dans la région CA1 de l’hippocampe. Nous avons porté notre attention, avant tout, sur les acteurs de ce contrôle : la glycine et la D-sérine, qui sont les ligands endogènes du site-co-agoniste. Nous nous sommes intéressés à leur contribution respective dans le contrôle des NMDARs, aux dynamiques de ce contrôle en fonction de l’activité neuronale, à ses variations en fonction de la localisation des NMDARs, ainsi qu’à ses modifications développementales. Nous montrons par des approches d’électrophysiologie que la D-sérine, et non la glycine, est le co-agoniste endogène des NMDARs à la synapse CA3-CA1 chez l’adulte. Elle est délivrée par les prolongements astrocytaires environnants, d’une manière qui est influencée par l’activité synaptique. Sa libération répond à un mécanisme vésiculaire et est dépendante de la signalisation calcique intra-astrocytaire. De cette manière, les astrocytes exercent un contrôle étroit et dynamique des NMDARs à l’état basal et au cours de phénomènes de plasticité synaptique. En contre partie, à l’inverse de leurs homologues localisés à la synapse, les NMDARs extrasynaptiques sont contrôlés par la glycine à l’âge adulte. Cette compartimentation spatiale est dictée par une disponibilité différentielle des deux co-agonistes aux différents sites. Elle est également favorisée par une composition en sous-unités des NMDARs synaptiques et extra-synaptiques différente qui leur confère une affinité distincte pour la glycine et la D-sérine. Enfin, le contrôle des NMDARs par la D-sérine astrocytaire observé à l’âge adulte n’est pas opérationnel à la naissance. En effet, il ne se met en place qu’au cours du premier mois post-natal, de façon concomitante au changement de composition en sous-unités des NMDARs. / N-methyl D-aspartate receptors (NMDARs) are central to many aspects of brain physiology and pathology, which they impact differently depending on their synaptic or extrasynaptic location, respectively. In addition to glutamate, they are gated by the necessary binding of a co-agonist on the so-called ‘glycine-binding site’. However, very little is known about the rules that govern the control of NMDARs through this site, in situ. Evidence now suggests that astrocytes could play a critical role in controlling NMDARs activity, in particular through the release of the gliotransmitter D-serine. In the present work, we aimed at understanding how NMDARs are endogenously controlled through their co-agonist binding site, in the CA1 region of rat hippocampus. We primarily focused on the role of two endogenous ligands of this site: glycine and D-serine. We investigated their relative contribution in the control of NMDARs at the different subcellular locations, the dynamics of such control according to synaptic activity, as well as possible changes during post-natal development. Using elecrophysiological approaches, we demonstrate that NMDARs are gated by Dserine, but not glycine, at CA3-CA1 synapses in adults. D-serine is supplied at least in part by surrounding astrocytes in an activity-dependant manner. Its release occurs in response to calcium signalling within the astrocyte and in a vesicular way. Correspondingly, we found astrocytic supply of D-serine to be essential for NMDARs-dependant functions such as synaptic plasticity. In contrast with their synaptic counterparts, extrasynaptic NMDARs are gated by endogenous glycine and not by D-serine. We provide evidence that this compartmentation relies on the differential availability of the two co-agonists at synaptic and extrasynaptic sites. Besides, due to differences in their subunit composition, synaptic and extrasynaptic NMDARs may have preferential affinity for D-serine and glycine respectively. Finally, we show that the control of the NMDAR co-agonist site is developmentally regulated. Early after birth, glycine is the endogenous co-agonist of synaptic NMDARs. The control exerted by D-serine only progressively appears during the first post-natal month, as the switch in NMDARs subunit composition occurs, suggesting a maturation of cellular interactions at the tripartite synapse.

Synaptic long-term modifications following neuronal activation are believed to be at the origin of learning and long-term memory. Recent experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states of a single synapse. The biochemical network involving calcium/calmodulin-dependent protein kinase II (CaMKII) and its regulating protein signaling cascade has been hypothesized to durably maintain the synaptic state in form of a bistable switch. Furthermore, it has been shown experimentally that CaMKII and associated proteins such as protein kinase A and calcineurin are necessary for the induction of long-lasting increases (long-term potentiation, LTP) and/or long-lasting decreases (long-term depression, LTD) of synaptic efficacy. However, the biochemical mechanisms by which experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such networks are still unknown. We present a detailed biochemical model of the calcium/calmodulin-dependent autophosphorylation of CaMKII and the protein signaling cascade governing the dephosphorylation of CaMKII. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentrations. Repetitive high calcium levels switch the system from a weakly- to a highly phosphorylated state (LTP). We show that the reverse transition (LTD) can be mediated by elevated phosphatase activity at intermediate calcium levels. It is shown that the CaMKII kinase-phosphatase system can qualitatively reproduce plasticity results in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. A reduced model based on the CaMKII system is used to elucidate which parameters control the synaptic plasticity outcomes in response to STDP protocols, and in particular how the plasticity results depend on the differential activation of phosphatase and kinase pathways and the level of noise in the calcium transients. Our results show that the protein network including CaMKII can account for (i) induction - through LTP/LTD-like transitions - and (ii) storage - due to its bistability - of synaptic changes. The model allows to link biochemical properties of the synapse with phenomenological 'learning rules' used by theoreticians in neural network studies.

Dans la région CA1 de l’hippocampe, une population d’interneurones exprimant la somatostatine (SOM-INs) est reconnue pour une potentialisation à long terme (PLT) dépendante des récepteurs métabotropes du glutamate de type 1a (mGluR1a) à leurs synapses excitatrices provenant des cellules pyramidales (CP). Il a récemment été démontré que cette PLT est induite par l’apprentissage contextuel lié à la peur, illustrant l’importance de cette PLT des SOM-INs dans l’apprentissage et la mémoire. Cependant, l’implication du neuropeptide somatostatine (SST) dans cette PLT demeure inconnue. Dans la présente étude, le rôle de la SST dans la PLT dépendante des mGluR1a a été étudié, tout comme, l’effet de la somatostatine-14 (SST-14) exogène aux synapses excitatrices des SOM-INs. Pour ce faire, des souris transgéniques exprimant la « enhanced yellow fluorescent protein » (eYFP) sous le contrôle du promoteur de la SST ont été utilisées. Des enregistrements électrophysiologiques jumelés à une approche pharmacologique ont été réalisés sur ces souris. Les résultats suggèrent que la SST-14 exogène engendre une PLT persistante grâce aux récepteurs à la somatostatine 1-5 (SST1-5), aux synapses excitatrices des SOM-INs, mais n’affecte pas les synapses des CP ou bien des interneurones exprimant la parvalbumine (PV-INs). Cette potentialisation induite par SST-14 était indépendante des récepteurs à l’acide N-méthyl-D-aspartique (NMDAR) et mGluR1a, dépendante de l’activité synaptique concomitante et inhibée par le blocage des récepteurs GABAA. De plus, la PLT dépendante des récepteurs mGluR1a a été affectée par l’inhibition des SST1-5 ou bien par un traitement avec de la cystéamine suggérant un rôle pour de la SST endogène dans cette PLT. Nos résultats suggèrent que la SST endogène pourrait contribuer à la PLT hébbienne aux synapses excitatrices des SOM-INs en contrôlant l’inhibition GABAA. La SST aurait alors un rôle dans la modulation de la plasticité à long terme des SOM-INs qui pourrait être important dans la mémoire dépendante de l’hippocampe. / The CA1 region of the hippocampus includes a population of GABAergic interneurons expressing somatostatin (SOM-INs). This type of interneurons displays a long-term potentiation (LTP) dependant on type 1a metabotropic glutamate receptors (mGluR1a) at their excitatory synapses from pyramidal cells (PC). It was recently demonstrated that mGluR1a dependent LTP can be induce by contextual fear learning showing an important role of this LTP in learning and memory. However, the implication of the peptide somatostatin (SST) in this LTP remains unknown. In the present study, the role of SST in mGluR1 dependent LTP and the effect of exogenous somatostatin-14 (SST-14) onto excitatory synapses of SOM-INs were investigated. To do this, transgenic mice expressing enhanced yellow fluorescent protein (eYFP) under the control of the promoter of SST were used. Patch clamp recordings and pharmacological approaches were used with these mice. Results suggested that application of exogenous SST-14 induces a LTP through type 1-5 somatostatin receptors (SST1-5) of excitatory synapses of SOM-INs but does not affect synapses of PC or parvalbumin-expressing interneurons (PV-INs). This LTP induced by SST-14 was independent of N-methyl-D-aspartate receptor (NMDAR) and mGluR1a, activity dependent, and prevented by blocking GABAA receptors. Furthermore, mGluR1a dependent LTP was prevented by inhibition of SST1-5 and by depletion of SST by cysteamine treatment, suggesting a role of endogenous SST in LTP. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses by controlling GABAA inhibition. SST would then have a role in regulating SOM-INs LTP that may be important for hippocampus dependent memory processes.