--- _id: '12809' abstract: - lang: eng text: "Understanding the mechanisms of learning and memory formation has always been one of\r\nthe main goals in neuroscience. Already Pavlov (1927) in his early days has used his classic\r\nconditioning experiments to study the neural mechanisms governing behavioral adaptation.\r\nWhat was not known back then was that the part of the brain that is largely responsible for\r\nthis type of associative learning is the cerebellum.\r\nSince then, plenty of theories on cerebellar learning have emerged. Despite their differences,\r\none thing they all have in common is that learning relies on synaptic and intrinsic plasticity.\r\nThe goal of my PhD project was to unravel the molecular mechanisms underlying synaptic\r\nplasticity in two synapses that have been shown to be implicated in motor learning, in an\r\neffort to understand how learning and memory formation are processed in the cerebellum.\r\nOne of the earliest and most well-known cerebellar theories postulates that motor learning\r\nlargely depends on long-term depression at the parallel fiber-Purkinje cell (PC-PC) synapse.\r\nHowever, the discovery of other types of plasticity in the cerebellar circuitry, like long-term\r\npotentiation (LTP) at the PC-PC synapse, potentiation of molecular layer interneurons (MLIs),\r\nand plasticity transfer from the cortex to the cerebellar/ vestibular nuclei has increased the\r\npopularity of the idea that multiple sites of plasticity might be involved in learning.\r\nStill a lot remains unknown about the molecular mechanisms responsible for these types of\r\nplasticity and whether they occur during physiological learning.\r\nIn the first part of this thesis we have analyzed the variation and nanodistribution of voltagegated calcium channels (VGCCs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid\r\ntype glutamate receptors (AMPARs) on the parallel fiber-Purkinje cell synapse after vestibuloocular reflex phase reversal adaptation, a behavior that has been suggested to rely on PF-PC\r\nLTP. We have found that on the last day of adaptation there is no learning trace in form of\r\nVGCCs nor AMPARs variation at the PF-PC synapse, but instead a decrease in the number of\r\nPF-PC synapses. These data seem to support the view that learning is only stored in the\r\ncerebellar cortex in an initial learning phase, being transferred later to the vestibular nuclei.\r\nNext, we have studied the role of MLIs in motor learning using a relatively simple and well characterized behavioral paradigm – horizontal optokinetic reflex (HOKR) adaptation. We\r\nhave found behavior-induced MLI potentiation in form of release probability increase that\r\ncould be explained by the increase of VGCCs at the presynaptic side. Our results strengthen\r\nthe idea of distributed cerebellar plasticity contributing to learning and provide a novel\r\nmechanism for release probability increase. " acknowledged_ssus: - _id: EM-Fac - _id: Bio - _id: PreCl alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Catarina full_name: Alcarva, Catarina id: 3A96634C-F248-11E8-B48F-1D18A9856A87 last_name: Alcarva citation: ama: 'Alcarva C. Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning. 2023. doi:10.15479/at:ista:12809' apa: 'Alcarva, C. (2023). Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12809' chicago: 'Alcarva, Catarina. “Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning.” Institute of Science and Technology Austria, 2023. https://doi.org/10.15479/at:ista:12809.' ieee: 'C. Alcarva, “Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning,” Institute of Science and Technology Austria, 2023.' ista: 'Alcarva C. 2023. Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning. Institute of Science and Technology Austria.' mla: 'Alcarva, Catarina. Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning. Institute of Science and Technology Austria, 2023, doi:10.15479/at:ista:12809.' short: 'C. Alcarva, Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning, Institute of Science and Technology Austria, 2023.' date_created: 2023-04-06T07:54:09Z date_published: 2023-04-06T00:00:00Z date_updated: 2023-04-26T12:16:56Z day: '06' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: RySh doi: 10.15479/at:ista:12809 file: - access_level: closed checksum: 35b5997d2b0acb461f9d33d073da0df5 content_type: application/pdf creator: cchlebak date_created: 2023-04-07T06:16:06Z date_updated: 2023-04-07T06:16:06Z embargo: 2024-04-07 embargo_to: open_access file_id: '12814' file_name: Thesis_CatarinaAlcarva_final pdfA.pdf file_size: 9881969 relation: main_file - access_level: closed checksum: 81198f63c294890f6d58e8b29782efdc content_type: application/pdf creator: cchlebak date_created: 2023-04-07T06:17:11Z date_updated: 2023-04-07T06:17:11Z file_id: '12815' file_name: Thesis_CatarinaAlcarva_final_for printing.pdf file_size: 44201583 relation: source_file - access_level: closed checksum: 0317bf7f457bb585f99d453ffa69eb53 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: cchlebak date_created: 2023-04-07T06:18:05Z date_updated: 2023-04-07T06:18:05Z file_id: '12816' file_name: Thesis_CatarinaAlcarva_final.docx file_size: 84731244 relation: source_file file_date_updated: 2023-04-07T06:18:05Z has_accepted_license: '1' language: - iso: eng month: '04' oa_version: Published Version page: '115' project: - _id: 267DFB90-B435-11E9-9278-68D0E5697425 name: 'Plasticity in the cerebellum: Which molecular mechanisms are behind physiological learning?' publication_identifier: issn: - 2663 - 337X publication_status: published publisher: Institute of Science and Technology Austria status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: 'Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning' type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2023' ... --- _id: '11393' abstract: - lang: eng text: "AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and their role is\r\nimplicated in complex processes such as learning and memory and various neurological\r\ndiseases. These receptors are composed of different subunits and the subunit composition can\r\naffect channel properties, receptor trafficking and interaction with other associated proteins.\r\nUsing the high sensitivity SDS-digested freeze-fracture replica labeling (SDS-FRL) for\r\nelectron microscopy I investigated the number, density, and localization of AMPAR subunits,\r\nGluA1, GluA2, GluA3, and GluA1-3 (panAMPA) in pyramidal cells in the CA1 area of mouse\r\nhippocampus. I have found that the immunogold labeling for all of these subunits in the\r\npostsynaptic sites was highest in stratum radiatum and lowest in stratum lacunosummoleculare. The labeling density for the all subunits in the extrasynaptic sites showed a gradual\r\nincrease from the pyramidal cell soma towards the distal part of stratum radiatum. The densities\r\nof extrasynaptic GluA1, GluA2 and panAMPA labeling reached 10-15% of synaptic densities,\r\nwhile the ratio of extrasynaptic labeling for GluA3 was significantly lower compared than those\r\nfor other subunits. The labeling patterns for GluA1, GluA2 and GluA1-3 are similar and their\r\ndensities were higher in the periphery than center of synapses. In contrast, the GluA3-\r\ncontaining receptors were more centrally localized compared to the GluA1- and GluA2-\r\ncontaining receptors.\r\nThe hippocampus plays a central role in learning and memory. Contextual learning has been\r\nshown to require the delivery of AMPA receptors to CA1 synapses in the dorsal hippocampus.\r\nHowever, proximodistal heterogeneity of this plasticity and particular contribution of different\r\nAMPA receptor subunits are not fully understood. By combining inhibitory avoidance task, a\r\nhippocampus-dependent contextual fear-learning paradigm, with SDS-FRL, I have revealed an\r\nincrease in synaptic density specific to GluA1-containing AMPA receptors in the CA1 area.\r\nThe intrasynaptic distribution of GluA1 also changed from the periphery to center-preferred\r\npattern. Furthermore, this synaptic plasticity was evident selectively in stratum radiatum but\r\nnot stratum oriens, and in the CA1 subregion proximal but not distal to CA2. These findings\r\nfurther contribute to our understanding of how specific hippocampal subregions and AMPA\r\nreceptor subunits are involved in physiological learning.\r\nAlthough the immunolabeling results above shed light on subunit-specific plasticity in\r\nAMPAR distribution, no tools to visualize and study the subunit composition at the single\r\nchannel level in situ have been available. Electron microscopy with conventional immunogold\r\nlabeling approaches has limitations in the single channel analysis because of the large size of\r\nantibodies and steric hindrance hampering multiple subunit labeling of single channels. I\r\nmanaged to develop a new chemical labeling system using a short peptide tag and small\r\nsynthetic probes, which form specific covalent bond with a cysteine residue in the tag fused to\r\nproteins of interest (reactive tag system). I additionally made substantial progress into adapting\r\nthis system for AMPA receptor subunits." acknowledged_ssus: - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Marijo full_name: Jevtic, Marijo id: 4BE3BC94-F248-11E8-B48F-1D18A9856A87 last_name: Jevtic citation: ama: Jevtic M. Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus. 2022. doi:10.15479/at:ista:11393 apa: Jevtic, M. (2022). Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:11393 chicago: Jevtic, Marijo. “Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:11393. ieee: M. Jevtic, “Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus,” Institute of Science and Technology Austria, 2022. ista: Jevtic M. 2022. Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus. Institute of Science and Technology Austria. mla: Jevtic, Marijo. Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus. Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:11393. short: M. Jevtic, Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus, Institute of Science and Technology Austria, 2022. date_created: 2022-05-17T08:57:41Z date_published: 2022-05-16T00:00:00Z date_updated: 2023-09-07T14:53:44Z day: '16' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: RySh doi: 10.15479/at:ista:11393 file: - access_level: closed checksum: 8fc695d88020d70d231dad0e9f10b138 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: cchlebak date_created: 2022-05-17T09:08:06Z date_updated: 2023-05-17T22:30:03Z embargo_to: open_access file_id: '11395' file_name: MJ thesis.docx file_size: 56427603 relation: source_file - access_level: open_access checksum: c1dd20a1aece521b3500607b00e463d6 content_type: application/pdf creator: cchlebak date_created: 2022-05-17T12:09:25Z date_updated: 2023-05-17T22:30:03Z embargo: 2023-05-16 file_id: '11397' file_name: MJ_thesis_PDFA.pdf file_size: 4351981 relation: main_file file_date_updated: 2023-05-17T22:30:03Z has_accepted_license: '1' language: - iso: eng month: '05' oa: 1 oa_version: Published Version page: '108' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '7391' relation: part_of_dissertation status: public status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2022' ... --- _id: '9562' abstract: - lang: eng text: Left-right asymmetries can be considered a fundamental organizational principle of the vertebrate central nervous system. The hippocampal CA3-CA1 pyramidal cell synaptic connection shows an input-side dependent asymmetry where the hemispheric location of the presynaptic CA3 neuron determines the synaptic properties. Left-input synapses terminating on apical dendrites in stratum radiatum have a higher density of NMDA receptor subunit GluN2B, a lower density of AMPA receptor subunit GluA1 and smaller areas with less often perforated PSDs. On the other hand, left-input synapses terminating on basal dendrites in stratum oriens have lower GluN2B densities than right-input ones. Apical and basal synapses further employ different signaling pathways involved in LTP. SDS-digested freeze-fracture replica labeling can visualize synaptic membrane proteins with high sensitivity and resolution, and has been used to reveal the asymmetry at the electron microscopic level. However, it requires time-consuming manual demarcation of the synaptic surface for quantitative measurements. To facilitate the analysis of replica labeling, I first developed a software named Darea, which utilizes deep-learning to automatize this demarcation. With Darea I characterized the synaptic distribution of NMDA and AMPA receptors as well as the voltage-gated Ca2+ channels in CA1 stratum radiatum and oriens. Second, I explored the role of GluN2B and its carboxy-terminus in the establishment of input-side dependent hippocampal asymmetry. In conditional knock-out mice lacking GluN2B expression in CA1 and GluN2B-2A swap mice, where GluN2B carboxy-terminus was exchanged to that of GluN2A, no significant asymmetries of GluN2B, GluA1 and PSD area were detected. We further discovered a previously unknown functional asymmetry of GluN2A, which was also lost in the swap mouse. These results demonstrate that GluN2B carboxy-terminus plays a critical role in normal formation of input-side dependent asymmetry. acknowledged_ssus: - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: David full_name: Kleindienst, David id: 42E121A4-F248-11E8-B48F-1D18A9856A87 last_name: Kleindienst citation: ama: 'Kleindienst D. 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning. 2021. doi:10.15479/at:ista:9562' apa: 'Kleindienst, D. (2021). 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:9562' chicago: 'Kleindienst, David. “2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning.” Institute of Science and Technology Austria, 2021. https://doi.org/10.15479/at:ista:9562.' ieee: 'D. Kleindienst, “2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning,” Institute of Science and Technology Austria, 2021.' ista: 'Kleindienst D. 2021. 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning. Institute of Science and Technology Austria.' mla: 'Kleindienst, David. 2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning. Institute of Science and Technology Austria, 2021, doi:10.15479/at:ista:9562.' short: 'D. Kleindienst, 2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning, Institute of Science and Technology Austria, 2021.' date_created: 2021-06-17T14:10:47Z date_published: 2021-06-01T00:00:00Z date_updated: 2023-09-11T12:55:53Z day: '01' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: RySh doi: 10.15479/at:ista:9562 file: - access_level: open_access checksum: 659df5518db495f679cb1df9e9bd1d94 content_type: application/pdf creator: dkleindienst date_created: 2021-06-17T14:03:14Z date_updated: 2022-07-02T22:30:04Z embargo: 2022-07-01 file_id: '9563' file_name: Thesis.pdf file_size: 77299142 relation: main_file - access_level: closed checksum: 3bcf63a2b19e5b6663be051bea332748 content_type: application/zip creator: dkleindienst date_created: 2021-06-17T14:04:30Z date_updated: 2022-07-02T22:30:04Z embargo_to: open_access file_id: '9564' file_name: Thesis_source.zip file_size: 369804895 relation: source_file file_date_updated: 2022-07-02T22:30:04Z has_accepted_license: '1' language: - iso: eng month: '06' oa: 1 oa_version: Published Version page: '124' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '9756' relation: part_of_dissertation status: public - id: '9437' relation: part_of_dissertation status: public - id: '8532' relation: part_of_dissertation status: public - id: '612' relation: part_of_dissertation status: public status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: '2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning' type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2021' ... --- _id: '7525' abstract: - lang: eng text: "The medial habenula (MHb) is an evolutionary conserved epithalamic structure important for the modulation of emotional memory. It is involved in regulation of anxiety, compulsive behavior, addiction (nicotinic and opioid), sexual and feeding behavior. MHb receives inputs from septal regions and projects exclusively to the interpeduncular nucleus (IPN). Distinct sub-regions of the septum project to different subnuclei of MHb: the bed nucleus of anterior commissure projects to dorsal MHb and the triangular septum projects to ventral MHb. Furthermore, the dorsal and ventral MHb project to the lateral and rostral/central IPN, respectively. Importantly, these projections have unique features of prominent co-release of different neurotransmitters and requirement of a peculiar type of calcium channel for release. In general, synaptic neurotransmission requires an activity-dependent influx of Ca2+ into the presynaptic terminal through voltage-gated calcium channels. The calcium channel family most commonly involved in neurotransmitter release comprises three members, P/Q-, N- and R-type with Cav2.1, Cav2.2 and Cav2.3 subunits, respectively. In contrast to most CNS synapses that mainly express Cav2.1 and/or Cav2.2, MHb terminals in the IPN exclusively express Cav2.3. In other parts of the brain, such as the hippocampus, Cav2.3 is mostly located to postsynaptic elements. This unusual presynaptic location of Cav2.3 in the MHb-IPN pathway implies unique mechanisms of glutamate release in this pathway. One potential example of such uniqueness is the facilitation of release by GABAB receptor (GBR) activation. Presynaptic GBRs usually inhibit the release of neurotransmitters by inhibiting presynaptic calcium channels. MHb shows the highest expression levels of GBR in the brain. GBRs comprise two subunits, GABAB1 (GB1) and GABAB2 (GB2), and are associated with auxiliary subunits, called potassium channel tetramerization domain containing proteins (KCTD) 8, 12, 12b and 16. Among these four subunits, KCTD12b is exclusively expressed in ventral MHb, and KCTD8 shows the strongest expression in the whole MHb among other brain regions, indicating that KCTD8 and KCTD12b may be involved in the unique mechanisms of neurotransmitter release mediated by Cav2.3 and regulated by GBRs in this pathway. \r\nIn the present study, we first verified that neurotransmission in both dorsal and ventral MHb-IPN pathways is mainly mediated by Cav2.3 using a selective blocker of R-type channels, SNX-482. We next found that baclofen, a GBR agonist, has facilitatory effects on release from ventral MHb terminal in rostral IPN, whereas it has inhibitory effects on release from dorsal MHb terminals in lateral IPN, indicating that KCTD12b expressed exclusively in ventral MHb may have a role in the facilitatory effects of GBR activation. In a heterologous expression system using HEK cells, we found that KCTD8 and KCTD12b but not KCTD12 directly bind with Cav2.3. Pre-embedding immunogold electron microscopy data show that Cav2.3 and KCTD12b are distributed most densely in presynaptic active zone in IPN with KCTD12b being present only in rostral/central but not lateral IPN, whereas GABAB, KCTD8 and KCTD12 are distributed most densely in perisynaptic sites with KCTD12 present more frequently in postsynaptic elements and only in rostral/central IPN. In freeze-fracture replica labelling, Cav2.3, KCTD8 and KCTD12b are co-localized with each other in the same active zone indicating that they may form complexes regulating vesicle release in rostral IPN. \r\nOn electrophysiological studies of wild type (WT) mice, we found that paired-pulse ratio in rostral IPN of KCTD12b knock-out (KO) mice is lower than those of WT and KCTD8 KO mice. Consistent with this finding, in mean variance analysis, release probability in rostral IPN of KCTD12b KO mice is higher than that of WT and KCTD8 KO mice. Although paired-pulse ratios are not different between WT and KCTD8 KO mice, the mean variance analysis revealed significantly lower release probability in rostral IPN of KCTD8 KO than WT mice. These results demonstrate bidirectional regulation of Cav2.3-mediated release by KCTD8 and KCTD12b without GBR activation in rostral IPN. Finally, we examined the baclofen effects in rostral IPN of KCTD8 and KCTD12b KO mice, and found the facilitation of release remained in both KO mice, indicating that the peculiar effects of the GBR activation in this pathway do not depend on the selective expression of these KCTD subunits in ventral MHb. However, we found that presynaptic potentiation of evoked EPSC amplitude by baclofen falls to baseline after washout faster in KCTD12b KO mice than WT, KCTD8 KO and KCTD8/12b double KO mice. This result indicates that KCTD12b is involved in sustained potentiation of vesicle release by GBR activation, whereas KCTD8 is involved in its termination in the absence of KCTD12b. Consistent with these functional findings, replica labelling revealed an increase in density of KCTD8, but not Cav2.3 or GBR at active zone in rostral IPN of KCTD12b KO mice compared with that of WT mice, suggesting that increased association of KCTD8 with Cav2.3 facilitates the release probability and termination of the GBR effect in the absence of KCTD12b.\r\nIn summary, our study provided new insights into the physiological roles of presynaptic Cav2.3, GBRs and their auxiliary subunits KCTDs at an evolutionary conserved neuronal circuit. Future studies will be required to identify the exact molecular mechanism underlying the GBR-mediated presynaptic potentiation on ventral MHb terminals. It remains to be determined whether the prominent presence of presynaptic KCTDs at active zone could exert similar neuromodulatory functions in different pathways of the brain.\r\n" acknowledged_ssus: - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Pradeep full_name: Bhandari, Pradeep id: 45EDD1BC-F248-11E8-B48F-1D18A9856A87 last_name: Bhandari orcid: 0000-0003-0863-4481 citation: ama: Bhandari P. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. 2020. doi:10.15479/AT:ISTA:7525 apa: Bhandari, P. (2020). Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:7525 chicago: Bhandari, Pradeep. “Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:7525. ieee: P. Bhandari, “Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway,” Institute of Science and Technology Austria, 2020. ista: Bhandari P. 2020. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. Institute of Science and Technology Austria. mla: Bhandari, Pradeep. Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:7525. short: P. Bhandari, Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway, Institute of Science and Technology Austria, 2020. date_created: 2020-02-26T10:56:37Z date_published: 2020-02-28T00:00:00Z date_updated: 2023-09-07T13:20:03Z day: '28' ddc: - '570' degree_awarded: PhD department: - _id: RySh doi: 10.15479/AT:ISTA:7525 file: - access_level: open_access checksum: 4589234fdb12b4ad72273b311723a7b4 content_type: application/pdf creator: pbhandari date_created: 2020-02-28T08:37:53Z date_updated: 2021-03-01T23:30:04Z embargo: 2021-02-28 file_id: '7538' file_name: Pradeep Bhandari Thesis.pdf file_size: 9646346 relation: main_file title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway - access_level: closed checksum: aa79490553ca0a5c9b6fbcd152e93928 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: pbhandari date_created: 2020-02-28T08:47:14Z date_updated: 2021-03-01T23:30:04Z embargo_to: open_access file_id: '7539' file_name: Pradeep Bhandari Thesis.docx file_size: 35252164 relation: source_file title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway file_date_updated: 2021-03-01T23:30:04Z has_accepted_license: '1' keyword: - Cav2.3 - medial habenula (MHb) - interpeduncular nucleus (IPN) language: - iso: eng month: '02' oa: 1 oa_version: Published Version page: '79' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '51' abstract: - lang: eng text: Asymmetries have long been known about in the central nervous system. From gross anatomical differences, such as the presence of the parapineal organ in only one hemisphere of the developing zebrafish, to more subtle differences in activity between both hemispheres, as seen in freely roaming animals or human participants under PET and fMRI imaging analysis. The presence of asymmetries has been demonstrated to have huge behavioural implications, with their disruption often leading to the generation of neurological disorders, memory problems, changes in personality, and in an organism's health and well-being. For my Ph.D. work I aimed to tackle two important avenues of research. The first being the process of input-side dependency in the hippocampus, with the goal of finding a key gene responsible for its development (Gene X). The second project was to do with experience-induced laterality formation in the hippocampus. Specifically, how laterality in the synapse density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental enrichment. Through unilateral tracer injections into the CA3, I was able to selectively measure the properties of synapses within the CA1 and investigate how they differed based upon which hemisphere the presynaptic neurone originated. Having found the existence of a previously unreported reversed (left-isomerism) i.v. mutant, through morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate a key gene responsible for the process of left or right determination of inputs to the CA1 s.r.. This work relates to the previous finding of input-side dependent asymmetry in the wild-type rodent, where the origin of the projecting neurone to the CA1 will determine the morphology of a synapse, to a greater degree than the hemisphere in which the projection terminates. Using left- and right-isomerism i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like (Evl) as a potential target for Gene X. In relation to this topic, I also highlight my work in the recently published paper of how knockout of PirB can lead to a lack of input-side dependency in the murine hippocampus. For the second question, I show that the environmental enrichment paradigm will lead to an asymmetry in the synapse densities in the hippocampus of mice. I also highlight that the nature of the enrichment is of less consequence than the process of enrichment itself. I demonstrate that the CA3 region will dramatically alter its projection targets, in relation to environmental stimulation, with the asymmetry in synaptic density, caused by enrichment, relying heavily on commissural fibres. I also highlight the vital importance of input-side dependent asymmetry, as a necessary component of experience-dependent laterality formation in the CA1 s.r.. However, my results suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism also at play. Upon further investigation, I highlight the significant, and highly important, finding that the changes seen in the CA1 s.r. were predominantly caused through projections from the left-CA3, with the right-CA3 having less involvement in this mechanism. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Matthew J full_name: Case, Matthew J id: 44B7CA5A-F248-11E8-B48F-1D18A9856A87 last_name: Case citation: ama: 'Case MJ. From the left to the right: A tale of asymmetries, environments, and hippocampal development. 2018. doi:10.15479/AT:ISTA:th_1032' apa: 'Case, M. J. (2018). From the left to the right: A tale of asymmetries, environments, and hippocampal development. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_1032' chicago: 'Case, Matthew J. “From the Left to the Right: A Tale of Asymmetries, Environments, and Hippocampal Development.” Institute of Science and Technology Austria, 2018. https://doi.org/10.15479/AT:ISTA:th_1032.' ieee: 'M. J. Case, “From the left to the right: A tale of asymmetries, environments, and hippocampal development,” Institute of Science and Technology Austria, 2018.' ista: 'Case MJ. 2018. From the left to the right: A tale of asymmetries, environments, and hippocampal development. Institute of Science and Technology Austria.' mla: 'Case, Matthew J. From the Left to the Right: A Tale of Asymmetries, Environments, and Hippocampal Development. Institute of Science and Technology Austria, 2018, doi:10.15479/AT:ISTA:th_1032.' short: 'M.J. Case, From the Left to the Right: A Tale of Asymmetries, Environments, and Hippocampal Development, Institute of Science and Technology Austria, 2018.' date_created: 2018-12-11T11:44:22Z date_published: 2018-06-27T00:00:00Z date_updated: 2023-09-07T12:39:22Z day: '27' ddc: - '571' - '576' degree_awarded: PhD department: - _id: RySh doi: 10.15479/AT:ISTA:th_1032 file: - access_level: closed checksum: dcc7b55619d8509dd62b8e99d6cdee44 content_type: application/msword creator: dernst date_created: 2019-04-09T07:16:26Z date_updated: 2021-02-11T23:30:13Z embargo_to: open_access file_id: '6251' file_name: 2018_Thesis_Case_Source.doc file_size: 141270528 relation: source_file - access_level: open_access checksum: f69fdd5c8709c4e618aa8c1a1221153d content_type: application/pdf creator: dernst date_created: 2019-04-09T07:16:23Z date_updated: 2021-02-11T11:17:14Z embargo: 2019-07-05 file_id: '6252' file_name: 2018_Thesis_Case.pdf file_size: 15193621 relation: main_file file_date_updated: 2021-02-11T23:30:13Z has_accepted_license: '1' language: - iso: eng month: '06' oa: 1 oa_version: Published Version page: '186' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '8003' pubrep_id: '1032' related_material: record: - id: '682' relation: part_of_dissertation status: public status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: 'From the left to the right: A tale of asymmetries, environments, and hippocampal development' type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2018' ...