{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/108222"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/108222","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Disrupted female reproductive cyclicity and gonadotropin-releasing hormone neuron dysfunction in a mouse model of temporal lobe epilepsy","abstract":"Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). However, the neural mechanisms linking epilepsy to comorbid reproductive endocrine disorders are unknown. In the intrahippocampal kainic acid (IHKA) mouse model of TLE, we observed that more than 60% percent of KA-injected mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length and increased time spent in diestrus estrus by 42 days post-KA injection. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key players in the neural control of reproduction through the hypothalamic-pituitary-gonadal (HPG) axis. At two months post-injection, the effects of epilepsy on the GnRH neuron function are dynamic across the estrous cycle, associated with comorbid estrous cycle disruption severity, and specific to sex. Compared to control mice, the GnRH neuron mean firing rate in KA-injected mice with prolonged estrous cycle was higher on diestrus, but lower on estrus. In mice that maintained regular estrous cycles, GnRH neurons showed normal firing rates on diestrus. Progesterone and estradiol levels in KA-injected females were also different from control, suggesting altered sex hormone negative feedback may contribute to the changes in GnRH neuron firing activity. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. For both males and females, GnRH neuron intrinsic excitability was higher than in controls on both diestrus and estrus. On diestrus, the GnRH neuron firing rate was not correlated with the EEG seizure burden or the plasma progesterone concentration. There was also no correlation between the degree of estrous cycle disruption and the EEG seizure burden. At one month post-injection, we did not observe altered GnRH neuron firing rates or progesterone and estradiol levels in KA-injected female mice, indicating that hippocampal seizures do not cause immediate HPG axis dysfunction phenotypes. To analyze seizures from long-term 24/7 EEG recordings, a convolutional neural network (CNN) was trained for the electrographic seizure detection. The CNN model achieved 91% recall and a false detection rate at 0.04 seizure/hr. Using the CNN model, we discovered that the seizure burden in the IHKA mouse model changes with the estrous cycle. Mice with frequent seizures (> 1% of the time in seizures) had more frequent and longer seizures during proestrus and estrus compared to diestrus. Together, we demonstrated that GnRH neuron function and estrous cyclicity are altered in the IHKA mouse model of TLE. There are interactions between the estrous cycle stage, epilepsy, and HPG axis dysfunction. The effects of epilepsy on GnRH neuron activity, as well as the hippocampal seizure burden, change with estrous cycle stages. However, hippocampal seizure burden does not determine the level of disruption to estrous cyclicity or GnRH neuron activity.","abstract_html":"Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). However, the neural mechanisms linking epilepsy to comorbid reproductive endocrine disorders are unknown. In the intrahippocampal kainic acid (IHKA) mouse model of TLE, we observed that more than 60% percent of KA-injected mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length and increased time spent in diestrus estrus by 42 days post-KA injection. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key players in the neural control of reproduction through the hypothalamic-pituitary-gonadal (HPG) axis. At two months post-injection, the effects of epilepsy on the GnRH neuron function are dynamic across the estrous cycle, associated with comorbid estrous cycle disruption severity, and specific to sex. Compared to control mice, the GnRH neuron mean firing rate in KA-injected mice with prolonged estrous cycle was higher on diestrus, but lower on estrus. In mice that maintained regular estrous cycles, GnRH neurons showed normal firing rates on diestrus. Progesterone and estradiol levels in KA-injected females were also different from control, suggesting altered sex hormone negative feedback may contribute to the changes in GnRH neuron firing activity. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. For both males and females, GnRH neuron intrinsic excitability was higher than in controls on both diestrus and estrus. On diestrus, the GnRH neuron firing rate was not correlated with the EEG seizure burden or the plasma progesterone concentration. There was also no correlation between the degree of estrous cycle disruption and the EEG seizure burden. At one month post-injection, we did not observe altered GnRH neuron firing rates or progesterone and estradiol levels in KA-injected female mice, indicating that hippocampal seizures do not cause immediate HPG axis dysfunction phenotypes. To analyze seizures from long-term 24/7 EEG recordings, a convolutional neural network (CNN) was trained for the electrographic seizure detection. The CNN model achieved 91% recall and a false detection rate at 0.04 seizure/hr. Using the CNN model, we discovered that the seizure burden in the IHKA mouse model changes with the estrous cycle. Mice with frequent seizures (> 1% of the time in seizures) had more frequent and longer seizures during proestrus and estrus compared to diestrus. Together, we demonstrated that GnRH neuron function and estrous cyclicity are altered in the IHKA mouse model of TLE. There are interactions between the estrous cycle stage, epilepsy, and HPG axis dysfunction. The effects of epilepsy on GnRH neuron activity, as well as the hippocampal seizure burden, change with estrous cycle stages. However, hippocampal seizure burden does not determine the level of disruption to estrous cyclicity or GnRH neuron activity.","abstract_has_math":false,"creators":["Li, Jiang"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Neuroscience","degree_department":null,"school":null,"contributors":["Christian, Catherine A","Chung, Hee Jung","Nelson, Mark E","Raetzman, Lori T"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-08-27T00:46:49Z","date_published":"2020-08-27T00:46:49Z","updated_at":"2026-07-22T22:24:48Z","subjects":["Epilepsy","HPG axis","Estrous cycle","Seizure detection"],"languages":["en"],"rights":["Copyright 2020 Jiang Li"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/108222","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Christian, Catherine A","Chung, Hee Jung","Nelson, Mark E","Raetzman, Lori T"]},{"key":"dc:creator","label":"Author","values":["Li, Jiang"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2020-08-27T00:46:49Z","2022-08-27T00:51:40Z","2020-02-07","2020-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Neuroscience"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Epilepsy","HPG axis","Estrous cycle","Seizure detection"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2020 Jiang Li"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/108222"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). However, the neural mechanisms linking epilepsy to comorbid reproductive endocrine disorders are unknown. In the intrahippocampal kainic acid (IHKA) mouse model of TLE, we observed that more than 60% percent of KA-injected mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length and increased time spent in diestrus estrus by 42 days post-KA injection. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key players in the neural control of reproduction through the hypothalamic-pituitary-gonadal (HPG) axis. At two months post-injection, the effects of epilepsy on the GnRH neuron function are dynamic across the estrous cycle, associated with comorbid estrous cycle disruption severity, and specific to sex. Compared to control mice, the GnRH neuron mean firing rate in KA-injected mice with prolonged estrous cycle was higher on diestrus, but lower on estrus. In mice that maintained regular estrous cycles, GnRH neurons showed normal firing rates on diestrus. Progesterone and estradiol levels in KA-injected females were also different from control, suggesting altered sex hormone negative feedback may contribute to the changes in GnRH neuron firing activity. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. For both males and females, GnRH neuron intrinsic excitability was higher than in controls on both diestrus and estrus. On diestrus, the GnRH neuron firing rate was not correlated with the EEG seizure burden or the plasma progesterone concentration. There was also no correlation between the degree of estrous cycle disruption and the EEG seizure burden. At one month post-injection, we did not observe altered GnRH neuron firing rates or progesterone and estradiol levels in KA-injected female mice, indicating that hippocampal seizures do not cause immediate HPG axis dysfunction phenotypes. To analyze seizures from long-term 24/7 EEG recordings, a convolutional neural network (CNN) was trained for the electrographic seizure detection. The CNN model achieved 91% recall and a false detection rate at 0.04 seizure/hr. Using the CNN model, we discovered that the seizure burden in the IHKA mouse model changes with the estrous cycle. Mice with frequent seizures (> 1% of the time in seizures) had more frequent and longer seizures during proestrus and estrus compared to diestrus. Together, we demonstrated that GnRH neuron function and estrous cyclicity are altered in the IHKA mouse model of TLE. There are interactions between the estrous cycle stage, epilepsy, and HPG axis dysfunction. The effects of epilepsy on GnRH neuron activity, as well as the hippocampal seizure burden, change with estrous cycle stages. However, hippocampal seizure burden does not determine the level of disruption to estrous cyclicity or GnRH neuron activity.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01","The student, Jiang Li, accepted the attached license on 2020-02-05 at 12:58.","The student, Jiang Li, submitted this Dissertation for approval on 2020-02-05 at 13:31.","This Dissertation was approved for publication on 2020-02-07 at 16:42.","DSpace SAF Submission Ingestion Package generated from Vireo submission #14868 on 2020-08-25 at 17:38:36","Made available in DSpace on 2020-08-27T00:46:49Z (GMT). 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However, the neural mechanisms linking epilepsy to comorbid reproductive endocrine disorders are unknown. In the intrahippocampal kainic acid (IHKA) mouse model of TLE, we observed that more than 60% percent of KA-injected mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length and increased time spent in diestrus estrus by 42 days post-KA injection. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are key players in the neural control of reproduction through the hypothalamic-pituitary-gonadal (HPG) axis. At two months post-injection, the effects of epilepsy on the GnRH neuron function are dynamic across the estrous cycle, associated with comorbid estrous cycle disruption severity, and specific to sex. Compared to control mice, the GnRH neuron mean firing rate in KA-injected mice with prolonged estrous cycle was higher on diestrus, but lower on estrus. In mice that maintained regular estrous cycles, GnRH neurons showed normal firing rates on diestrus. Progesterone and estradiol levels in KA-injected females were also different from control, suggesting altered sex hormone negative feedback may contribute to the changes in GnRH neuron firing activity. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. For both males and females, GnRH neuron intrinsic excitability was higher than in controls on both diestrus and estrus. On diestrus, the GnRH neuron firing rate was not correlated with the EEG seizure burden or the plasma progesterone concentration. There was also no correlation between the degree of estrous cycle disruption and the EEG seizure burden. At one month post-injection, we did not observe altered GnRH neuron firing rates or progesterone and estradiol levels in KA-injected female mice, indicating that hippocampal seizures do not cause immediate HPG axis dysfunction phenotypes. To analyze seizures from long-term 24/7 EEG recordings, a convolutional neural network (CNN) was trained for the electrographic seizure detection. The CNN model achieved 91% recall and a false detection rate at 0.04 seizure/hr. Using the CNN model, we discovered that the seizure burden in the IHKA mouse model changes with the estrous cycle. Mice with frequent seizures (> 1% of the time in seizures) had more frequent and longer seizures during proestrus and estrus compared to diestrus. Together, we demonstrated that GnRH neuron function and estrous cyclicity are altered in the IHKA mouse model of TLE. There are interactions between the estrous cycle stage, epilepsy, and HPG axis dysfunction. The effects of epilepsy on GnRH neuron activity, as well as the hippocampal seizure burden, change with estrous cycle stages. However, hippocampal seizure burden does not determine the level of disruption to estrous cyclicity or GnRH neuron activity.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01","The student, Jiang Li, accepted the attached license on 2020-02-05 at 12:58.","The student, Jiang Li, submitted this Dissertation for approval on 2020-02-05 at 13:31.","This Dissertation was approved for publication on 2020-02-07 at 16:42.","DSpace SAF Submission Ingestion Package generated from Vireo submission #14868 on 2020-08-25 at 17:38:36","Made available in DSpace on 2020-08-27T00:46:49Z (GMT). No. of bitstreams: 3 LI-DISSERTATION-2020.pdf: 13743451 bytes, checksum: d199bcb6589bcafa478b93eb5499a107 (MD5) LICENSE.txt: 4205 bytes, checksum: c1ec688506f0da753c6f2c630dee7dc7 (MD5) PROQUEST_LICENSE.txt: 4551 bytes, checksum: ba77d0e1f4b740d990b9b4b0cd540666 (MD5) Previous issue date: 2020-02-07","Embargo set by: Seth Robbins for item 115835 Lift date: 2022-08-27T00:46:59Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115835 Lift date: 2022-08-27T00:50:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115835 Lift date: 2022-08-27T00:51:40Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Author requested closed access (OA after 2yrs) in Vireo ETD system","Limited"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/108222"],"dc:language":["en"],"dc:rights":["Copyright 2020 Jiang Li"],"dc:subject":["Epilepsy","HPG axis","Estrous cycle","Seizure detection"],"dc:title":["Disrupted female reproductive cyclicity and gonadotropin-releasing hormone neuron dysfunction in a mouse model of temporal lobe epilepsy"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Neuroscience"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:48Z"}