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Title:Disrupted female reproductive cyclicity and gonadotropin-releasing hormone neuron dysfunction in a mouse model of temporal lobe epilepsy
Author(s):Li, Jiang
Director of Research:Christian, Catherine A
Doctoral Committee Chair(s):Christian, Catherine A
Doctoral Committee Member(s):Chung, Hee Jung; Nelson, Mark E; Raetzman, Lori T
Department / Program:Neuroscience Program
Degree Granting Institution:University of Illinois at Urbana-Champaign
HPG axis
Estrous cycle
Seizure detection
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.
Issue Date:2020-02-07
Rights Information:Copyright 2020 Jiang Li
Date Available in IDEALS:2020-08-27
Date Deposited:2020-05

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