Papers by Jessica Carlsen
Annals of Neurology
ObjectiveTemporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes ... more ObjectiveTemporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and hippocampal neural circuit remodeling that results in spontaneous seizures and cognitive dysfunction. Targeting these cascades may provide disease‐modifying treatments for TLE patients. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors have emerged as potential disease‐modifying therapies; a more detailed understanding of JAK/STAT participation in epileptogenic responses is required, however, to increase the therapeutic efficacy and reduce adverse effects associated with global inhibition.MethodsWe developed a mouse line in which tamoxifen treatment conditionally abolishes STAT3 signaling from forebrain excitatory neurons (nSTAT3KO). Seizure frequency (continuous in vivo electroencephalography) and memory (contextual fear conditioning and motor learning) were analyzed in wild‐type and nSTAT3KO mice after intrahippocampal kainate...
Frontiers in Neurology, 2021
Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the gl... more Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results...
Neurobiology of disease, Jan 22, 2017
In this study, we used the pilocarpine model of epilepsy to evaluate the involvement of calpain d... more In this study, we used the pilocarpine model of epilepsy to evaluate the involvement of calpain dysregulation on epileptogenesis. Detection of spectrin breakdown products (SBDPs, a hallmark of calpain activation) after induction of pilocarpine-induced status epilepticus (SE) and before appearance of spontaneous seizure suggested the existence of sustained calpain activation during epileptogenesis. Acute treatment with a cell permeable inhibitor of calpain, MDL-28170, resulted in a partial but significant reduction on seizure burden. The reduction on seizure burden was associated with a limited reduction on the generation of SBDPs but was correlated with a reduction in astrocytosis, microglia activation and cell sprouting. Together, these observations provide evidence for the role of calpain in epileptogenesis. In addition, provide proof-of-principle for the use of calpain inhibitors as a novel strategy to prevent epileptic seizures and its associated pathologies.
Neurobiology of disease, Jan 11, 2015
In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane... more In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥24h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into t...
Neurobiology of disease, 2014
Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rod... more Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE affects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and lo...
When an exhaustive search is impractical in non-clinical environs, people tend to use heuristic m... more When an exhaustive search is impractical in non-clinical environs, people tend to use heuristic methods to expedite their search. Conversely, clinicians trust exhaustive searches rather than heuristics such as clinical decision-support systems (CDSS), particularly when electroencephalography (EEG) sequences are used to search for pathologic oscillations in an epileptogenic brain. This paradigm will only change when a CDSS incorporates intelligence that identifies, learns and reprograms itself without human intervention each time it procures a false positive or false negative resultant. In essence, CDSSs need autonomous intelligence. In the ongoing goal to establish an autonomous machinelearning CDSS for detecting seizures the authors present a further embodiment of their existing neuroClustering system that optimizes calculating the limit of rectangular approximations of the EEG above and below a bisecting line using Riemann sums. The authors plot these approximations against the ch...
eNeuro
Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leadi... more Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABAA receptor α1 subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in astrocytes. Analysis of the proteolytic machinery...
Experimental Neurology, 2015
Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) ty... more Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABAAR). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABAAR subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABAAR α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABAAR α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABAAR α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABAAR α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABAAR α1 protein levels and improves vestibular motor recovery.
When an exhaustive search is impractical in non-clinical environs, people tend to use heuristic m... more When an exhaustive search is impractical in non-clinical environs, people tend to use heuristic methods to expedite their search. Conversely, clinicians trust exhaustive searches rather than heuristics such as clinical decision-support systems (CDSS), particularly when electroencephalography (EEG) sequences are used to search for pathologic oscillations in an epileptogenic brain. This paradigm will only change when a CDSS incorporates intelligence that identifies, learns and reprograms itself without human intervention each time it procures a false positive or false negative resultant. In essence, CDSSs need autonomous intelligence. In the ongoing goal to establish an autonomous machinelearning CDSS for detecting seizures the authors present a further embodiment of their existing neuroClustering TM system that optimizes calculating the limit of rectangular approximations of the EEG above and below a bisecting line using Riemann sums. The authors plot these approximations against the change of time using a novel K-means clustering approach. In this paper we present a methodology that reduces analyzing 7 days of EGG data, something that takes a human expert many days to accomplish, into a 40-minute task that renders the resulting timestamps of pathologic oscillations in an artificial intelligent-ready array.
Lecture Notes in Computer Science, 2014
In the continuing goal to merge the fields of computational neuroscience with medical based neuro... more In the continuing goal to merge the fields of computational neuroscience with medical based neurodiagnostic clinical research this paper presents advancements on machine learning Big Electroencephalogram (EEG) Data. The authors' clinical decision-support systems (CDSS) presented in previous work was able to distinguish, within minutes, pathological oscillations hidden in terabytes of complex signal analysis. This paper presents training and learning elements that compliment and advance this previous work. This paper shows how perceptrons, that predate modern-day neural network constructs, remain relevant in many modern classification applications where a clear linear separation is present in the data. Furthermore, the perceptrons also compliment the domain adaptation covariant shifts later used when the system is used in the neuroICU (Intensive Care Unit). Accordingly, we present supervised learning for the neuroICU using single-layer perceptron classifiers.
Epilepsia, 2014
Temporal lobe epilepsy (TLE) is frequently medically intractable and often progressive. Compromis... more Temporal lobe epilepsy (TLE) is frequently medically intractable and often progressive. Compromised inhibitory neurotransmission due to altered γ-aminobutyric acid (GABA)A receptor α4 subunit (GABAA Rα4) expression has been emphasized as a potential contributor to the initial development of epilepsy following a brain insult (primary epileptogenesis), but the regulation of GABAA Rα4 during chronic epilepsy, specifically, how expression is altered following spontaneous seizures, is less well understood. Continuous video-electroencephalography (EEG) recordings from rats with pilocarpine-induced TLE were used to capture epileptic animals within 3 h of a spontaneous seizure (SS), or >24 h after the last SS, to determine whether recent occurrence of a seizure was associated with altered levels of GABAA Rα4 expression. We further evaluated whether this GABAA Rα4 plasticity is regulated by signaling mechanisms active in primary epileptogenesis, specifically, increases in brain-derived neurotrophic factor (BDNF) and early growth response factor 3 (Egr3). Elevated levels of GABAA Rα4 messenger RNA (mRNA) and protein were observed following spontaneous seizures, and were associated with higher levels of BDNF and Egr3 mRNA. These data suggest that spontaneous, recurrent seizures that define chronic epilepsy may influence changes in GABAA Rα4 expression, and that signaling pathways known to regulate GABAA Rα4 expression after status epilepticus may also be activated after spontaneous seizures in chronically epileptic animals.
Journal of Neuroscience Research, 2014
Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a pre... more Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro-BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell-signaling pathways, including prosurvival and cell-death machinery in a receptor-specific manner. Pro-BDNF preferentially binds to the p75 neurotrophin receptor (p75(NTR) ), whereas mBDNF is the major ligand of the tropomyosin-related kinase receptor. To elucidate a potential role for p75(NTR) in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small-molecule ligand that binds to p75(NTR) to promote survival signaling and inhibit neuronal cell death. Modulation of early p75(NTR) signaling and its effects on electrographic SE, SE-induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75(NTR) activation during epileptogenesis and in seizure-induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy.
Neurobiology of disease, Jan 11, 2015
In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane... more In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥24h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into t...
Uploads
Papers by Jessica Carlsen