School of Neuroscience

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Case study on the use of intensive pediatric neurorehabilitation in the treatment of kernicterus
Mann, Jessie; Wallace, Dory A.; DeLuca, Stephanie C. (2020-02-03)
Background Kernicterus Spectrum Disorder (KSD) is the result of prolonged bilirubin toxicity resulting in widespread neurological injury. Once the bilirubin levels are normalized the encephalopathy becomes static, however the consequences of the injury can have life-long effects. The sequelae of KSD include motor impairments, auditory deficits, dental dysplasia, and potentially cognitive impairments. While KSD is a rare diagnosis, particularly in developed countries, there is evidence that there may be a global increase in incidence (Hansen, Semin Neonatol 7:103–9, 2002; Johnson, J Perinatol 29:S25–45, 2009; Kaplan etal. Neonatology 100:354–62, 2011; Maisels, Early Hum Dev 85:727–32, 2009; Olusanya etal., Arch Dis Child 99:1117–21, 2014; Steffensrud, Newborn Infant Nurs Rev 4:191–200, 2004). The literature on the treatment of various specific sequelae of KSD is varied, but in general specific therapeutic efforts to improve motor skills are not evidenced-based. The following is a case report on the use of Acquire therapy, an intensive neuromotor intervention, to ameliorate some of the motor-function deficits secondary to KSD. Case presentation This case-report presents the results of two intensive therapeutic intervention sessions in one male child with KSD. Treatments occurred at 28 and 34 months. The child presented with fine and gross motor deficits as well as communication delays. Each session consisted of daily therapy for 4 h each weekday for 3 weeks. The child was assessed before and after treatment with 2 standardized measures, the Gross Motor Function Measure (GMFM) and The Bayley Scales of Infant and Toddler Development (Bayley). Conclusions The GMFM at the 1st assessment was 34, 74at the 2nd assessment (after intervention 1), and 64 at the third assessment and 104 at the 4th assessment (after intervention 2). The Bayley at the 3rd assessment was 18, and 38 at the 4th assessment (after intervention 2).
Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats
Cohen, Joshua L.; Ata, Anoosha E.; Jackson, Nateka L.; Rahn, Elizabeth J.; Ramaker, Ryne C.; Cooper, Sara; Kerman, Ilan A.; Clinton, Sarah M. (2017-02)
Chronic stress triggers a variety of physical and mental health problems, and how individuals 2 cope with stress influences risk for emotional disorders. To investigate molecular mechanisms 3 underlying distinct stress coping styles, we utilized rats that were selectively-bred for differences 4 in emotionality and stress reactivity. We show that high novelty responding (HR) rats readily 5 bury a shock probe in the defensive burying test, a measure of proactive stress coping behavior, 6 while low novelty responding (LR) rats exhibit enhanced immobility, a measure of reactive 7 coping. Shock exposure in the defensive burying test elicited greater activation of HR rats’ 8 caudal dorsal raphe serotonergic cells compared to LRs, but lead to more pronounced 9 activation throughout LRs’ amygdala (lateral, basolateral, central, and basomedial nuclei) 10 compared to HRs. RNA-sequencing revealed 271 mRNA transcripts and 33 microRNA species 11 that were differentially expressed in HR/LR raphe and amygdala. We mapped potential 12 microRNA-mRNA networks by correlating and clustering mRNA and microRNA expression and 13 identified networks that differed in either the HR/LR dorsal raphe or amygdala. A dorsal raphe 14 network linked three microRNAs which were down-regulated in LRs (miR-206-3p, miR-3559-5p, 15 and miR-378a-3p) to repression of genes related to microglia and immune response (Cd74, 16 Cyth4, Nckap1l, and Rac2), the genes themselves were up-regulated in LR dorsal raphe. In the 17 amygdala, another network linked miR-124-5p, miR-146a-5p, miR-3068-3p, miR-380-5p, miR-18 539-3p, and miR-7a-1-3p with repression of chromatin remodeling-related genes (Cenpk, 19 Cenpq, Itgb3bp, and Mis18a). Overall this work highlights potential drivers of gene-networks 20 and downstream molecular pathways within the raphe and amygdala that contribute to 21 individual differences in stress coping styles and stress vulnerabilities.
Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus
Sabbagh, Ubadah; Govindaiah, Gubbi; Somaiya, Rachana D.; Ha, Ryan V.; Wei, Jessica C.; Guido, William; Fox, Michael A. (Wiley, 2020-05-19)
In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation
Navabpour, Shaghayegh; Rogers, Jessie; McFadden, Taylor; Jarome, Timothy J. (MDPI, 2020-11-26)
Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.
Gut metabolite S-equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus-induced acute seizures
Gallucci, Allison; Patel, Dipan C.; Thai, K'Ehleyr; Trinh, Jonathan; Gude, Rosalie; Shukla, Devika; Campbell, Susan L. (2021-07-02)
Objective A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. Methods We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. Results We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. Significance Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.
Mental Health and Social Development Effects of the Abecedarian Approach
Sparling, Joseph; Ramey, Sharon L.; Ramey, Craig T. (MDPI, 2021-06-30)
The Abecedarian Approach is an early intervention and contains a broad-spectrum adult/child curriculum. The Approach has been studied in three longitudinal randomized controlled trials in the USA, starting in 1972 and continuing today. Recent research studies in multiple countries have examined the Abecedarian Approach during the first three years of life. The collective findings from these studies lead to the conclusion that human development is malleable, especially in the years before school entry, and that high-quality early intervention exerts positive, early, and long-lasting influences on human development, including social development and mental health.
Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress-reactive Wistar Kyoto rats
McCoy, Chelsea R.; Rana, Samir; Stringfellow, Sara anne; Day, Jeremy; Wyss, J. Michael; Clinton, Sarah M.; Kerman, Ilan A. (Wiley-Blackwell, 2016-11-01)
Early-life stress (ELS) can alter neurodevelopment in variable ways, ranging from producing deleterious outcomes to stress resilience. While most ELS studies focus on its harmful effects, recent work by our lab and others shows that ELS elicits positive effects in certain individuals. We exposed Wistar-Kyoto (WKY) rats, known for a stress reactive, anxiety-/depression-like phenotype, to maternal separation (MS), a model of ELS. MS exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult WKY offspring. The present study interrogates an epigenetic mechanism (DNA methylation) that may confer the adaptive effects of MS in WKY offspring. We quantified global genome methylation levels in limbic brain regions of adult WKYs exposed to daily 180-min MS or neonatal handling from postnatal day 1-14. MS exposure triggered dramatic DNA hypermethylation specifically in the hippocampus. Next-generation sequencing methylome profiling revealed reduced methylation at intragenic sites within two key nodes of insulin signaling pathways: the insulin receptor and one of its major downstream targets, mitogen activated protein kinase kinase kinase 5 (Map3k5). We then tested the hypothesis that enhancing DNA methylation in WKY rats would elicit adaptive changes akin to the effects of MS. Dietary methyl donor supplementation improved WKY rats’ anxiety/depression-like behaviors and also improved cardiovascular measures, similar to previous observations following MS. Overall these data suggest a potential molecular mechanism that mediates a predicted adaptive response whereby ELS induces DNA methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood.
Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy
Tewari, Bhanu P.; Chaunsali, Lata; Campbell, Susan L.; Patel, Dipan C.; Goode, Adam E.; Sontheimer, Harald (Springer Nature, 2018-11-09)
Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits.
Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes
Campbell, Susan C.; Muñoz-Ballester, Carmen; Chaunsali, Lata; Mills, William A.; Yang, Jennifer H.; Sontheimer, Harald; Robel, Stefanie (Elsevier, 2019-12-09)
Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.
Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro
Swartwout, Brianna K.; Zlotnick, Marta G.; Saver, Ashley E.; McKenna, Caroline M.; Bertke, Andrea S. (MDPI, 2017-10-13)
Zika virus (ZIKV) has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

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