Scholarly Works, School of Neuroscience

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3D electron microscopy and volume-based bouton sorting reveal the selectivity of inputs onto geniculate relay cell and interneuron dendrite segments
Maher, Erin E.; Briegel, Alex C.; Imtiaz, Shahrozia; Fox, Michael A.; Golino, Hudson; Erisir, Alev (Frontiers, 2023-03)
IntroductionThe visual signals evoked at the retinal ganglion cells are modified and modulated by various synaptic inputs that impinge on lateral geniculate nucleus cells before they are sent to the cortex. The selectivity of geniculate inputs for clustering or forming microcircuits on discrete dendritic segments of geniculate cell types may provide the structural basis for network properties of the geniculate circuitry and differential signal processing through the parallel pathways of vision. In our study, we aimed to reveal the patterns of input selectivity on morphologically discernable relay cell types and interneurons in the mouse lateral geniculate nucleus. MethodsWe used two sets of Scanning Blockface Electron Microscopy (SBEM) image stacks and Reconstruct software to manually reconstruct of terminal boutons and dendrite segments. First, using an unbiased terminal sampling (UTS) approach and statistical modeling, we identified the criteria for volume-based sorting of geniculate boutons into their putative origins. Geniculate terminal boutons that were sorted in retinal and non-retinal categories based on previously described mitochondrial morphology, could further be sorted into multiple subpopulations based on their bouton volume distributions. Terminals deemed non-retinal based on the morphological criteria consisted of five distinct subpopulations, including small-sized putative corticothalamic and cholinergic boutons, two medium-sized putative GABAergic inputs, and a large-sized bouton type that contains dark mitochondria. Retinal terminals also consisted of four distinct subpopulations. The cutoff criteria for these subpopulations were then applied to datasets of terminals that synapse on reconstructed dendrite segments of relay cells or interneurons. ResultsUsing a network analysis approach, we found an almost complete segregation of retinal and cortical terminals on putative X-type cell dendrite segments characterized by grape-like appendages and triads. On these cells, interneuron appendages intermingle with retinal and other medium size terminals to form triads within glomeruli. In contrast, a second, presumed Y-type cell displayed dendrodendritic puncta adherentia and received all terminal types without a selectivity for synapse location; these were not engaged in triads. Furthermore, the contribution of retinal and cortical synapses received by X-, Y- and interneuron dendrites differed such that over 60% of inputs to interneuron dendrites were from the retina, as opposed to 20% and 7% to X- and Y-type cells, respectively. ConclusionThe results underlie differences in network properties of synaptic inputs from distinct origins on geniculate cell types.
Acutely enhancing affective state and social connection following an online dance intervention during the COVID-19 social isolation crisis
Humphries, Ashlee; Tasnim, Noor; Rugh, Rachel; Patrick, Morgan; Basso, Julia C. (2023-01-16)
The COVID-19 pandemic has forced many throughout the world to isolate themselves from their respective communities to stop the spread of disease. Although this form of distancing can prevent the contraction of a virus, it results in social isolation and physical inactivity. Consequently, our communities have become heavily reliant on digital solutions to foster social connection and increase physical activity when forced to isolate. Dance is a multidimensional form of physical activity that includes sensory, motor, cognitive, rhythmic, creative, and social elements. Long-term, interventional studies in dance have shown positive effects on both mental and social health; however, little has been done to examine the acute effects and no studies to date have explored the relationship between the affective state and social outcomes of dance. We examined the hypothesis that online dance is associated with improvements in affective state and social connection during a time of social isolation, namely, the COVID-19 crisis. Healthy adults (age ≥ 18; n = 47) engaged in a single session of 60 min of self-selected online dance, completing a series of validated self-reported questionnaires before and after class. We found that online dance was associated with improvements in affective state as measured by increased positive affect and self-esteem and decreased negative affect and depressive symptoms. Additionally, online dance was associated with improvements in social and community connectedness. Further, we found that those who experienced the largest increases in self-esteem and decreases in negative affect demonstrated the largest gains in social connectivity. Although in-person dance classes may be optimal for formalized dance training, online dance instruction offers an accessible platform that can provide mental and social health benefits during the COVID-19 social isolation crisis. We conclude that through online dance, individuals can experience a connection between the body, mind, and community.
Adenosine Signaling through A1 Receptors Inhibits Chemosensitive Neurons in the Retrotrapezoid Nucleus
James, S. D.; Hawkins, V. E.; Falquetto, B.; Ruskin, D. N.; Masino, S. A.; Moreira, T. S.; Olsen, Michelle L.; Mulkey, D. K. (Society for Neuroscience, 2018)
A subset of neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating depth and frequency of breathing in response to changes in tissue CO2/H. The activity of chemosensitive RTN neurons is also subject to modulation by CO2/H-dependent purinergic signaling. However, mechanisms contributing to purinergic regulation of RTN chemoreceptors are not entirely clear. Recent evidence suggests adenosine inhibits RTN chemoreception in vivo by activation of A1 receptors. The goal of this study was to characterize effects of adenosine on chemosensitive RTN neurons and identify intrinsic and synaptic mechanisms underlying this response. Cell-attached recordings from RTN chemoreceptors in slices from rat or wild-type mouse pups (mixed sex) show that exposure to adenosine (1 M) inhibits chemoreceptor activity by an A1 receptor-dependent mechanism. However, exposure to a selective A1 receptor antagonist (8-cyclopentyl-1,3- dipropylxanthine, DPCPX; 30 nM) alone did not potentiate CO2/H-stimulated activity, suggesting activation of A1 receptors does not limit chemoreceptor activity under these reduced conditions. Whole-cell voltage-clamp from chemosensitive RTN neurons shows that exposure to adenosine activated an inward rectifying K conductance, and at the network level, adenosine preferentially decreased frequency of EPSCs but not IPSCs. These results show that adenosine activation of A1 receptors inhibits chemosensitive RTN neurons by direct activation of a G-protein-regulated inward-rectifier K (GIRK)-like conductance, and presynaptically, by suppression of excitatory synaptic input to chemoreceptors.
Age, but Not Sex, Modulates Foxp3 Expression in the Rat Brain across Development
Taylor, Makenzlie R.; Roby, Clinton R.; Elziny, Soad; Duricy, Erin; Taylor, Tina M.; Bowers, J. Michael (Elsevier, 2020)
The interconnectivity between brain development and the immune system has become an area of interest for many neuroscientists. However, to date, a limited number of known immune mediators of the peripheral nervous system (PNS) have been found to influence the development of the central nervous system (CNS). FOXP3 is a well-established mediator of regulatory T-cells in the PNS. However, the expression pattern of FOXP3 in the CNS and the PNS throughout development is unknown. To fill this void, we have characterized, in several brain regions, the developmental profile of Foxp3 for both sexes using rats. We found different patterns of Foxp3 in the CNS and PNS. In the CNS, we found Foxp3 was ubiquitously expressed, with the levels of Foxp3 varying by brain region. We also found both Foxp3 mRNA and protein levels peak during embryonic development and then steadily decrease with a peak increase during adulthood. In adulthood, the protein but not mRNA increases to the equivalent levels found at the embryonic stage of life. In the PNS, Foxp3 protein levels were low embryonically and increased steadily over the life of the animal with maximal levels reached in adulthood. Patterns observed for both the PNS and CNS were similar in males and females across all developmental timepoints. Our novel findings have implications for understanding how the neural immune system impacts neurodevelopmental disorders such as autism and schizophrenia.
Age-Related Intrinsic Functional Connectivity Changes of Locus Coeruleus from Childhood to Older Adults
Song, Inuk; Neal, Joshua; Lee, Tae-Ho (MDPI, 2021-11-10)
The locus coeruleus is critical for selective information processing by modulating the brain’s connectivity configuration. Increasingly, studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has shown that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the unoptimized LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using a public fMRI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study.
Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome
Kiraly, D. D.; Horn, S. R.; Van Dam, N. T.; Costi, S.; Schwartz, J.; Kim-Schulze, S.; Patel, M.; Hodes, Georgia E.; Russo, Scott J.; Merad, Miriam; Iosifescu, D. V.; Charney, D. S.; Murrough, J.W. (2017-03-21)
A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg-1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Antibiotic exposure is associated with decreased risk of psychiatric disorders
Kerman, Ilan A.; Glover, Matthew E.; Lin, Yezhe; West, Jennifer L.; Hanlon, Alexandra L.; Kablinger, Anita S.; Clinton, Sarah M. (Frontiers, 2024-01-08)
Objective: This study sought to investigate the relationship between antibiotic exposure and subsequent risk of psychiatric disorders. Methods: This retrospective cohort study used a national database of 69 million patients from 54 large healthcare organizations. We identified a cohort of 20,214 (42.5% male; 57.9 ± 15.1 years old [mean ± SD]) adults without prior neuropsychiatric diagnoses who received antibiotics during hospitalization. Matched controls included 41,555 (39.6% male; 57.3 ± 15.5 years old) hospitalized adults without antibiotic exposure. The two cohorts were balanced for potential confounders, including demographics and variables with potential to affect: the microbiome, mental health, medical comorbidity, and overall health status. Data were stratified by age and by sex, and outcome measures were assessed starting 6 months after hospital discharge. Results: Antibiotic exposure was consistently associated with a significant decrease in the risk of novel mood disorders and anxiety and stressor-related disorders in: men (mood (OR 0.84, 95% CI 0.77, 0.91), anxiety (OR 0.88, 95% CI 0.82, 0.95), women (mood (OR 0.94, 95% CI 0.89,1.00), anxiety (OR 0.93, 95% CI 0.88, 0.98), those who are 26–49 years old (mood (OR 0.87, 95% CI 0.80, 0.94), anxiety (OR 0.90, 95% CI 0.84, 0.97)), and in those ≥50 years old (mood (OR 0.91, 95% CI 0.86, 0.97), anxiety (OR 0.92, 95% CI 0.87, 0.97). Risk of intentional harm and suicidality was decreased in men (OR 0.73, 95% CI 0.55, 0.98) and in those ≥50 years old (OR 0.67, 95% CI 0.49, 0.92). Risk of psychotic disorders was also decreased in subjects ≥50 years old (OR 0.83, 95 CI: 0.69, 0.99). Conclusion: Use of antibiotics in the inpatient setting is associated with protective effects against multiple psychiatric outcomes in an age- and sex-dependent manner.
Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy
Browning, Jack L.; Wilson, Kelsey A.; Shandra, Oleksii; Wei, Xiaoran; Mahmutovic, Dzenis; Maharathi, Biswajit; Robel, Stefanie; VandeVord, Pamela J.; Olsen, Michelle L. (MDPI, 2024-03-01)
Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE⁺), those without epilepsy (PTE⁻), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE⁺ and PTE⁻ relative to sham. Focusing on protein pathways unique to PTE⁺, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE⁻. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.
Assessing Human Spatial Navigation in a Virtual Space and its Sensitivity to Exercise
Smith, Alana J.; Tasnim, Noor; Psaras, Zach; Gyamfi, Daphne; Makani, Krishna; Suzuki, Wendy A.; Basso, Julia C. (MyJove Corporation, 2024-01-26)
Spatial navigation (SN) is the ability to locomote through the environment, which requires an understanding of where one is located in time and space. This capacity is known to rely on the sequential firing of place cells within the hippocampus. SN is an important behavior to investigate as this process deteriorates with age, especially in neurodegenerative disorders. However, the investigation of SN is limited by the lack of sophisticated behavioral techniques to assess this hippocampal-dependent task. Therefore, the goal of this protocol was to develop a novel, real-world approach to studying SN in humans. Specifically, an active virtual SN task was developed using a cross-platform game engine. During the encoding phase, participants navigated their way through a virtual city to locate landmarks. During the remembering phase, participants remembered where these reward locations were and delivered items to these locations. Time to find each location was captured and episodic memory was assessed by a free recall phase, including aspects of place, order, item, and association. Movement behavior (x, y, and z coordinates) was assessed through an asset available in the game engine. Importantly, results from this task demonstrate that it accurately captures both spatial learning and memory abilities as well as episodic memory. Further, findings indicate that this task is sensitive to exercise, which improves hippocampal functioning. Overall, the findings suggest a novel way to track human hippocampal functioning over the course of time, with this behavior being sensitive to physical activity training paradigms.
Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness
Zhu, Jackie; Hawkins, Elisa; Phillips, Kristin; Deshpande, Laxmikant S. (MDPI, 2020-06-30)
Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.
Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1
Holt, Leanne M.; Hernandez, Raymundo D.; Pacheco, Natasha L.; Ceja, Beatriz Torres; Hossain, Muhannah; Olsen, Michelle L. (2019-08-21)
Brain-derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of the CNS, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF's receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1, which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1, globally and astrocyte-specifically, in mice revealed morphologically immature astrocytes with significantly reduced volume, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte function. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis or function. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.
Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy
Gudenschwager-Basso, Erwin Kristobal; Shandra, Oleksii; Volanth, Troy; Patel, Dipan C.; Kelly, Colin; Browning, Jack L.; Wei, Xiaoran; Harris, Elizabeth A.; Mahmutovic, Dzenis; Kaloss, Alexandra M.; Correa, Fernanda Guilhaume; Decker, Jeremy; Maharathi, Biswajit; Robel, Stefanie; Sontheimer, Harald; VandeVord, Pamela J.; Olsen, Michelle L.; Theus, Michelle H. (MDPI, 2023-04-25)
Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus—a structure that is highly susceptible to injury—has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2–4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE⁺) vs. those animals that did not (PTE⁻), which may be associated with epileptogenesis. Results: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE⁺ compared to PTE⁻ mice. We uniquely identified Cst3 as a PTE⁺-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE⁺ hilus. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.
Biomolecules Triggering Altered Food Intake during Pathogenic Challenge in Chicks
Tachibana, Tetsuya; Cline, Mark A. (Japan Poultry Science Association, 2023-04)
Food intake is regulated by several complicated synergistic mechanisms that are affected by a variety of internal and ex-ternal influences. Some of these factors include those that are released from pathogens such as bacteria, fungi, and viruses, and most of these factors are associated with suppression of the chick's food intake. Although chicks are well-known to decrease their food intake when they experience a pathogenic challenge, the mechanisms that mediate this type of satiety are poorly understood. One of the goals of our research group has been to better understand these mechanisms in chicks. We recently provided evidence that pathogen-associated molecular patterns, which are recognized by pattern-recognition receptors such as Toll-like receptors, likely contribute to satiety in chicks that are experiencing a pathogenic challenge. Additionally, we identified several inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor-like cytokine 1A, prostaglandins, and nitric oxide, that likely contribute to satiety during a pathogenic challenge. This review summarizes the current knowl-edge on pathogen-induced satiety in chicks mainly accumulated through our recent research. The research will give good information to improve the loss of production during infection in poultry production in the future.
Brain Similarity as a Protective Factor in the Longitudinal Pathway Linking Household Chaos, Parenting, and Substance Use
Kim-Spoon, Jungmeen; Lee, Tae-Ho; Clinchard, Claudia; Lindenmuth, Morgan; Brieant, Alexis; Steinberg, Laurence; Deater-Deckard, Kirby; Casas, Brooks (Elsevier, 2023-04-29)
Background: Socioecological factors such as family environment and parenting behaviors contribute to the development of substance use. While biobehavioral synchrony has been suggested as the foundation for resilience that can modulate environmental effects on development, the role of brain similarity that attenuates deleterious effects of environmental contexts has not been clearly understood. We tested whether parent-adolescent neural similarity—the level of pattern similarity between parent-adolescent functional brain connectivity representing the level of attunement within each dyad—moderates the longitudinal pathways in which household chaos (a stressor) predicts adolescent substance use directly and indirectly via parental monitoring. Methods: In a sample of 70 parent-adolescent dyads, similarity in resting-state brain activity was identified using multipattern connectivity similarity estimation. Adolescents and parents reported on household chaos and parental monitoring, and adolescent substance use was assessed at a 1-year follow-up. Results: The moderated mediation model indicated that for adolescents with low neural similarity, but not high neural similarity, greater household chaos predicted higher substance use over time directly and indirectly via lower parental monitoring. Our data also indicated differential susceptibility in the overall association between household chaos and substance use: Adolescents with low neural similarity exhibited high substance use under high household chaos but low substance use under low household chaos. Conclusions: Neural similarity acts as a protective factor such that the detrimental effects of suboptimal family environment and parenting behaviors on the development of adolescent health risk behaviors may be attenuated by neural similarity within parent-adolescent bonds.
Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy
Patel, Dipan C.; Thompson, Emily G.; Sontheimer, Harald (Frontiers, 2022-07-08)
Well over 100 different viruses can infect the brain and cause brain inflammation. In the developing world, brain inflammation is a leading cause for epilepsy and often refractory to established anti-seizure drugs. Epilepsy generally results from an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission. GABAergic inhibition is determined by the intracellular Cl- concentration which is established through the opposing action of two cation chloride cotransporters namely NKCC1 and KCC2. Brain-derived neurotrophic factor (BDNF) signaling is known to regulate expression of KCC2. Hence we hypothesized that viral induced epilepsy may result from aberrant BDNF signaling. We tested this hypothesis using a mouse model of Theiler's murine encephalomyelitis virus (TMEV) infection-induced epilepsy. We found that BDNF levels in the hippocampus from TMEV-infected mice with seizures was increased at the onset of acute seizures and continued to increase during the peak of acute seizure as well as in latent and chronic phases of epilepsy. During the acute phase of epilepsy, we found significant reduction in the expression of KCC2 in hippocampus, whereas the level of NKCC1 was unaltered. Importantly, inhibiting BDNF using scavenging bodies of BDNF in live brain slices from TMEV-infected mice with seizures normalized the level of KCC2 in hippocampus. Our results suggest that BDNF can directly decrease the relative expression of NKCC1 and KCC2 such as to favor accumulation of chloride intracellularly which in turn causes hyperexcitability by reversing GABA-mediated inhibition. Although our attempt to inhibit the BDNF signaling mediated through tyrosine kinase B-phospholipase C gamma 1 (TrkB-PLC gamma 1) using a small peptide did not change the course of seizure development following TMEV infection, alternative strategies for controlling the BDNF signaling could be useful in preventing seizure generation and development of epilepsy in this model.
Building Interdisciplinary Partnerships for Community-Engaged Environmental Health Research in Appalachian Virginia
Satterwhite, Emily M.; Bell, Shannon E.; Marr, Linsey C.; Thompson, Christopher K.; Prussin, Aaron J. II; Buttling, Lauren G.; Pan, Jin; Gohlke, Julia M. (MDPI, 2020-03-05)
This article describes a collaboration among a group of university faculty, undergraduate students, local governments, local residents, and U.S. Army staff to address long-standing concerns about the environmental health effects of an Army ammunition plant. The authors describe community-responsive scientific pilot studies that examined potential environmental contamination and a related undergraduate research course that documented residents’ concerns, contextualized those concerns, and developed recommendations. We make a case for the value of resource-intensive university–community partnerships that promote the production of knowledge through collaborations across disciplinary paradigms (natural/physical sciences, social sciences, health sciences, and humanities) in response to questions raised by local residents. Our experience also suggests that enacting this type of research through a university class may help promote researchers’ adoption of “epistemological pluralism”, and thereby facilitate the movement of a study from being “multidisciplinary” to “transdisciplinary”.
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).
A cell–ECM mechanism for connecting the ipsilateral eye to the brain
Su, Jianmin; Sabbagh, Ubadah; Liang, Yanping; Olejníková, Lucie; Dixon, Karen G.; Russell, Ashley L.; Chen, Jiang; Pan, Yuchin Albert; Triplett, Jason W.; Fox, Michael A. (National Academy of Sciences, 2021-10-15)
Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.
Central Taurine Attenuates Hyperthermia and Isolation Stress Behaviors Augmented by Corticotropin-Releasing Factor with Modifying Brain Amino Acid Metabolism in Neonatal Chicks
Elhussiny, Mohamed Z.; Tran, Phuong V.; Tsuru, Yuriko; Haraguchi, Shogo; Gilbert, Elizabeth R.; Cline, Mark A.; Bungo, Takashi; Furuse, Mitsuhiro; Chowdhury, Vishwajit S. (MDPI, 2022-01-16)
The objective of this study was to determine the effects of centrally administered taurine on rectal temperature, behavioral responses and brain amino acid metabolism under isolation stress and the presence of co-injected corticotropin-releasing factor (CRF). Neonatal chicks were centrally injected with saline, 2.1 pmol of CRF, 2.5 μmol of taurine or both taurine and CRF. The results showed that CRF-induced hyperthermia was attenuated by co-injection with taurine. Taurine, alone or with CRF, significantly decreased the number of distress vocalizations and the time spent in active wakefulness, as well as increased the time spent in the sleeping posture, compared with the saline- and CRF-injected chicks. An amino acid chromatographic analysis revealed that diencephalic leucine, isoleucine, tyrosine, glutamate, asparagine, alanine, β-alanine, cystathionine and 3-methylhistidine were decreased in response to taurine alone or in combination with CRF. Central taurine, alone and when co-administered with CRF, decreased isoleucine, phenylalanine, tyrosine and cysteine, but increased glycine concentrations in the brainstem, compared with saline and CRF groups. The results collectively indicate that central taurine attenuated CRF-induced hyperthermia and stress behaviors in neonatal chicks, and the mechanism likely involves the repartitioning of amino acids to different metabolic pathways. In particular, brain leucine, isoleucine, cysteine, glutamate and glycine may be mobilized to cope with acute stressors.
Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor
van der Heijden, Meike E.; Brown, Amanda M.; Kizek, Dominic J.; Sillitoe, Roy (eLife, 2024-07-29)
The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.

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