Scholarly Works, Fralin Biomedical Research Institute at VTC

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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.
3D models of glioblastoma interaction with cortical cells
Abedin, Md Joynal; Michelhaugh, Sharon K.; Mittal, Sandeep; Berdichevsky, Yevgeny (Frontiers, 2023-03-09)
Introduction: Glioblastoma (GBM) invasiveness and ability to infiltrate deep into the brain tissue is a major reason for the poor patient prognosis for this type of brain cancer. Behavior of glioblastoma cells, including their motility, and expression of invasion-promoting genes such as matrix metalloprotease-2 (MMP2), are strongly influenced by normal cells found in the brain parenchyma. Cells such as neurons may also be influenced by the tumor, as many glioblastoma patients develop epilepsy. In vitro models of glioblastoma invasiveness are used to supplement animal models in a search for better treatments, and need to combine capability for high-throughput experiments with capturing bidirectional interactions between GBM and brain cells.Methods: In this work, two 3D in vitro models of GBM-cortical interactions were investigated. A matrix-free model was created by co-culturing GBM and cortical spheroids, and a matrix-based model was created by embedding cortical cells and a GBM spheroid in Matrigel.Results: Rapid GBM invasion occurred in the matrix-based model, and was enhanced by the presence of cortical cells. Little invasion occurred in the matrix-free model. In both types of models, presence of GBM cells resulted in a significant increase in paroxysmal neuronal activity.Discussion: Matrix-based model may be better suited for studying GBM invasion in an environment that includes cortical cells, while matrix-free model may be useful in investigation of tumor-associated epilepsy.
A 4-year longitudinal neuroimaging study of cognitive control using latent growth modeling: developmental changes and brain-behavior associations
Kim-Spoon, Jungmeen; Herd, Toria; Brieant, Alexis; Elder, Jacob; Lee, Jacob; Deater-Deckard, Kirby; Casas, Brooks (2021-08-15)
Despite theoretical models suggesting developmental changes in neural substrates of cognitive control in adolescence, empirical research has rarely examined intraindividual changes in cognitive control-related brain activation using multi-wave multivariate longitudinal data. We used longitudinal repeated measures of brain activation and behavioral performance during the multi-source interference task (MSIT) from 167 adolescents (53% male) who were assessed annually over four years from ages 13 to 17 years. We applied latent growth modeling to delineate the pattern of brain activation changes over time and to examine longitudinal associations between brain activation and behavioral performance. We identified brain regions that showed differential change patterns: (1) the fronto-parietal regions that involved bilateral insula, bilateral middle frontal gyrus, left pre-supplementary motor area, left inferior parietal lobule, and right precuneus; and (2) the rostral anterior cingulate cortex (rACC) region. Longitudinal confirmatory factor analyses of the fronto-parietal regions revealed strong measurement invariance across time implying that multivariate functional magnetic resonance imaging data during cognitive control can be measured reliably over time. Latent basis growth models indicated that fronto-parietal activation decreased over time, whereas rACC activation increased over time. In addition, behavioral performance data, age-related improvement was indicated by a decreasing trajectory of intraindividual variability in response time across four years. Testing longitudinal brain-behavior associations using multivariate growth models revealed that better behavioral cognitive control was associated with lower fronto-parietal activation, but the change in behavioral performance was not related to the change in brain activation. The current findings suggest that reduced effects of cognitive interference indicated by fronto-parietal recruitment may be a marker of a maturing brain that underlies better cognitive control performance during adolescence.
A 52-Year-Old HIV-Positive Man with Abdominal Pain
Mehmood, Tashfeen; Chua, Matt J.; Khasawneh, Faisal A. (Hindawi, 2015-01-01)
Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome
Motahari, Zahra; Maynard, Thomas M.; Popratiloff, Anastas; Moody, Sally A.; LaMantia, Anthony-Samuel (2020-09-15)
We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel(+/-) mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior-posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel(+/-). In the additional 22q11.2-related genotypes: Tbx1(+/-), Ranbp1(+/-), Ranbp1(+/-) and LgDel(+/-):Raldh2(+/-); axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.
Aberrant placental immune parameters in the feline immunodeficiency virus (FIV)-infected cat suggest virus-induced changes in T cell function
Chumbley, Lyndon B.; Boudreaux, Crystal E.; Coats, Karen S. (2013-07-19)
Background Immune activity during pregnancy must be tightly regulated to ensure successful pregnancy. This regulation includes the suppression of inflammatory activity that could target the semi-allogeneic fetus. Tregs are immunosuppressive; Th17 cells are pro-inflammatory. A precise balance in the two cell populations is critical to pregnancy maintenance, while dysregulation in this balance accompanies compromised pregnancy in humans and mice. FIV is known to target Tregs preferentially in the infected cat. Therefore, it may be hypothesized that FIV infection alters the placental Treg/Th17 cell balance resulting in aberrant immunomodulator expression by these cells and consequent pregnancy perturbation. Methods RNA was purified from random sections of whole placental tissues collected from both uninfected and FIV-infected queens at early pregnancy, including tissues from viable and nonviable fetuses. Real time qPCR was performed to quantify expression of intranuclear markers of Tregs (FoxP3) and Th17 cells (RORΩ); cytokine products of Tregs (IL-10 and TGF-β), Th17 cells (IL-2, IL-6, and IL-17a), and macrophages (IL-1β); and the FIV gag gene. Pairwise comparisons were made to evaluate coexpression patterns between the cytokines and between the cytokines and the virus. Results Both FoxP3 and RORΩ were reduced in placentas of infected animals. Neither infection status nor fetal viability affected placental expression of IL-1β. However, fetal nonviability was associated with reduced levels of all other cytokines. Infection and fetal nonviability impacted coexpression of various cytokine pairs. No obvious bias toward Treg or Th17 cells was observed. Conclusions FIV infection coupled with fetal nonviability alters expression patterns of T cell cytokines. These data suggest that functionally altered placental T cell leukocyte populations may occur in the infected queen and possibly contribute to fetal nonviability.
Access to Autism Spectrum Disorder Services for Rural Appalachian Citizens
Scarpa, Angela; Jensen, Laura S.; Gracanin, Denis; Ramey, Sharon L.; Dahiya, Angela V.; Ingram, L. Maria; Albright, Jordan; Gatto, Alyssa J.; Scott, Jen Pollard; Ruble, Lisa (2020-01)
Background: Low-resource rural communities face significant challenges regarding availability and adequacy of evidence-based services. Purposes: With respect to accessing evidence-based services for Autism Spectrum Disorder (ASD), this brief report summarizes needs of rural citizens in the South-Central Appalachian region, an area notable for persistent health disparities. Methods: A mixed-methods approach was used to collect quantitative and qualitative data during focus groups with 33 service providers and 15 caregivers of children with ASD in rural southwest Virginia. Results: Results supported the barriers of availability and affordability of ASD services in this region, especially relating to the need for more ASD-trained providers, better coordination and navigation of services, and addition of programs to assist with family financial and emotional stressors. Results also suggested cultural attitudes related to autonomy and trust towards outside professionals that may prevent families from engaging in treatment. Implications: Relevant policy recommendations are discussed related to provider incentives, insurance coverage, and telehealth. Integration of autism services into already existing systems and multicultural sensitivity of providers are also implicated.
Accurate human microsatellite genotypes from high-throughput resequencing data using informed error profiles
Highnam, Gareth; Franck, Christopher T.; Martin, Andy; Stephens, Calvin; Puthige, Ashwin; Mittelman, David (Oxford University Press, 2013-01)
Repetitive sequences are biologically and clinically important because they can influence traits and disease, but repeats are challenging to analyse using short-read sequencing technology. We present a tool for genotyping microsatellite repeats called RepeatSeq, which uses Bayesian model selection guided by an empirically derived error model that incorporates sequence and read properties. Next, we apply RepeatSeq to high-coverage genomes from the 1000 Genomes Project to evaluate performance and accuracy. The software uses common formats, such as VCF, for compatibility with existing genome analysis pipelines. Source code and binaries are available at http://github.com/adaptivegenome/repeatseq.
Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion
Thompson, Emily G.; Sontheimer, Harald (MDPI, 2019-10-05)
Grade IV astrocytomas, or glioblastomas (GBMs), are the most common malignant primary brain tumor in adults. The median GBM patient survival of 12–15 months has remained stagnant, in spite of treatment strategies, making GBMs a tremendous challenge clinically. This is at least in part due to the complex interaction of GBM cells with the brain microenvironment and their tendency to aggressively infiltrate normal brain tissue. GBMs frequently invade supratentorial brain regions that are richly innervated by neurotransmitter projections, most notably acetylcholine (ACh). Here, we asked whether ACh signaling influences the biology of GBMs. We examined the expression and function of known ACh receptors (AChRs) in large GBM datasets, as well as, human GBM cell lines and patient-derived xenograft lines. Using RNA-Seq data from the “The Cancer Genome Atlas” (TCGA), we confirmed the expression of AChRs and demonstrated the functionality of these receptors in GBM cells with time-lapse calcium imaging. AChR activation did not alter cell proliferation or migration, however, it significantly increased cell invasion through complex extracellular matrices. This was due to the enhanced activity of matrix metalloproteinase-9 (MMP-9) from GBM cells, which we found to be dependent on an intracellular calcium-dependent mechanism. Consistent with these findings, AChRs were significantly upregulated in regions of GBM infiltration in situ (Ivy Glioblastoma Atlas Project) and elevated expression of muscarinic AChR M₃ correlated with reduced patient survival (TCGA). Data from the Repository for Molecular Brain Neoplasia Data (REMBRANDT) dataset also showed the co-expression of choline transporters, choline acetyltransferase, and vesicular acetylcholine transporters, suggesting that GBMs express all the proteins required for ACh synthesis and release. These findings identify ACh as a modulator of GBM behavior and posit that GBMs may utilize ACh as an autocrine signaling molecule.
Active inference and agency: optimal control without cost functions
Friston, Karl J.; Samothrakis, Spyridon; Montague, P. Read (Springer, 2012-08-03)
This paper describes a variational free-energy formulation of (partially observable) Markov decision problems in decision making under uncertainty. We show that optimal control can be cast as active inference. In active inference, both action and posterior beliefs about hidden states minimise a free energy bound on the negative log-likelihood of observed states, under a generative model. In this setting, reward or cost functions are absorbed into prior beliefs about state transitions and terminal states. Effectively, this converts optimal control into a pure inference problem, enabling the application of standard Bayesian filtering techniques.We then consider optimal trajectories that rest on posterior beliefs about hidden states in the future. Crucially, this entails modelling control as a hidden state that endows the generative model with a representation of agency. This leads to a distinction between models with and without inference on hidden control states; namely, agency-free and agency-based models, respectively.
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.
Adenovirus transduction to express human ACE2 causes obesity-specific morbidity in mice, impeding studies on the effect of host nutritional status on SARS-CoV-2 pathogenesis
Rai, Pallavi; Chuong, Christina; LeRoith, Tanya; Smyth, James W.; Panov, Julia; Levi, Moshe; Kehn-Hall, Kylene; Duggal, Nisha K.; Weger-Lucarelli, James (Elsevier, 2021-11-01)
The COVID-19 pandemic has paralyzed the global economy and resulted in millions of deaths globally. People with co-morbidities like obesity, diabetes and hypertension are at an increased risk for severe COVID-19 illness. This is of overwhelming concern because 42% of Americans are obese, 30% are pre-diabetic and 9.4% have clinical diabetes. Here, we investigated the effect of obesity on disease severity following SARS-CoV-2 infection using a well-established mouse model of diet-induced obesity. Diet-induced obese and lean control C57BL/6 N mice, transduced for ACE2 expression using replication-defective adenovirus, were infected with SARS-CoV-2, and monitored for lung pathology, viral titers, and cytokine expression. No significant differences in tissue pathology or viral replication was observed between AdV transduced lean and obese groups, infected with SARS-CoV-2, but certain cytokines were expressed more significantly in infected obese mice compared to the lean ones. Notably, significant weight loss was observed in obese mice treated with the adenovirus vector, independent of SARS-CoV-2 infection, suggesting an obesity-dependent morbidity induced by the vector. These data indicate that the adenovirus-transduced mouse model of SARS-CoV-2 infection, as described here and elsewhere, may be inappropriate for nutrition studies.
The adhesion function of the sodium channel beta subunit (beta 1) contributes to cardiac action potential propagation
Veeraraghavan, Rengasayee; Hoeker, Gregory S.; Alvarez-Laviada, Anita; Hoagland, Daniel T.; Wan, Xiaoping; King, D. Ryan; Sanchez-Alonso, Jose; Chen, Chunling; Jourdan, L. Jane; Isom, Lori L.; Deschenes, Isabelle; Smith, James W.; Gorelik, Julia; Poelzing, Steven; Gourdie, Robert G. (2018-08-14)
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that beta 1(SCN1B) - mediated adhesion scaffolds trans-activating Na(V)1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential beta 1 localization at the perinexus, where it co-locates with Na(V)1.5. Smart patch clamp (SPC) indicated greater sodium current density (I-Na) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, beta adp1, potently and selectively inhibited beta 1-mediated adhesion, in electric cell-substrate impedance sensing studies. beta adp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal I-Na, but not whole cell I-Na, in myocyte monolayers. In optical mapping studies, beta adp1 precipitated arrhythmogenic conduction slowing. In summary, beta 1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.
Advances in Behavioral Remote Data Collection in the Home Setting: Assessing the Mother-Infant Relationship and Infant's Adaptive Behavior via Virtual Visits
Shin, Eunkyung; Smith, Cynthia L.; Howell, Brittany R. (Frontiers, 2021-10-01)
Psychological science is struggling with moving forward in the midst of the COVID-19 pandemic, especially due to the halting of behavioral data collection in the laboratory. Safety barriers to assessing psychological behavior in person increased the need for remote data collection in natural settings. In response to these challenges, researchers, including our team, have utilized this time to advance remote behavioral methodology. In this article, we provide an overview of our group’s strategies for remote data collection methodology and examples from our research in collecting behavioral data in the context of psychological functioning. Then, we describe the design and development of our strategies for remote data collection of mother-infant interactions, with the goal being to assess maternal sensitivity and intrusiveness, as well as infants’ adaptive behaviors in several developmental domains. During these virtual visits over Zoom, mother-infant dyads watched a book-reading video and were asked to participate in peek-a-boo, toy play, and toy removal tasks. After the behavioral tasks, a semi-structured interview (Vineland Adaptive Behavior Scale – VABS III) was conducted to assess the infant’s adaptive behavior in communication, socialization, daily living skills, and motor domains. We delineate the specific strategies we applied to integrate laboratory tasks and a semi-structured interview into remote data collection in home settings with mothers and infants. We also elaborate on issues encountered during remote data collection and how we resolved these challenges. Lastly, to inform protocols for future remote data collection, we address considerations and recommendations, as well as benefits and future directions for behavioral researchers in developmental psychology research.
Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable Perception
Dowlati, Ehsan; Adams, Sarah E.; Stiles, Alexandra; Moran, Rosalyn J. (Frontiers, 2016-03-31)
Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to Lingual gyrus (LIN) by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology.
Agrin and Synaptic Laminin Are Required to Maintain Adult Neuromuscular Junctions
Samuel, Melanie; Valdez, Gregorio; Tapia, Juan C.; Lichtman, Jeff W.; Sanes, Joshua R. (PLOS, 2012-10-03)
As synapses form and mature the synaptic partners produce organizing molecules that regulate each other’s differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-a4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.
Alexithymic Trait and Voluntary Control in Healthy Adults
Gu, Xiaosi; Liu, Xun; Guise, Kevin G.; Fossella, John; Wang, Kaiwen; Fan, Jin (PLOS, 2008-11-12)
Background: Alexithymia is a personality trait characterized by deficiency in understanding, processing, or describing emotions. Recent studies have revealed that alexithymia is associated with less activation of the anterior cingulate cortex, a brain region shown to play a role in cognitive and emotional processing. However, few studies have directly investigated the cognitive domain in relation to alexithymia to examine whether alexithymic trait is related to less efficient voluntary control. Methodology/ Principal Findings: We examined the relationship between alexithymic trait and voluntary control in a group of healthy volunteers. We used the 20-item Toronto Alexithymia Scale (TAS-20) to measure alexithymic trait. Additionally, we examined state and trait voluntary control using the revised Attention Network Test (ANT-R) and the Adult Temperament Questionnaire (ATQ), respectively. Alexithymic trait was positively correlated with the overall reaction time of the ANT-R, and negatively correlated with the Effortful Control factor of the ATQ. Conclusions/Significance: Our results suggest that alexithymic trait is associated with less efficient voluntary control.
Almost Everything We Need to Better Serve Children of the Opioid Crisis We Learned in the 80s and 90s
Horn, Kimberly A.; Pack, Robert P.; Trestman, Robert L.; Lawson, Gerard F. (Frontiers, 2018-10-16)
Opioid use disorder impedes dependent parents' abilities to care for their children. In turn, children may languish in unpredictability and persistent chaos. Societal responses to these children are often guided by a belief that unless the drug dependent parent receives treatment, there is little help for the child. While a preponderance of the drug dependence research is adult-centric, a significant body of research demonstrates the importance of not only addressing the immediate well being of the children of drug dependent caregivers but preventing the continuing cycle of drug dependence. The present commentary demonstrates through a brief review of the US history of drug dependence crises and research from the 1980s and 1990s, a range of "tried and true" family, school, and community interventions centered on children. We already know that these children are at high risk of maladjustment and early onset of drug dependence; early intervention is critical; multiple risk factors are likely to occur simultaneously; comprehensive strategies are optimal; and multiple risk-focused strategies are most protective. Where we need now to turn our efforts is on how to effectively implement and disseminate best practices, many of which we learned in the 1980s and 1990s. The greatest opportunity in both changing the nature of the opioid epidemic at scale and influencing rapid translation of existing research findings into policy and practice is not in asking what to do, but in asking how to do the right things well, and quickly.
The ALS-inducing factors, TDP43A315T and SOD1G93A, directly affect and sensitize sensory neurons to stress
Vaughan, Sydney K.; Sutherland, Natalia M.; Zhang, Sihui; Hatzipetros, Theo; Vieira, Fernando; Valdez, Gregorio (Nature, 2018-11-08)
There is increased recognition that sensory neurons located in dorsal root ganglia (DRG) are affected in amyotrophic lateral sclerosis (ALS). However, it remains unknown whether ALS-inducing factors, other than mutant superoxide dismutase 1 (SOD1G93A), directly affect sensory neurons. Here, we examined the effect of mutant TAR DNA-binding protein 1 (TDP43A315T) on sensory neurons in culture and in vivo. In parallel, we reevaluated sensory neurons expressing SOD1G93A. We found that cultured sensory neurons harboring either TDP43A315T or SOD1G93A grow neurites at a slower rate and elaborate fewer neuritic branches compared to control neurons. The presence of either ALS-causing mutant gene also sensitizes sensory neurons to vincristine, a microtubule inhibitor that causes axonal degeneration. Interestingly, these experiments revealed that cultured sensory neurons harboring TDP43A315T elaborate shorter and less complex neurites, and are more sensitive to vincristine compared to controls and to SOD1G93A expressing sensory neurons. Additionally, levels of two molecules involved in stress responses, ATF3 and PERK are significantly different between sensory neurons harboring TDP43A315T to those with SOD1G93A in vitro and in vivo. These findings demonstrate that sensory neurons are directly affected by two ALS-inducing factors, suggesting important roles for this neuronal subpopulation in ALS-related pathogenesis.
Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism
Moran, Rosalyn J.; Mallet, Nicolas; Litvak, Vladimir; Dolan, Raymond J.; Magill, Peter J.; Friston, Karl J.; Brown, Peter (PLOS, 2011-08-11)
Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson’s disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modeling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10–35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modeling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.

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