Neurosciences Commons^™

Determinants Of Occupational Injuries Among Building Construction Workers In Kampala City, Uganda, Arthur Kiconco, Nathan Ruhinda, Abdullah Ali Halage, Stephen Watya, William Bazeyo, John C. Ssempebwa, Joseph Byonanebye

Biomedical Sciences Faculty Research and Publications

Background

Globally, about 1000 people die and close to 860,000 people sustain injury at work daily. Injury prevention and control require contextual evidence, although most studies in Uganda have focused on general causes. Factors associated with occupational injuries among building construction workers were assessed in this study.

Methods

A cross-sectional study among building construction workers was conducted in Kampala, Uganda. A standardized semi-structured questionnaire was used to collect data. Three hundred nineteen (319) participants were randomly and proportionately selected from 57 construction sites. Descriptive statistics were used to describe the variables while generalized linear modeling was used to estimate the …

Mice, Acorns, And Lyme Disease: A Case Study To Teach The Ecology Of Emerging Infectious Diseases, Laurieann Klockow

Biomedical Sciences Faculty Research and Publications

Ebola, Zika, the recall of contaminated lettuce - these are just a few recent outbreaks making headlines. Students should be able to connect what they learn in their biology courses to explain these events happening around them. Unfortunately, students do not necessarily make those connections. Therefore, it is important, as instructors, to provide opportunities where students engage with societal issues and problems related to course content and case studies, using headlines from the news are one way to do this.

Here I describe a case study about Lyme disease that engages students in learning about the ecology of infectious disease. …

Prefrontal-Accumbens Opioid Plasticity: Implications For Relapse And Dependence, Matthew C. Hearing

Biomedical Sciences Faculty Research and Publications

In addiction, an individual’s ability to inhibit drug seeking and drug taking is thought to reflect a pathological strengthening of drug-seeking behaviors or impairments in the capacity to control maladaptive behavior. These processes are not mutually exclusive and reflect drug-induced modifications within prefrontal cortical and nucleus accumbens circuits, however unlike psychostimulants such as cocaine, far less is known about the temporal, anatomical, and cellular dynamics of these changes. We discuss what is known regarding opioid-induced adaptations in intrinsic membrane physiology and pre-/postsynaptic neurotransmission in principle pyramidal and medium spiny neurons in the medial prefrontal cortex and nucleus accumbens from electrophysiological …

Global Connectivity And Function Of Descending Spinal Input Revealed By 3d Microscopy And Retrograde Transduction, Zimei Wang, Brian Maunze, Yunfang Wang, Pantelis Tsoulfas, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

The brain communicates with the spinal cord through numerous axon tracts that arise from discrete nuclei, transmit distinct functions, and often collateralize to facilitate the coordination of descending commands. This complexity presents a major challenge to interpreting functional outcomes from therapies that target supraspinal connectivity after injury or disease, while the wide distribution of supraspinal nuclei complicates the delivery of therapeutics. Here we harness retrograde viral vectors to overcome these challenges. We demonstrate that injection of AAV2-Retro to the cervical spinal cord of adult female mice results in highly efficient transduction of supraspinal populations throughout the brainstem, midbrain, and cortex. …

Developmental Chromatin Restriction Of Pro‐Growth Gene Networks Acts As An Epigenetic Barrier To Axon Regeneration In Cortical Neurons, Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Ben Califf, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age‐dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome‐wide maps of chromatin accessibility. When applied …

Organic Cation Transporter 3: A Cellular Mechanism Underlying Rapid, Non-Genomic Glucocorticoid Regulation Of Monoaminergic Neurotransmission, Physiology, And Behavior, Paul J. Gasser, Christopher A. Lowry

Biomedical Sciences Faculty Research and Publications

Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by “uptake₂” transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits …

Pituitary Adenylate Cyclase-Activating Polypeptide (Pacap) Signaling In The Prefrontal Cortex Modulates Cued Fear Learning, But Not Spatial Working Memory, In Female Rats, Adam J. Kirry, Matthew R. Herbst, Sarah E. Poirier, Michelle M. Maskeri, Amy C. Rothwell, Robert C. Twining, Marieke R. Gilmartin

Biomedical Sciences Faculty Research and Publications

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to …

Endogenous Dopamine And Endocannabinoid Signaling Mediate Cocaine-Induced Reversal Of Ampar Synaptic Potentiation In The Nucleus Accumbens Shell, Anna E. Ingebretson, Matthew C. Hearing, Ethan D. Huffington, Mark J. Thomas

Biomedical Sciences Faculty Research and Publications

Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within meso-corticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During a 10–14 day period of abstinence from cocaine, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, rapidly reverses and depotentiates enhanced AMPAR signaling. To understand how re-exposure to cocaine alters AMPAR synaptic transmission, we investigated the roles of dopamine …

Kappa Counterconditioning Of Cocaine Cues, John R. Mantsch, Robert C. Twining

Biomedical Sciences Faculty Research and Publications

No abstract provided.

Klf6 And Stat3 Co-Occupy Regulatory Dna And Functionally Synergize To Promote Axon Growth In Cns Neurons, Zimei Wang, Vatsal Mehra, Matthew T. Simpson, Brian Maunze, Dan C. Eastwood, Lyndsey Holan, Murray G. Blackmore, Ishwariya Venkatesh

Biomedical Sciences Faculty Research and Publications

The failure of axon regeneration in the CNS limits recovery from damage and disease. Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration, but the underlying mechanisms are unclear. Here we show that forced expression of KLF6 promotes axon regeneration by corticospinal tract neurons in the injured spinal cord. RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in vitro, including sub-networks that were highly enriched for functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis, and bioenergetics. In addition, promoter analysis predicted a functional interaction …

What Does The Fos Say? Using Fos-Based Approaches To Understand The Contribution Of Stress To Substance Use Disorders, Jayme R. Mcreynolds, John P. Christianson, Jordan M. Blacktop, John Mantsch

Biomedical Sciences Faculty Research and Publications

Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity …

17Β-Estradiol Potentiates The Reinstatement Of Cocaine Seeking In Female Rats: Role Of The Prelimbic Prefrontal Cortex And Cannabinoid Type-1 Receptors, Elizabeth M. Doncheck, Luke A. Urbanik, Margot C. Debaker, Laura M. Barron, Gage T. Liddiard, Jennifer J. Tuscher, Karyn M. Frick, Cecilia J. Hillard, John Mantsch

Biomedical Sciences Faculty Research and Publications

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose …

Transport Of Bmaa Into Neurons And Astrocytes By System XC-, Rebecca Albano, Doug Lobner

Biomedical Sciences Faculty Research and Publications

The study of the mechanism of β-N-methylamino-l-alanine (BMAA) neurotoxicity originally focused on its effects at the N-methyl-d-aspartate (NMDA) receptor. In recent years, it has become clear that its mechanism of action is more complicated. First, there are certain cell types, such as motor neurons and cholinergic neurons, where the dominate mechanism of toxicity is through action at AMPA receptors. Second, even in cortical neurons where the primary mechanism of toxicity appears to be activation of NMDA receptors, there are other mechanisms involved. We found that along with NMDA receptors, activation of mGLuR5 receptors and effects on the …

The Opiod Epidemic: Clinical Dental Update, Matthew Hearing

Biomedical Sciences Faculty Research and Publications

No abstract provided.

Role Of Membrane Gm1 On Early Neuronal Membrane Actions Of Aβ During Onset Of Alzheimer's Disease, E. J. Fernandez-Perez, Fernando Sepulveda, Robert W. Peoples, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The ability of beta-amyloid peptide (Aβ) to disrupt the plasma membrane through formation of pores and membrane breakage has been previously described. However, the molecular determinants for these effects are largely unknown. In this study, we examined if the association and subsequent membrane perforation induced by Aβ was dependent on GM1levels. Pretreatment of hippocampal neurons with D-PDMP decreased GM1 and Aβ clustering at the membrane (Aβ fluorescent-punctas/20 μm, control = 16.2 ± 1.1 vs. D-PDMP = 6.4 ± 0.4, p < 0.001). Interestingly, membrane perforation with Aβ occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control = 7.8 ± 2 vs. low GM1 = 12.1 ± 0.5, p < 0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by Aβ. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control = 7.8 ± 2 vs. GM1 = 6.2 ± 1 min, p < 0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of Aβ with GM1 attenuated membrane perforation significantly. Furthermore, …

Corticosterone Regulates Both Naturally Occurring And Cocaine‐Induced Dopamine Signaling By Selectively Decreasing Dopamine Uptake, Daniel S. Wheeler, Amanda L. Ebben, Beliz Kurtoglu, Marissa E. Lovell, Austin T. Bohn, Isabella A. Jasek, David A. Baker, John R. Mantsch, Paul J. Gasser, Robert A. Wheeler

Biomedical Sciences Faculty Research and Publications

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic …

Extending The Family: Roles For Uptake2 Transporters In Regulation Of Monoaminergic Signaling, Paul J. Gasser, Lynette C. Daws

Biomedical Sciences Faculty Research and Publications

No abstract provided.

Editorial For The Special Issue: Monoamine Transporters In Health And Disease, Paul J. Gasser, Lynette C. Daws

Biomedical Sciences Faculty Research and Publications

No abstract provided.

Organic Cation Transporter 3 (Oct3) Is Localized To Intracellular And Surface Membranes In Select Glial And Neuronal Cells Within The Basolateral Amygdaloid Complex Of Both Rats And Mice, Paul J. Gasser, Matthew M. Hurley, June Chan, Virginia M. Pickel

Biomedical Sciences Faculty Research and Publications

Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates corticosterone-sensitive uptake of monoamines including norepinephrine, epinephrine, dopamine, histamine and serotonin. OCT3 is expressed widely throughout the amygdaloid complex and other brain regions where monoamines are key regulators of emotional behaviors affected by stress. However, assessing the contribution of OCT3 to the regulation of monoaminergic neurotransmission and monoamine-dependent regulation of behavior requires fundamental information about the subcellular distribution of OCT3 expression. We used immunofluorescence and immuno-electron microscopy to examine the cellular and subcellular distribution of the transporter in the basolateral amygdaloid complex of the rat and mouse brain. …

The Application Of Crispr Technology To High Content Screening In Primary Neurons, Ben L. Callif, Brian Maunze, Nick L. Krueger, Matthew T. Simpson, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Axon growth is coordinated by multiple interacting proteins that remain incompletely characterized. High content screening (HCS), in which manipulation of candidate genes is combined with rapid image analysis of phenotypic effects, has emerged as a powerful technique to identify key regulators of axon outgrowth. Here we explore the utility of a genome editing approach referred to as CRISPR (Clustered Regularly Interspersed Palindromic Repeats) for knockout screening in primary neurons. In the CRISPR approach a DNA-cleaving Cas enzyme is guided to genomic target sequences by user-created guide RNA (sgRNA), where it initiates a double-stranded break that ultimately results in frameshift mutation …

Combined Chondroitinase And Klf7 Expression Reduce Net Retraction Of Sensory And Cst Axons From Sites Of Spinal Injury, Zimei Wang, Kristen N. Winsor, Evan Hess, Murray G. Blackmore, Christopher Nienhaus

Biomedical Sciences Faculty Research and Publications

Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Krüppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here …

Corticosterone Potentiation Of Cocaine-Induced Reinstatement Of Conditioned Place Preference In Mice Is Mediated By Blockade Of The Organic Cation Transporter 3, Jayme R. Mcreynolds, Analisa Taylor, Oliver Vranjkovic, Terra Ambrosius, Olivia Derricks, Brittany Nino, Beliz Kurtoglu, Robert A. Wheeler, David A. Baker, Paul J. Gasser, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using …

Long Days Enhance Recognition Memory And Increase Insulin-Like Growth Factor 2 In The Hippocampus, Adriano Dellapolla, Ian Kloehn, Harshida Pancholi, Ben L. Callif, David Wertz, Kayla Rohr, Matthew M. Hurley, Kimberly Baker, Samer Hattar, Marieke R. Gilmartin, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered …

Selecting Optimal Combinations Of Transcription Factors To Promote Axon Regeneration: Why Mechanisms Matter, Ishwariya Venkatesh, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low ability of many CNS neurons to mount an effective regenerative growth response. To improve outcomes, it is essential to understand and ultimately reverse these neuron-intrinsic constraints. Genetic manipulation of key transcription factors (TFs), which act to orchestrate production of multiple regeneration-associated genes, has emerged as a promising strategy. It is likely that no single TF will be sufficient to fully restore neuron-intrinsic growth potential, and that multiple, functionally interacting factors will be needed. An extensive literature, mostly from non-neural cell …

Epigenetic Profiling Reveals A Developmental Decrease In Promoter Accessibility During Cortical Maturation In Vivo, Ishwariya Venkatesh, Matthew T. Simpson, Denise M. Coley, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve …

Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- And Palatability-Induced Binge Eating, Matthew M. Hurley, Brian Maunze, Megan E. Block, Michael J. Reilly, Eugene Kim, Yao Chen, Yan Li, David A. Baker, Qing-Song Liu, Sujean Choi

Biomedical Sciences Faculty Research and Publications

While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, …

Collective Timekeeping Among Cells Of The Master Circadian Clock, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the master circadian clock that coordinates daily rhythms in behavior and physiology in mammals. Like other hypothalamic nuclei, the SCN displays an impressive array of distinct cell types characterized by differences in neurotransmitter and neuropeptide expression. Individual SCN neurons and glia are able to display self-sustained circadian rhythms in cellular function that are regulated at the molecular level by a 24h transcriptional–translational feedback loop. Remarkably, SCN cells are able to harmonize with one another to sustain coherent rhythms at the tissue level. Mechanisms of cellular communication in the SCN network are …

Intersubunit Interactions At Putative Sites Of Ethanol Action In The M3 And M4 Domains Of The Nmda Receptor Glun1 And Glun2b Subunits, Robert W. Peoples, Hong Ren, Yulin Zhao

Biomedical Sciences Faculty Research and Publications

Background and Purpose: The N-methyl-D-aspartate (NMDA) receptor is an important target of alcohol action in the brain. Recent studies in this laboratory have demonstrated that alcohol-sensitive positions in the intersubunit interfaces of the M3 and M4 domains of GluN1 and GluN2A subunits interact with respect to ethanol sensitivity and receptor kinetics, and that alcohol-sensitive positions in the M domains of GluN2A and GluN2B subunits differ. In this study we tested for interactions among alcohol-sensitive positions at the M domain intersubunit interfaces in GluN1/GluN2B NMDA receptors.

Experimental Approach: We used whole-cell patch-clamp recording in tsA201 cells expressing tryptophan substitution mutants at …

Optogenetic Interrogation Of Functional Synapse Formation By Corticospinal Tract Axons In The Injured Spinal Cord, Naveen Jayaprakash, Zimei Wang, Brian Hoeynck, Nicholas Krueger, Audra A. Kramer, Eric Balle, Daniel S. Wheeler, Robert A. Wheeler, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial …

Pituitary Adenylate Cyclase-Activating Polypeptide Orchestrates Neuronal Regulation Of The Astrocytic Glutamate-Releasing Mechanism System XC−, Linghai Kong, Rebecca Albano, Aric Madayag, Nicholas Raddatz, John R. Mantsch, Sujean Choi, Doug Lobner, David A. Baker

Biomedical Sciences Faculty Research and Publications

Glutamate signaling is achieved by an elaborate network involving neurons and astrocytes. Hence, it is critical to better understand how neurons and astrocytes interact to coordinate the cellular regulation of glutamate signaling. In these studies, we used rat cortical cell cultures to examine whether neurons or releasable neuronal factors were capable of regulating system x_c^-(Sxc), a glutamate-releasing mechanism that is expressed primarily by astrocytes and has been shown to regulate synaptic transmission. We found that astrocytes cultured with neurons or exposed to neuronal-conditioned media displayed significantly higher levels of Sxc activity. Next, we demonstrated that the pituitary …