Neurosciences Commons^™

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 …

The Opiod Epidemic: Clinical Dental Update, Matthew Hearing

Biomedical Sciences Faculty Research and Publications

No abstract provided.

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 …

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 …

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.

Aging, Executive Function, Fronto-Parietal Network Cortical Thickness: Insights From Cognitive Reserve, Katherine Reiter

Dissertations (1934 -)

Cognitive reserve (CR) indexes the nonlinear relationship between neurological insult and behavioral change. CR is manifested in both static factors (e.g., childhood environment, education) and modifiable lifestyle factors, (e.g., leisure activities). Detailed investigation of the influence of CR on cortical thickness, which indexes neuropathology, and cognitive functioning could be particularly important in understanding the heterogeneity of Alzheimer’s disease (AD). While memory decline is the hallmark of AD, executive functioning (EF) decline often predates memory changes, making EF an important target for investigating CR influences. The current study examines the relationship of CR and genetic risk for AD (ε4) on EF …

The Neural Encoding Of Reward In The Striatal-Pallidal Circuitry, Chung Lung Chan

Dissertations (1934 -)

Humans and animals are constantly exposed to external stimuli. The ability to process reward value of a stimulus is critical to guiding appropriate behavior and essential for survival. These processes are regulated by neuronal activity and neurochemical signaling in the reward circuitry, particularly in the nucleus accumbens (NAc). The NAc receives dopaminergic inputs from the midbrain ventral tegmental area (VTA) and sends GABAergic projections to the ventral pallidum (VP). Electrophysiological studies have characterized phasic neuronal responses in the NAc that differential encode appetitive and aversive taste stimuli. Exposure to an appetitive taste stimulus evoked predominantly phasic inhibitory responses in the …

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 …

Regulation Of System Xc-By The Neuropeptide Pacap: Implications For Glutamate Transmission In Drug Addiction, Linghai Kong

Dissertations (1934 -)

Drug addiction is a chronic brain disorder characterized by heightened relapse susceptibility. Drug-induced aberrant glutamate signaling in corticostriatal circuitry contributes to behaviors in virtually every preclinical model of drug seeking and correlates with drug craving in human. Here, we propose that glutamate signaling is a product of integrated activity between neurons and astrocytes, such that disruptions within astrocytes can stem from abnormal neuronal signaling (e.g., altered corticostriatal firing) and be the source of additional disruptions in other neuronal circuits. The astrocytic mechanism studied in these experiments is system xc- (Sxc) since drug-induced changes to this non-vesicular glutamate release mechanism contribute …

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 …

In Synch But Not In Step: Circadian Clock Circuits Regulating Plasticity In Daily Rhythms, Jennifer A. Evans, M. R. Gorman

Biomedical Sciences Faculty Research and Publications

The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network. Here we review the current understanding of communication among SCN clock cells and highlight a collection of formal assays where changes in SCN interactions provide for plasticity in the waveform of circadian rhythms in behavior. Future …

The Neural Encoding Of Cocaine-Induced Devaluation In The Ventral Pallidum, Chung-Lung Chan, Daniel S. Wheeler, Robert A. Wheeler

Biomedical Sciences Faculty Research and Publications

Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague–Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20 mg/kg, ip) or saline injection. Finally, the …

Antagonism Of Gaba-B But Not Gaba-A Receptors In The Vta Prevents Stress- And Intra-Vta Crf-Induced Reinstatement Of Extinguished Cocaine Seeking In Rats, Jordan M. Blacktop, Oliver Vranjkovic, Matthieu Mayer, Matthew Van Hoof, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 …

The Reliability And Validity Of Functional Brain Connectivity Compared To A Self-Reported Measure Of Pain, Ali Alsouhibani

Maria Dittman Library Research Competition: Student Award Winners

Pain is a multidimensional perception that is complex in nature. It is a unitary construct that includes overlapping domains such as intensity, affect, quality, and frequency. These domains do not reflect the amount of tissue damage. It reflects the end result of the perception of pain in which multiple biopsychosocial factors are involved (Gatchel et al., 2007). Multiple self-reported measures have been used in an attempt to capture most factors that may influence pain such as psychological factors. However, there is no one scale that can be used to characterize pain as a whole with all its factors. Furthermore, physical …

Stress-Induced Reinstatement Of Drug Seeking: 20 Years Of Progress, John R. Mantsch, David A. Baker, Douglas Funk, Anh D. Lê, Yavin Shaham

Biomedical Sciences Faculty Research and Publications

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, …

The Level Of Nmda Receptor In The Membrane Modulates Amyloid-Β Association And Perforation, Christian Peters, Fernando J. Sepúlveda, Eduardo Fernández-Pérez, Robert W. Peoples, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA …

N-Acetylcysteine Decreases Binge Eating In A Rodent Model, M. M. Hurley, Jon M. Resch, Brian Maunze, M. M. Frenkel, David A. Baker, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine–glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high-fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either …