Medicine and Health Sciences Commons^™

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 …

The Relevance Of Sex Differences In Performance Fatigability, Sandra K. Hunter

Exercise Science Faculty Research and Publications

Performance fatigability differs between men and women for a range of fatiguing tasks. Women are usually less fatigable than men, and this is most widely described for isometric fatiguing contractions and some dynamic tasks. The sex difference in fatigability is specific to the task demands so that one mechanism is not universal, including any sex differences in skeletal muscle physiology, muscle perfusion, and voluntary activation. However, there are substantial knowledge gaps about the task dependency of the sex differences in fatigability, the involved mechanisms, and the relevance to clinical populations and with advanced age. The knowledge gaps are in part …

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 …

Cb1 Receptor Antagonism Blocks Stress-Potentiated Reinstatement Of Cocaine Seeking In Rats, Jayme R. Mcreynolds, Elizabeth M. Doncheck, Oliver Vranjkovic, Geoffrey S. Ganzman, David A. Baker, Cecilia J. Hillard, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Rationale

Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Objectives

The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.

Methods

Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is …

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 …

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 …

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 …