Neurosciences Commons^™

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 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 …

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, …

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 …

Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking, Daniel S. Wheeler, Mykel A. Robble, Emily M. Hebron, Matthew J. Dupont, Amanda L. Ebben, Robert A. Wheeler

Biomedical Sciences Faculty Research and Publications

Drug-associated cues have profound effects on an addict’s emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, …

Overexpression Of Sox11 Promotes Corticospinal Tract Regeneration After Spinal Injury While Interfering With Functional Recovery, Zimei Wang, Ashley Reynolds, Adam Kirry, Christopher Nienhaus, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes …

A New Obesity Model Reveals The Hypophagic Properties Of Pacap Involve The Regulation Of Homeostatic Feeding In The Ventromedial Hypothalamic Nucleus And Hedonic Feeding In The Nucleus Accumbens, Matthew M. Hurley, Brian Maunze, Jon M. Resch, Mogen M. Frenkel, M. J. Reilley, Megan E. Block, David A. Baker, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Binge eating in humans is a complex disorder that often involves discrete, compulsive feeding sessions of highly palatable foods even in the absence of a deprivation state or hunger. Binging can be effectively modeled in rodents by providing subjects with limited access to a palatable food source (Western Diet; WD) as an adjunct to ad lib access to normal chow (Standard Chow; SC). Although this design recapitulates several fundamental characteristics observed in binge eating disorder, the binge eating observed in this paradigm is likely a product of both hedonic and homeostatic drives with the need to balance energy stores still …

Pacap And Cocaine Reinstatement: A Neuropeptide Expressed By Corticostriatal Neurons That Regulates Nucleus Accumbens Astrocytes, Linghai Kong, E. Hess, Brian Maunze, Matthew M. Hurley, Khadijah Makky, Sujean Choi, John R. Mantsch, David A. Baker

Biomedical Sciences Faculty Research and Publications

Drug addiction involves heightened relapse vulnerability arising from persistent drug-induced neuro-adaptations, including a) hypofrontality which is thought to reflect reduced firing of cortical afferents to the nucleus accumbens (NAcc) and b) altered glutamate homeostasis in NAcc that likely involves reduced glutamate release and uptake by astrocytes. An important question is whether these forms of pathological plasticity are functionally linked such that reduced corticostriatal firing may result in aberrant regulation of astrocytes in the NAcc. To begin to evaluate this possibility, we first determined whether neurons regulate system xc- (Sxc) activity, a mechanism of non-vesicular glutamate release by astrocytes. We found …

Regulation Of System XC- By Pharmacological Manipulation Of Cellular Thiols, Rebecca Albano, Nicholas J. Raddatz, Julie Hjelmhaug, David A. Baker, Doug Lobner

Biomedical Sciences Faculty Research and Publications

The cystine/glutamate exchanger (system x_c^-) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, system x_c^- can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and may protect cells against oxidative stress. We tested two different compounds that deplete primary cortical cultures containing both neurons and astrocytes of intracellular GSH, L-buthionine-sulfoximine (L-BSO), and diethyl maleate (DEM). Both compounds caused significant concentration and time dependent decreases in intracellular GSH levels. However; DEM caused an increase …

Expression Patterns Of Bdnf With Central Anorexigenic Signaling Pathways Involving Pacap In The Hypothalamic Ventromedial Nuclei, Brian Maunze, Matthew M. Hurley, Jon M. Resch, M. J. Reilley, E. M. Wassmann, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid polypeptide belonging to the secretin super family of peptides. PACAP binds to its type 1 receptor (PAC1R) with greater affinity than for the receptors for vasoactive intestinal polypeptides (VIP), VPAC1 and VPAC2. Although mRNA for PACAP and its receptor PAC1R are found throughout the central nervous system, they are abundantly expressed in the hypothalamic ventromedial nuclei (VMN). In male Sprague Dawley rats, infusions of PACAP into the VMN produce a robust decrease in food intake with concomitant increased energy expenditure, decreased body weight, and significantly elevated brain-derived neurotrophic factor (BDNF) mRNA …

Behavioral Assessment Of Acute Inhibition Of System XC - In Rats, Victoria Lutgen, Jon M. Resch, Krista Qualmann, Nicholas J. Raddatz, Cristina Panhans, Ellen M. Olander, Linghai Kong, Sujean Choi, John R. Mantsch, David A. Baker

Biomedical Sciences Faculty Research and Publications

Rationale

Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System x_c ^- is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases.

Objectives

This study aims to determine whether system x_c ^- contributes to behaviors used to model features of CNS disease states.

Methods

In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue …

Augmented Cystine–Glutamate Exchange By Pituitary Adenylate Cyclase-Activating Polypeptide Signaling Via The Vpac1 Receptor, Jon M. Resch, Rebecca Albano, Xiaoqian Liu, Julie Hjelmhaug, Doug Lobner, David A. Baker, Sujean Choi

Biomedical Sciences Faculty Research and Publications

In the central nervous system, cystine import in exchange for glutamate through system x_c^- is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system x_c^- activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuronally derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine–glutamate exchange via system x_c^-. In this study, 24-h treatment of primary cortical …

Phosphate And Acidosis Act Synergistically To Depress Peak Power In Rat Muscle Fibers, Cassandra R. Nelson, Edward P. Debold, Robert H. Fitts

Biomedical Sciences Faculty Research and Publications

Skeletal muscle fatigue is characterized by the buildup of H⁺ and inorganic phosphate (P_i), metabolites that are thought to cause fatigue by inhibiting muscle force, velocity, and power. While the individual effects of elevated H⁺ or P_i have been well characterized, the effects of simultaneously elevating the ions, as occurs during fatigue in vivo, are still poorly understood. To address this, we exposed slow and fast rat skinned muscle fibers to fatiguing levels of H⁺ (pH 6.2) and P_i (30 mM) and determined the effects on contractile properties. At 30°C, elevated P_{i …}

Stress-Induced Cocaine Seeking Requires A Beta-2 Adrenergic Receptor-Regulated Pathway From The Ventral Bed Nucleus Of The Stria Terminalis That Regulates Crf Actions In The Ventral Tegmental Area, Oliver Vranjkovic, Paul J. Gasser, Clayton H. Gerndt, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the β-2 AR antagonist, ICI-118,551, but not the β-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of …

Cyclic Ovarian Hormone Modulation Of Supraspinal Δ9-Tetrahydrocannabinol-Induced Antinociception And Cannabinoid Receptor Binding In The Female Rat, Alexa A. Wakley, Alisha A. Mcbride, Linda K. Vaughn, Rebecca M. Craft

Biomedical Sciences Faculty Research and Publications

Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which major ovarian hormone modulates the antinociceptive effects of i.c.v. THC, and whether hormone modulation of THC's behavioral effects could be due to changes in brain cannabinoid receptors (CBr). Vehicle (oil) or hormones (estradiol or progesterone, or both) were administered to female rats on days 3 and 7 post-ovariectomy. On the morning or afternoon of day 8 or day 9, vehicle or THC (100 μg) was administered i.c.v. Paw pressure, tail withdrawal, locomotor activity and catalepsy tests were conducted …

Inhibition Of Food Intake By Pacap In The Hypothalamic Ventromedial Nuclei Is Mediated By Nmda Receptors, Jon M. Resch, Brian Maunze, Kailynn A. Phillips, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Central injections of pituitary adenylate cyclase-activating polypeptide (PACAP) into the ventromedial nuclei (VMN) of the hypothalamus produce hypophagia that is dependent upon the PAC1 receptor; however, the signaling downstream of this receptor in the VMN is unknown. Though PACAP signaling has many targets, this neuropeptide has been shown to influence glutamate signaling in several brain regions through mechanisms involving NMDA receptor potentiation via activation of the Src family of protein tyrosine kinases. With this in mind, we examined the Src-NMDA receptor signaling pathway as a target for PACAP signaling in the VMN that may mediate its effects on feeding behavior. …

Nature Of The Neurotoxic Membrane Actions Of Amyloid-Β On Hippocampal Neurons In Alzheimer's Disease, Fernando J. Sepúlveda, Humberto Fierro, Eduardo Fernandez, Carolina Castillo, Robert W. Peoples, Carlos Opazo, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The mechanism by which amyloid-β (Aβ) produces brain dysfunction in patients with Alzheimer's disease is largely unknown. According to previous studies, Aβ might share perforating properties with gramicidin, a well-accepted membrane-disrupting peptide. Therefore, we hypothesize that the key steps leading to synaptotoxicity by Aβ and gramicidin involve peptide aggregation, pore formation, and calcium dysregulation. Here, we show that Aβ and gramicidin form aggregates enriched in β-sheet structures using electron microscopy, and Thioflavin and Congo Red staining techniques. Also, we found that Aβ and gramicidin display fairly similar actions in hippocampal cell membranes, i.e. inducing Ca²⁺ entry and synaptoxicity characterized …

Fgf-2 Induces Neuronal Death Through Upregulation Of System Xc-, Xiaoqian Liu, Rebecca Albano, Doug Lobner

Biomedical Sciences Faculty Research and Publications

The cystine/glutamate antiporter (system xc-) transports cystine into cell in exchange for glutamate. Fibroblast growth factor-2 (FGF-2) upregulates system xc- selectively on astrocytes, which leads to increased cystine uptake, the substrate for glutathione production, and increased glutamate release. While increased intracellular glutathione can limit oxidative stress, the increased glutamate release can potentially lead to excitotoxicity to neurons. To test this hypothesis, mixed neuronal and glial cortical cultures were treated with FGF-2. Treatment with FGF-2 for 48 h caused a significant neuronal death in these cultures. Cell death was not observed in neuronal-enriched cultures, or astrocyte-enriched …