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Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.
ContributorsHoffman, Ann (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Hammer, Jr., Ronald P. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
Description
Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus with adeno- associated viral vectors containing the coding sequence for short interfering (si)RNA directed against BDNF or a scrambled sequence (Scr), with both containing the coding information for green fluorescent protein to aid in anatomical localization. Rats were then chronically restrained (wire mesh, 6h/d/21d) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trial. Rats in the Str-Imm group, regardless of viral vector contents, committed more errors in the spatial reference memory domain than did non-stressed controls. Importantly, the typical improvement in spatial memory following recovery from chronic stress was blocked with the siRNA against BDNF, as Str-Rec-siRNA performed worse on the RAWM compared to the non-stressed controls or Str-Rec-Scr. These effects were specific for the reference memory domain as repeated entry errors that reflect spatial working memory were unaffected by stress condition or viral vector contents. These results demonstrate that hippocampal BDNF is necessary for the recovery from stress-induced hippocampal dependent spatial memory deficits in the reference memory domain.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Taylor, Sara (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cells live in complex environments and must be able to adapt to environmental changes in order to survive. The ability of a cell to survive and thrive in a changing environment depends largely on its ability to receive and respond to extracellular signals. Initiating with receptors, signal transduction cascades begin translating extracellular signals into intracellular messages. Such signaling cascades are responsible for the regulation of cellular metabolism, cell growth, cell movement, transcription, translation, proliferation and differentiation. This dissertation seeks to dissect and examine critical signaling pathways involved in the regulation of proliferation in neural stem cells (Chapter 2) and the regulation of Glioblastoma Multiforme pathogenesis (GBM; Chapter 3). In Chapter 2 of this dissertation, we hypothesize that the mTOR signaling pathway plays a significant role in the determination of neural stem cell proliferation given its control of cell growth, metabolism and survival. We describe the effect of inhibition of mTOR signaling on neural stem cell proliferation using animal models of aging. Our results show that the molecular method of targeted inhibition may result in differential effects on neural stem cell proliferation as the use of rapamycin significantly reduced proliferation while the use of metformin did not. Abnormal signaling cascades resulting in unrestricted proliferation may lead to the development of brain cancer, such as GBM. In Chapter 3 of this dissertation, we hypothesize that the inhibition of the protein kinase, aPKCλ results in halted GBM progression (invasion and proliferation) due to its central location in multiple signaling cascades. Using in-vitro and in-vivo models, we show that aPKCλ functions as a critical node in GBM signaling as both cell-autonomous and non-cell-autonomous signaling converge on aPKCλ resulting in pathogenic downstream effects. This dissertation aims to uncover the molecular mechanisms involved in cell signaling pathways which are responsible for critical cellular effects such as proliferation, invasion and transcriptional regulation.
ContributorsKusne, Yael (Author) / Sanai, Nader (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Tran, Nhan (Committee member) / Hammer, Ronald (Committee member) / Narayanan, Vinodh (Committee member) / Shapiro, Joan (Committee member) / Arizona State University (Publisher)
Created2014
Description
Patients with schizophrenia have impaired cognitive flexibility, as evidenced by behaviors of perseveration. Cognitive impairments may be due to dysregulation of glutamate and/or loss of neuronal plasticity in the medial prefrontal cortex (mPFC). The purpose of these studies was to examine the effects of mGluR5 positive allosteric modulators (PAMs) alone and in combination with the NMDAR antagonist MK-801, a pharmacological model of schizophrenia. An operant-based cognitive set-shifting task was utilized to assess cognitive flexibility, in vivo microdialysis procedures to measure extracellular glutamate levels in the mPFC, and diolistic labeling to assess the effects on dendritic spine density and morphology in the mPFC. Results revealed that chronic administration of the mGluR5 PAM CDPPB was able to significantly reduce the effects of chronically administered MK-801 on both behavioral perseveration and glutamate neurotransmission. Results also showed that CDPPB had no evidence of an effect on dendritic spine density or morphology, but the mGluR5 negative allosteric modulator fenobam caused significant increases in spine density and the frequency of occurrence of spines with smaller head diameters. Conclusions include that CDPPB is able to reverse MK-801 induced cognitive deficits as well as alterations in mPFC glutamate neurochemistry. The culmination of these studies add further support for targeting mGluR5 with PAMs as a novel mechanism to alleviate cognitive impairments in patients with schizophrenia.
ContributorsLaCrosse, Amber (Author) / Olive, Michael (Committee member) / Gallitano-Mendel, Amelia (Committee member) / Sanabria, Federico (Committee member) / Hammer, Ronald (Committee member) / Arizona State University (Publisher)
Created2014
Description
Tobacco and alcohol are the most commonly abused drugs worldwide. Many people smoke and drink together, but the mechanisms of this nicotine (NIC) -ethanol (EtOH) dependence are not fully known. EtOH has been shown to affect some nicotinic acetylcholine receptors (nAChRs), which potentially underlies NIC-EtOH codependence. Ventral Tegmental Area (VTA) dopamine (DA) and γ-aminobutyric acid (GABA) neurons express different nAChR subtypes, whose net activation results in enhancement of DA release in the Prefrontal Cortex (PFC) and Nucleus Accumbens (NAc). Enhancement of DA transmission in this mesocorticolimbic system is thought to lead to rewarding properties of EtOH and NIC, clarification of which is relevant to public health and clinical diseases. The aim of this study was to elucidate pharmacological mechanisms of action employed by both NIC and EtOH through nAChRs in VTA neurons by evaluating behavioral, network, synaptic and receptor functions therein. It was hypothesized that VTA GABA neurons are controlled by α7 nAChRs on presynaptic GLUergic terminals and α6 nAChRs on presynaptic GABAergic terminals. NIC and EtOH, via these nAChRs, modulate VTA GABA neuronal function. This modulation may underlie NIC and EtOH reward and reinforcement, while pharmacological manipulation of these nAChRs may be a therapeutic strategy to treat NIC or EtOH dependence. This data demonstrates that in VTA GABA neurons, α7 nAChRs on GLUergic terminals play a key role in the mediation of local NIC-induced firing increase. α6*-nAChRs on GABA terminals enhances presynaptic GABA release, and leads to greater inhibition to VTA GABA neurons, which results in an increase VTA DA neuron firing via a disinhibition mechanism. Genetic knockout of these nAChRs significantly prevents EtOH-induced animal conditioned place preference (CPP). Furthermore, levo-tetrahydropalmadine (l-THP), a compound purified from natural Chinese herbs, blocks nAChRs, prevents NIC-induced DA neuronal firing, and eliminates NIC CPP, suggesting it as a promising candidate in a new generation of interventions for smoking cessation. Improved understanding of underlying mechanisms and development of new drugs will increase the number of successful quitters each year and dramatically improve the quality of life for millions suffering from addiction, as well as those around them.
ContributorsTaylor, Devin (Author) / Wu, Jie (Committee member) / Olive, M F (Committee member) / Whiteaker, Paul (Committee member) / Vu, Eric (Committee member) / Hammer, Ronald (Committee member) / Arizona State University (Publisher)
Created2015
Description
ABSTRACT
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
ContributorsParga Becerra, Alejandro (Author) / Neisewander, Janet (Thesis advisor) / Hammer, Ronald (Thesis advisor) / Gallitano-Mendel, Amelia (Committee member) / McLoone, Jim (Committee member) / Vu, Jie (Committee member) / Arizona State University (Publisher)
Created2014
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015