Molecular and Cellular Neuroscience Commons^™

Molecular Analysis Of Cone Photoreceptor Genesis From A Specific Retinal Progenitor Population, Diego F. Buenaventura

Dissertations, Theses, and Capstone Projects

There are two types of photosensitive cells of the retina that contribute to image formation: Cone photoreceptors that mediate color discrimination and rods that provide photosensitivity in low-light conditions. Given the importance of cones in high acuity and color vision, deficiencies in this cell type that result from ailments such as retinitis pigmentosa and macular degeneration can lead to a debilitating loss of vision. Currently, one of the most pressing goals in the field of retinal development is the elucidation of the gene regulatory networks (GRN) involved in inducing an undifferentiated cell into becoming a functional cone photoreceptor.

Recently, an …

The Master Synaptic Regulator: Activity Regulated Cytoskeleton Associated Protein, Arc, In Normal Aging And Diseases With Cognitive Impairment, Amber Khan

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with complex underlying pathogenic mechanisms. Epidemiological studies have forecasted that in the next 3 decades, the number of AD cases will rise to epidemic proportions with enormous medical, emotional and financial burdens impacting individuals affected and society. Among many risk factors for AD, advancing age is clearly essential and necessary. Revelation of molecular changes in synaptic activities leading to the prodromal, mild cognitive impairment (MCI) stage may help illuminate the course of pathogenic progression and its cause-effect relationship with various targets thereby enabling target-driven disease-modifying therapeutic agents for AD.

Activity-regulated cytoskeleton-associated (Arc) …

Post-Synaptic Mechanisms Of Early And Late Prepulse Inhibition In The Goldfish, Daniel Bronson

Dissertations, Theses, and Capstone Projects

Sensorimotor gating, or prepulse inhibition (PPI), attenuates the startle response during sensory processing by limiting sensory input to the startle circuit. In the goldfish startle circuit, a single action potential in the Mauthner-cell (M-cell) triggers the startle response. PPI in the M-cell is mediated by multiple post-synaptic mechanisms, including the activation of a tonic, shunting inhibition as well as a voltage-sensitive conductance, both of which briefly reduce M-cell excitability. However, the specific channels and pathways that modulate PPI are not fully known. This work further characterizes the post-synaptic conductances that mediate PPI by blocking voltage-gated and inward-rectifying potassium channels, antagonizing …

Mechanisms Of Microglia Mediated Apolipoprotien E Neurotoxicity, Pardeep Singh

Dissertations and Theses

No abstract provided.

Sonic Hedgehog Is Expressed By Hilar Mossy Cells And Regulates Cellular Survival And Neurogenesis In The Adult Hippocampus, Luis E. Gonzalez-Reyes, Chia-Chu Chiang, Mingming Zhang, Joshua Johnson, Manuel Arrillaga-Tamez, Nicholas H. Couturier, Neha Reddy, Lev Starikov, Jeffrey R. Capadona, Andreas H. Kottmann, Dominique M. Durand

Publications and Research

Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration …

Hyperphosphorylation Of Tau Associates With Changes In Its Function Beyond Microtubule Stability, Alejandra D. Alonso, Leah S. Cohen, Christopher Corbo, Viktoriya Morozova, Abdeslem Elldrissi, Greg R. Phillips, Frida E. Kleiman

Publications and Research

Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an amazing protein that plays a key role in cognitive processes, however, deposits of abnormal forms of tau are associated with several neurodegenerative diseases, including Alzheimer disease (AD), the most prevalent, and Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI), the most recently associated to abnormal tau. Tau post-translational modifications (PTMs) are responsible for its gain of toxic function. Alonso et al. …

Tributyltin Inhibits Neural Induction Of Human Induced Pluripotent Stem Cells, Shigeru Yamada, Yusuke Kubo, Daiju Yamazaki, Yuko Sekino, Yoko Nomura, Sachiko Yoshida, Yusunari Kanda

Publications and Research

Tributyltin (TBT), one of the organotin compounds, is a well-known environmental pollutant. In our recent study, we reported that TBT induces mitochondrial dysfunction, in human-induced pluripotent stem cells (iPSCs) through the degradation of mitofusin1 (Mfn1), which is a mitochondrial fusion factor. However, the effect of TBT toxicity on the developmental process of iPSCs was not clear. The present study examined the effect of TBT on the differentiation of iPSCs into the ectodermal, mesodermal, and endodermal germ layers. We found that exposure to nanomolar concentration of TBT (50 nM) selectively inhibited the induction of iPSCs into the ectoderm, which is the …

Carbonic Anhydrase Inhibition Selectively Prevents Amyloid B Neurovascular Mitochondrial Toxicity, María E. Solesio, Pablo M. Peixoto, Ludovic Debure, Stephen M. Madamba, Mony J. De Leon, Thomas Wisniewski, Evgeny V. Pavlov, Silvia Fossati

Publications and Research

Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer’s disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid b (Ab)-mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Ab, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Ab, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than …

The Role Of Oxidative Stress And Signal Transduction In Chemotherapy-Mediated Cognitive Impairment In The Menopause Rat Model, Ciara Bagnall

Dissertations, Theses, and Capstone Projects

Systemic chemotherapy treatment is associated with long-term cognitive impairment in breast cancer survivors. While many studies have established the forms of cognition and corresponding regions in the brain most affected, very little is revealed about the potential molecular mechanisms that mediate these changes. The effects of systemic treatment on the brain is likely attributed to many different mechanisms including oxidative stress and immune dysregulation. Earlier studies from our lab have investigated the effects of the chemotherapy cocktail doxorubicin and cyclophosphamide (AC Chemotherapy) in an ovariectomized menopause animal model of ‘chemo brain’ (Salas-Ramirez et al., 2015). We observed that animals injected …

Non-Canonical Activation Of Creb/Crh-1 Mediates Neuroprotection In A Caenorhabditis Elegans Model Of Excitotoxic Necrosis, K. Genevieve Feldmann

Dissertations, Theses, and Capstone Projects

Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a C. elegans model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed …

Neonatal Stimulation Of Pkc Epsilon Signaling Normalizes Fragile X-Associated Deficits In Pvn Oxytocin Expression And Later-Life Social And Anxiety Behavior, Alexandra E. Marsillo

Dissertations, Theses, and Capstone Projects

Fragile X Syndrome (FXS) is an inherited developmental disorder characterized by disturbances in emotional and social behavior. Our studies have revealed suppressed hippocampal PKCε expression in Fmr1 knockout (KO) mice, the leading model of FXS. To compensate for this deficiency, we stimulated PKCε in neonatal KO mice by administering a selective PKCε activator, dicyclopropyl-linoleic acid (DCP-LA), and studied its effect on ventral hippocampal neurons and a proximal target of the ventral hippocampus, the hypothalamus, which regulates social and emotional behavior. We observed that at postnatal day 18 (P18), vehicle-treated KO mice displayed increased surface localization of the 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) …

Pharmacological Antagonism And The Olfactory Code, Mihwa Na

Dissertations, Theses, and Capstone Projects

Mammals can detect and discriminate uncountable odors through their odorant receptors. To accommodate the countless and diverse odors, exceptionally large numbers of odorant receptor (OR) genes are expressed in mammals. In addition, the mammals utilize a combinatorial code, where an odorant molecule can activate multiple ORs; an OR also responds to a set of multiple odorants. In nature, an odor is often a complex mixture of multiple odorant molecules. The combination of the ORs activated by each constituent generates the unique olfactory code for the particular odor.

Some odorants can antagonize select ORs, as discussed in Chapter 1. An antagonist …

Regulation Of The Amyloid Precursor Protein By Prostaglandin J2, A Mediator Of Inflammation: Relevance To Alzheimer’S Disease, Teneka L. Jean-Louis

Dissertations, Theses, and Capstone Projects

Inflammation plays a major role in Alzheimer’s disease (AD). Investigating how specific mediators of inflammation contribute to neurodegeneration in AD is crucial. Our studies focused on cyclooxygenases, which are key enzymes in inflammation and highly relevant to AD. Cyclooxygenases (COX -1, constitutive; COX-2, inducible) have emerged as important determinants of AD pathogenesis and progression. COX-2 is highly induced in AD, correlating with AD severity, and COX-1 is also involved in AD. Cyclooxygenases are the rate-limiting enzymes that convert arachidonic acid into prostaglandins (PGs), the principal mediators of CNS neuroinflammation.

The overall GOAL of these studies was to address the mechanisms …

Modulation Of The Sodium/Potassium Atpase Function And Expression By Transcranial Direct Current Stimulation Of The Right Sensorimotor Cortex In Mice, Salim Bendaoud

Dissertations, Theses, and Capstone Projects

Direct current stimulation is used as a noninvasive therapeutic technique to enhance motor recovery following stroke, and to improve cognitive functions. This technique also showed promising results in the treatment of depression, schizophrenia, and multiple sclerosis. Transcranial direct current stimulation has been proven to cause a polarization (depolarization or hyperpolarization) of the target tissues depending on the polarity of the current and cell orientation. Because of the induced polarization, the spontaneous activity of the neurons is further affected. With exception to this electrophysiological effect, the overall biological mechanisms of transcranial direct current stimulation on the underlying tissues remain largely unknown. …

Modulation Of Spasticity By Trans-Spinal Direct Current Stimulation In Animals With Spinal Cord Injury, Wagdy Mekhael

Dissertations, Theses, and Capstone Projects

Central nervous system injuries usually produce motor impairments that are exacerbated by pathologically altered muscle tone. Abnormal muscle tone interferes with voluntary movement and is associated with loss of dexterity. Prior work in our laboratory demonstrated that 30-second trans-spinal direct current (DC) stimulation can temporarily modify muscle tone in anesthetized spastic mice after spinal cord injury (SCI). These experiments described DC-induced muscle tone responses to be polarity-dependent. That is, anodal stimulation (current passed from the lumbar spine to sciatic nerve) decreased muscle tone, and cathodal stimulation (current passed from the sciatic nerve to the lumbar spine) increased it. The present …

Distribution And Activation Of Catecholaminergic Neurons In The Brain Of Male Plainfin Midshipman Fish: Divergence In Behavior And Reproductive Phenotype, Zachary Ghahramani

Dissertations, Theses, and Capstone Projects

The plainfin midshipman fish, Porichthys notatus, provides an excellent opportunity for delimiting the influence of neurochemical content on vertebrate vocal behavior, in part because the production and recognition of social-acoustic signals is vital to their reproductive behavior. There are two distinct reproductive male morphs that follow divergent developmental trajectories with corresponding alternative reproductive tactics: type I males are the territorial/nesting morph that vocally court females during the summer breeding season while type II males do not court females, but instead sneak spawn in competition with type I males. Catecholaminergic neurons, which synthesize and release the neurotransmitters dopamine or noradrenaline, …

Physical Mechanisms And Biological Consequences Of Voltage-Gated Sodium Channel Modulation By Fhf Proteins, Yue Liu

Dissertations, Theses, and Capstone Projects

Purpose: FHFs are cytosolic proteins that bind to voltage-gated sodium channels (Na_Vs) and modulate their functions to control membrane excitability. FHFs raise the voltage dependence of Na_V fast inactivation to promote excitability, while A isoforms FHF (A-FHFs) also capture open sodium channels into a long-term inactivated (LTI) state to limit excitability. My research has addressed how FHFs balance membrane excitability as it relates to normal and pathological brain functions. Part of this work stemmed from the discovery of a missense FHF1 mutation in patients with severe early onset epilepsy. Methods and Results: Wild-type FHF1A and FHF1B were …

Protein Kinase M Zeta-Mediated Ltp Maintenance In The Non-Human Primate Hippocampus: A Role For Stress And Serotonergic Signaling In Affective Processing, Sasha L. Fulton

Theses and Dissertations

Early-Life Stress (ELS) is associated with vulnerability to mood disorder, but it’s not well understood how ELS contributes to deficits in cognitive function. Atypical PKMzeta is critical for LTP maintenance and memory. The current study aims to characterize the ELS phenotype with respect to this key marker of hippocampal LTP.

Neurodevelopmental Defects Associated With Gestational Exposure To Low Levels Of Dbp In Mice, Françoise Sidime

Dissertations, Theses, and Capstone Projects

The etiology of autism is thought to involve the complex interplay among genetic and environmental factors. Patterns of inheritance suggest an epigenetic component to the development of autism. A variety of environmental risk factors are known to induce epigenetic changes in DNA, affecting many genes including those autism-associated genes (AAG). The plasticizer dibutyl phthalate (DBP; CAS 84-74-2) is a developmental and reproductive toxin that causes a broad range of birth defects resulting in neurological impairments.

To date, although the effect of DBP as an endocrine and a reproductive disruptor are established, there are only few studies that address the effects …

Messenger Rna Transport And Translation Regulated By The 3' Utrs Of Dendritic Mrnas And Abnormal Alternative Splicing Of Neuroligin1 In The Fmr1 Ko Mouse Hippocampus, Tianhui Zhu

Dissertations, Theses, and Capstone Projects

Fragile X Syndrome (FXS) is one of the most commonly inherited mental retardations. It is caused by the loss of functional fragile X mental retardation protein (FMRP). Loss of functional FMRP is the most widespread single-gene cause of autism. The most prominent phenotype of FXS patients is an IQ ranging from 20 to 70. FMRP is an RNA binding protein, widely expressed in almost all tissues and highly expressed in brain. As a RNA binding protein, 85-90 % of FMRP in the brain is associated with polyribosomes. Approximately 4 % of total mRNA is associated with FMRP, which functions in …

The Ubiquitin-Proteasome System: Potential Therapeutic Targets For Alzheimer’S Disease And Spinal Cord Injury, Bing Gong, Miroslav Radulovic, Maria E. Figueiredo-Pereira, Christopher Cardozo

Publications and Research

The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer’s disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression. More recently, the UPS has been shown to have vital roles in recovery of function after SCI. The ubiquitin hydrolase (Uch-L1) has been proposed to …

Overlapping Signatures Of Chronic Pain In The Dna Methylation Landscape Of Prefrontal Cortex And Peripheral T Cells, Renaud Massart, Sergiy Dymov, Magali Millecamps, Matthew Suderman, Stephanie Gregoire, Kevin Koenigs, Sebastian Alvarado, Maral Tajerian, Laura S. Stone, Moshe Szyf

Publications and Research

We tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain. Finally, only 11 differentially methylated probes in …

Death Associated Protein Kinase (Dapk) -Mediated Neurodegenerative Mechanisms In Nematode Excitotoxicity, John S. Del Rosario, Katherine Genevieve Feldmann, Towfiq Ahmed, Uzair Amjad, Bakkeung Ko, Junhyung An, Tauhid Mahmud, Maha Salama, Shirley Mei, Daniel Asemota, Itzhak Mano

Publications and Research

Background: Excitotoxicity (the toxic overstimulation of neurons by the excitatory transmitter Glutamate) is a central process in widespread neurodegenerative conditions such as brain ischemia and chronic neurological diseases. Many mechanisms have been suggested to mediate excitotoxicity, but their significance across diverse excitotoxic scenarios remains unclear. Death Associated Protein Kinase (DAPK), a critical molecular switch that controls a range of key signaling and cell death pathways, has been suggested to have an important role in excitotoxicity. However, the molecular mechanism by which DAPK exerts its effect is controversial. A few distinct mechanisms have been suggested by single (sometimes contradicting) studies, and …

Neuroinflammation And J2 Prostaglandins: Linking Impairment Of The Ubiquitin-Proteasome Pathway And Mitochondria To Neurodegeneration, Maria E. Figueiredo-Pereira, Patricia Rockwell, Thomas Schmidt-Glenewinkel, Peter Serrano

Publications and Research

The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly …

An Epigenetic Hypothesis For The Genomic Memory Of Pain, Sebastian Alvarado, Maral Tajerian, Matthew Suderman, Ziv Machnes, Stephanie Pierfelice, Magali Millecamps, Laura S. Stone, Moshe Szyf

Publications and Research

Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA,serve as a “genomic” memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC). We have previously reported …

The Insulin/Igf Signaling Regulators Cytohesin/Grp-1 And Pip5k/Ppk-1 Modulate Susceptibility To Excitotoxicity In C. Elegans, Nazila Tehrani, John Del Rosario, Moises Dominguez, Robert Kalb, Itzhak Mano

Publications and Research

During ischemic stroke, malfunction of excitatory amino acid transporters and reduced synaptic clearance causes accumulation of Glutamate (Glu) and excessive stimulation of postsynaptic neurons, which can lead to their degeneration by excitotoxicity. The balance between cell death-promoting (neurotoxic) and survival-promoting (neuroprotective) signaling cascades determines the fate of neurons exposed to the excitotoxic insult. The evolutionary conserved Insulin/IGF Signaling (IIS) cascade can participate in this balance, as it controls cell stress resistance in nematodes and mammals. Blocking the IIS cascade allows the transcription factor FoxO3/DAF-16 to accumulate in the nucleus and activate a transcriptional program that protects cells from a range …

Long-Term Cre-Mediated Retrograde Tagging Of Neurons Using A Novel Recombinant Pseudorabies Virus, Hysell V. Oviedo, Hassasna K. Oyibo, Petr Znamenskiy, Lynn W. Enquist, Anthony M. Zador

Publications and Research

Brain regions contain diverse populations of neurons that project to different long-range targets. The study of these subpopulations in circuit function and behavior requires a toolkit to characterize and manipulate their activity in vivo. We have developed a novel set of reagents based on Pseudorabies Virus (PRV) for efficient and long-term genetic tagging of neurons based on their projection targets. By deleting IE180, the master transcriptional regulator in the PRV genome, we have produced a mutant virus capable of infection and transgene expression in neurons but unable to replicate in or spread from those neurons. IE180-null mutants showed no cytotoxicity, …

Inhibition Of Phosphodiesterase10a Attenuates Morphine-Induced Conditioned Place Preference, Ying Mu, Zhaoxiang Ren, Jia Jia, Bo Gao, Longtai Zheng, Eitan Friedman

Publications and Research

Background: Phosphodiesterase (PDE) 10A is selectively expressed in medium spiny neurons of the striatum. Nucleus accumbens (NAc) is a key region that mediates drug reward and addiction-related behaviors. To investigate the potential role of PDE10A in the reinforcement properties of morphine, we tested the effect of MP-10, a selective inhibitor of PDE10A, on acquisition, expression, and extinction of morphine-induced conditioned place preference (CPP).

Results: The results show that 2.5 mg/kg MP-10, administered subcutaneously, significantly inhibited the acquisition of morphine-induced CPP. The same dose of MP-10 alone did not result in the CPP. Moreover, MP-10 did not alter the expression of …

Peripheral Nerve Injury Is Associated With Chronic, Reversible Changes In Global Dna Methylation In The Mouse Prefrontal Cortex, Maral Tajerian, Sebastian Alvarado, Magali Millecamps, Pascal Vachon, Cecilia Crosby, M. Catherine Bushnell, Moshe Szyf, Laura S. Stone

Publications and Research

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with …

Dynamic Gene Expression In The Human Cerebral Cortex Distinguishes Children From Adults, Kirstin N. Sterner, Amy Weckle, Harry T. Chugani, Adi L. Tarca, Chet C. Sherwood, Patrick R. Hof, Christopher W. Kuzawa, Amy M. Boddy, Asad Abbas, Ryan L. Raaum, Lucie Grégoire, Leonard Lipovich, Lawrence I. Grossman, Monica Uddin, Morris Goodman, Derek E. Wildman

Publications and Research

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR>0). Moreover, genes known to …