Neuroscience and Neurobiology Commons^™

How Does Schizophrenia Affect The Expression Of Alpha 7 Nicotinic Acetylcholine Receptors In The Brain?, Shruti Varshney, Nimish Acharya

Rowan-Virtua Research Day

Schizophrenia (SZ) is a psychiatric disorder with a pathophysiology that has not yet been fully understood. This mental illness is characterized by disruptions in cognition, social activity, affect, and perception, and affects approximately 0.085% of individuals worldwide. The Alpha 7 Nicotinic Acetylcholine Receptor (α7nAChR) has been connected to auditory function gating deficits. The purpose of this review is to understand the current literature in how the levels of α7nAChR expression and function are affected by SZ, information that could be used to develop therapies to modulate auditory hallucinations in patients with SZ. A literature search was conducted for peer-reviewed journal …

Alpha 7 Nicotinic Acetylcholine Receptor Expression In The Hippocampus Of Patients With Schizophrenia, Shruti Varshney, Ananya Nethikunta, Minjal Patel, Mary Kosciuk, Randel L. Swanson, Venkat Venkataraman, Robert Nagele, Eric Goldwaser, Nimish Acharya

Rowan-Virtua Research Day

Background: Schizophrenia (SZ) is a heterogenous psychiatric condition characterized by disruptions in cognition, social activity, affect, and perception often associated with a varied combination of positive and negative symptoms. The pathophysiology behind SZ remains poorly elucidated. Earlier reports have cited the importance of the alpha 7 nicotinic acetylcholine receptors (α7nAChR) in the hippocampus and the receptor’s association with auditory sensory gating and cognitive function. Specifically, variations in the expression and functionality of α7nAChR can be linked to auditory hallucinations experienced by patients with SZ and several therapies have been researched that target α7nAChRs. However, there are very few primary research …

Investigating Brainstem Mechanisms Underlying Prepulse Inhibition Of Startle Impaired In Schizophrenia, Wanyun Huang

Doctoral Dissertations

Sensorimotor gating is a fundamental pre-attentive process, which can be operationally measured through prepulse inhibition (PPI) of the startle response. PPI describes the suppression of the startle response when a non-startling stimulus (“prepulse”) precedes the startling stimulus (“pulse”). As a hallmark of schizophrenia, PPI deficits are also found in other neuropsychiatric disorders and are associated with cognitive overload and attention impairments (Braff et al., 2001). However, currently-used dopaminergic antipsychotics exhibit inconsistent effects on PPI in affected individuals (Geyer et al., 2001; Frau et al., 2014; Lally et al., 2016). Therefore, it’s critical to investigate the precise cellular and synaptic mechanisms …

Modelling Prenatal Hypoxia As A Risk Factor For Schizophrenia Vulnerability In Patient-Derived Cerebral Organoids, Dana M. Gummerson

Electronic Thesis and Dissertation Repository

Prenatal hypoxia during fetal development is a significant environmental risk factor linked to schizophrenia (SCZ) vulnerability. However, hypoxia’s impact on human brain development at the cellular level remains unclear. Our laboratory has developed human cerebral organoids using induced pluripotent stem cells (iPSCs) derived from healthy control or SCZ patient cell lines to address these questions. This creates a platform that allows for the investigation into the pathophysiology of SCZ and hypoxia in tandem. Organoids were exposed to hypoxic conditions at one month of development, mimicking the early stages of cortical growth in the human fetus. Results reveal innate differences in …

Identifying Functional Imaging Markers In Psychosis Using Fmri, Ruiqi Wang

MUSC Theses and Dissertations

Major types of psychotic disorders include schizophrenia (SCZ), bipolar disorder (BP) and schizoaffective disorder (SZA). These disorders have profound and overlapping symptoms with marked cognitive deficits, and their diagnosis relies on symptom clusters. The treatments for psychosis are usually focused on positive symptoms such as delusions and hallucinations. Although cognitive impairments underlie both positive and negative symptoms, functional brain imaging biomarkers that can reliably predict a patient's cognitive deficits are still lacking. Therefore, this project used functional MRI to explore the feasibility of using functional connectivity (FC) to predict cognitive performance.

A total of 207 subjects (BP: 79, SZ/SZA: 48, …

Glutamate, And Its Relationship To Task-Induced Functional Connectivity In The Human Brain: A Focus On Schizophrenia, Kathleen Liu Young, John Kopchick, Jeffrey Stanley, Vaibhav Diwadkar

Medical Student Research Symposium

Glutamate is the brain’s major excitatory neurotransmitter mediating both neuroplasticity and network function (Zhou & Danbolt, 2014). Basal glutamate (Glu) measured using proton magnetic resonance spectroscopy (1H-MRS) provides insight into a region’s density of neuropil related to the glutamatergic system. Moreover, given the role of glutamate in mediating brain network function, Glu levels may play a role in the brain’s functional connectivity (FC), which is typically estimated from functional magnetic resonance imaging (fMRI) time series data. These questions converge when considering the clinical syndrome of schizophrenia (SCZ). Patients with SCZ show abnormalities in basal Glu in the hippocampus and prefrontal …

Prefrontal Coding Of Naturalistic Working Memory: Mechanisms During Normal Maintenance And Modelled Disease, Megan P. Roussy

Electronic Thesis and Dissertation Repository

Neural activity in the primate lateral prefrontal cortex (LPFC) has been causally linked to working memory (WM) ⁠— the brief maintenance and mental manipulation of information. Primates use WM to perform tasks in complex contexts; however, neural mechanisms of WM and the pathophysiology related to WM deficits have traditionally been studied using simple tasks that deviate from naturalistic conditions. This raises the question, how is WM processed in naturalistic conditions? To explore this, I trained two macaque monkeys on a spatial WM task set in a naturalistic virtual environment. During the task, a target was presented in 1 of 9 …

Validation Of The 40 Hz Auditory Steady State Response As A Pharmacodynamic Biomarker Of Evoked Neural Synchrony, Muhammad Ummear Raza

Electronic Theses and Dissertations

Schizophrenia is a troubling and severe mental illness that is only incompletely treated by currently available drugs. New drug development is hindered by a scarcity of functionally relevant pharmacodynamic biomarkers that are translatable across preclinical and human subjects. Although psychosis is a major feature of schizophrenia, cognitive and negative symptoms determine the long-term functional outcomes for patients. Stimulus-evoked neural synchrony at gamma (~ 40 Hz) frequency plays an important role in the processing and integration of sensory information. Not surprisingly, schizophrenia patients show deficits in gamma oscillations. NMDA receptor (NMDAR) activation on fast-spiking parvalbumin-positive interneurons is deemed important for the …

Genetic Heterogeneity In Schizophrenia And Contribution Of Context To Vowel Recognition, Eva Childers

Dartmouth College Ph.D Dissertations

This dissertation is composed of three chapters that address two distinct topics. Chapter 2 addresses the use of consonantal context in vowel perception. Previous studies have demonstrated that context is important for vowel identification, however, this effect may be an artifact of stimuli production. To address this potential confound, we used stimuli extracted from an audiobook and asked subjects to identify vowels encased in consonants and isolated by themselves. We show that subjects had improved vowel identification when the vowel is presented with a consonantal framing, suggesting there is information contained in the surrounding context that is important for phoneme …

Examining Limbic Sexual Dimorphisms In Schizophrenia, Kennedy S. Madrid

Undergraduate Honors Theses

Schizophrenia is a mental disorder that affects a significant number of individuals in the United States and can have numerous different symptoms. Recently, interest in the differences between the neuroanatomy of individuals with schizophrenia and individuals without schizophrenia has emerged, specifically the sexual dimorphism in individuals with schizophrenia. This study aimed to gain a better understanding of the sexual dimorphisms of two structures in the limbic system: the hippocampus and amygdala. Data was harmonized and analyzed from two datasets to determine the sexual dimorphic factor of these structures in healthy controls and individuals with schizophrenia. Demographic features were also taken …

A Preliminary Report: The Hippocampus And Surrounding Temporal Cortex Of Patients With Schizophrenia Have Impaired Blood-Brain Barrier, Eric L. Goldwaser, Randel L. Swanson, Edgardo J. Arroyo, Venkat Venkataraman, Mary C. Kosciuk, Robert G. Nagele, L. Elliot Hong, Nimish K. Acharya

Rowan-Virtua Research Day

Schizophrenia (SZ) is one of the most severe forms of mental illness, yet mechanisms remain unclear. A widely established brain finding in SZ is hippocampal atrophy, and a coherent explanation similarly is lacking. Epidemiological evidence suggests increased cerebrovascular and cardiovascular complications in SZ independent of lifestyle and medication, pointing to disease-specific pathology. Endothelial cell contributions to blood-brain barrier (BBB) compromise may influence neurovascular unit and peripheral vascular function, and we hypothesize that downstream functional and structural abnormalities may be explained by impaired BBB.

A Psychopharmacology Review Of Brexpiprazole, Nicole A. Marion

Conspectus Borealis

Brexpiprazole is an antipsychotic drug often used to help treat schizophrenia and major depressive disorder. This review paper breaks down the drugs history including what it is used for, how it is used, and how it was developed. Pharmacokinetics including administration routes, steady states, and metabolism. This review also describes pharmacodynamics, focusing on drug affinity. It will also discuss pharmacological effects pulling evidence from clinical trials. Last this review will describe the toxicology and safety of brexpiprazole.

Investigating The Effects Of Maternal Immune Activation On Sensory Processing: Timing, Immune Mechanisms, And Gene-Environment Interactions, Faraj Haddad

Electronic Thesis and Dissertation Repository

Maternal infection during the first or second trimester of pregnancy poses a risk factor for the child to have neurodevelopmental disorders like autism spectrum disorder (ASD) and schizophrenia. Various clinical and preclinical studies have shown that the maternal immune response to infection, also known as maternal immune activation (MIA), can disrupt fetal brain development.

Over the past two decades, MIA has been studied in rodents using the Polyinosinic Polycytidylic acid (Poly I:C) rodent model. Poly I:C has a molecular pattern resembling viruses that can induce a robust immune response. Following exposure to Poly I:C MIA, rodent offspring exhibit many brain …

Validation Of Induced Microglia-Like Cells (Img Cells) For Future Studies Of Brain Diseases, Atoshi Banerjee, Yimei Lu, Kenny Do, Travis Mize, Xiaogang Wu, Xiangning Chen, Jingchun Chen

School of Medicine Faculty Publications

Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG …

Apathy And Striatal Gray Matter Patterns In Schizophrenia And Huntington’S Disease, Gabriel Martinez, Skylar Walters, J S. Paulsen, Vince Calhoun, Jessica Turner

Neuroscience Institute Faculty Publications

Apathy is a symptom of many neurodegenerative and neuropsychiatric disorders, such as Huntington's disease and schizophrenia. Apathy is often conceptualized as a combination of three domains, cognitive, behavioral, and emotional, characterized by impaired goal-directed behavior. The striatum has been shown to be significantly associated with executive functions and planned motor behavior via projection to the prefrontal cortex (PFC). Due to its connection to the PFC and its involvement in the basal ganglia motor circuit, the striatum is thought to be a significant part of the circuit that controls goal-directed behavior. The purpose of this study was to investigate the relationship …

Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti

Theses and Dissertations

Class A serotonin (5-hydroxytryptamine) 2A (5-HT_2AR) and class C metabotropic glutamate 2 receptors (mGluR2) are seven transmembrane receptors (7TMRs or G protein-coupled receptors – GPCRs) involved in multiple neuropsychiatric disorders including schizophrenia. Previous findings from our laboratory reported that 5-HT_2AR and mGluR2 are dysregulated in the prefrontal cortex of patients suffering from this psychiatric condition, although 5-HT_2AR’s expression was recovered in antipsychotic-medicated patients. Genome-wide association studies on schizophrenia reported that endosomal trafficking that regulates cell surface abundance of another 7TMR implicated in this disease (dopamine D2 receptor) can be altered. Ligand-activated receptors, including the …

Glucocorticoid Receptor Dysregulation Underlies 5-Ht2a Receptor-Dependent Synaptic And Behavioral Deficits In A Mouse Neurodevelopmental Disorder Model, Justin M. Saunders

Theses and Dissertations

Schizophrenia is a severe neuropsychiatric disorder that presents with diverse symptoms, some of which remain resistant to treatment. Increased risk of neurodevelopmental disorders such as schizophrenia has been observed following gestational infection in humans, leading to development of maternal immune activation (MIA) animal models. Increased density of the serotonin 5-HT2AR receptor (5-HT2AR), the primary target of hallucinogenic drugs and a key target of atypical antipsychotics, has been observed in postmortem antipsychotic-free prefrontal cortex samples from schizophrenia subjects, a change reflected in frontal cortex of adult MIA offspring. To model MIA, we administered 20 mg/kg i.p. of the viral mimetic poly-(I:C) …

The Subplate And Its Role In The Gaba System In The Prefrontal Cortex, Gaeul Kyla Lee

Electronic Thesis and Dissertation Repository

During early brain development, the subplate relays thalamocortical afferents. Lesions to the subplate have been implicated in developmental abnormalities of cortical GABAergic circuits. This thesis examined the effects of subplate lesions in the prefrontal cortex of rats on the expression of GABA markers (parvalbumin and GAD67) and GABA synapse maturation [potassium-chloride cotransporter (KCC2) and sodium-potassium- chloride cotransporter (NKCC1)] with relevance to the characterization of a rat model for schizophrenia. Lesions were made on postnatal day 1 (P1). Lesioned and control rats were sacrificed between P5 and P90 and immunolabelled for parvalbumin, GAD67, KCC2, and NKCC1. We found decreased parvalbumin expression …

Alcohol Consumption In A Preclinical Model Of Schizophrenia, Liza Hernandez

Electronic Theses and Dissertations

Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the global population. Schizophrenia is highly comorbid with other psychiatric disorders such as Alcohol Use Disorder (AUD) with a prevalence rate of 27% - 65%, which is significantly higher than AUD exhibited by the general population (6%). Research indicates that a higher rate of AUD in individuals suffering from schizophrenia may be related to the common neuronal pathways that underlie the expression of both disorders. The present study will determine whether the neonatal quinpirole (NQ) rodent model of schizophrenia will approximate the human condition and exhibit increased EtOH consumption. …

Learning And Motivation For Rewards In Schizophrenia: Implications For Behavioral Rehabilitation, Victoria Martin, Alexandra Brereton, Jicheng Tang

Publications and Research

Purpose of review: Impaired reward processing and amotivation are well documented in schizophrenia. We aim to review the current state of neuroimaging and behavioral research addressing components of motivational deficits in this complex and impairing syndrome. Evidence will be integrated to inform the ongoing development of effective strategies for behavioral rehabilitation. Recent findings: While striatal dopamine and aberrant reward prediction errors have been connected to amotivation in schizophrenia, they are not sufficiently full explanations of reward processing impairments. Frontal dysfunction and associated cognitive control deficits also have evidenced involvement in atypical reward prediction, learning, and valuation. Ongoing work supports the …

The Effects Of Two Novel Anti-Inflammatory Compounds On Prepulse Inhibition And Neural Microglia Cell Activation In A Rodent Model Of Schizophrenia, Heath W. Shelton

Electronic Theses and Dissertations

Recent studies have shown elevated neuroinflammation in a large subset of individuals diagnosed with schizophrenia. A pro-inflammatory cytokine, tumor necrosis factor-alpha (TNFα), has been directly linked to this neuroinflammation. This study examined the effects of two TNFα modulators (PD2024 and PD340) produced by our collaborators at P2D Bioscience, Inc., to alleviate auditory sensorimotor gating deficits and reduce microglial cell activation present in the polyinosinic:polycytidylic (Poly I:C) rodent model of schizophrenia. Auditory sensorimotor gating was assessed using prepulse inhibition and microglial activation was examined and quantified using immunohistochemistry and confocal microscopy, respectively. Both PD2024 and PD340 alleviated auditory sensorimotor gating deficits …

Neurological Discrepancies Between Bipolar Disorder, Schizophrenia And Schizoaffective Disorder, Nat Bush

Senior Theses and Projects

As neurological research advances, so does the understanding of how disorders and diseases develop and how they can be treated. The debate of how mental disorders develop has been ongoing and complicated, as there is still no clear understanding of their cause. In this study, fMRI scans of individuals with bipolar disorder (BPD), schizophrenia (SZP), and schizoaffective disorder (SAD), and a control group were collected in six cities in the United States and were preprocessed to screen out scans that do not succeed in the standardization process. The subjects were included in three analyses: one that compares the subjects based …

Antibodies In The Diagnosis, Prognosis, And Prediction Of Psychotic Disorders., Thomas A Pollak, Jonathan P Rogers, Robert G Nagele, Mark Peakman, James M Stone, Anthony S David, Philip Mcguire

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Blood-based biomarker discovery for psychotic disorders has yet to impact upon routine clinical practice. In physical disorders antibodies have established roles as diagnostic, prognostic and predictive (theranostic) biomarkers, particularly in disorders thought to have a substantial autoimmune or infective aetiology. Two approaches to antibody biomarker identification are distinguished: a "top-down" approach, in which antibodies to specific antigens are sought based on the known function of the antigen and its putative role in the disorder, and emerging "bottom-up" or "omics" approaches that are agnostic as to the significance of any one antigen, using high-throughput arrays to identify distinctive components of the …

The Opposing Roles Of Glun2c And Glun2d Nmda Receptor Subunits In Modulating Neuronal Oscillations, Zhihao Mao

Theses & Dissertations

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects.

NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain …

Cannabinoid Transmission In The Basolateral Amygdala Modulates Prefrontal Cortex And Ventral Hippocampal Activity, Brian J. Pereira

Electronic Thesis and Dissertation Repository

The cannabinoid system is important for maintaining neuron-to-neuron communication within the mammalian brain. One of the most commonly used substances to alter the cannabinoid system is cannabis. Individuals who are exposed to cannabis report having dissociable effects; both positive and negative. High amounts of THC have been commonly associated with the negative effects of cannabis, whereas CBD can be used to counter these. Pre-clinical evidence suggests that the combination of the two compounds can produce a therapeutic benefit for individuals who are susceptible to the effects of THC. The present study investigates whether the combination of THC+CBD can prevent electrophysiological …

Neurocognitive Markers Of Cognitive Control In Schizophrenia And Functional Outcomes, Sephira Ryman

Psychology ETDs

Impaired cognitive function results in decreased objective quality of life and community functioning in schizophrenia, resulting in the largest indirect costs from the disease. Disrupted proactive cognitive control, a form of early selection and active goal maintenance, is hypothesized to underlie the broad cognitive deficits observed in patients with schizophrenia. The current study utilized novel electrophysiological (EEG) analytic approach to examine proactive and reactive cognitive control deficits in schizophrenia patients. Behavioral results highlight that patients exhibited a general reduction in reaction time across two multisensory cognitive control tasks, with selective deficits on proactive conditions relative to reactive conditions. The relative …

A Computational Assessment Of Target Engagement In The Treatment Of Auditory Hallucinations With Transcranial Direct Current Stimulation, Won Hee Lee, Nigel I. Kennedy, Marom Bikson, Sophia Frangou

Publications and Research

We use auditory verbal hallucinations (AVH) to illustrate the challenges in defining and assessing target engagement in the context of transcranial direct current stimulation (tDCS) for psychiatric disorders. We defined the target network as the cluster of regions of interest (ROIs) that are consistently implicated in AVH based on the conjunction of multimodal meta-analytic neuroimaging data. These were prescribed in the New York Head (a population derived model) and head models of four single individuals. We appraised two potential measures of target engagement, tDCS-induced peak electric field strength and tDCS-modulated volume defined as the percentage of the volume of the …

Chromatin Organizer Ctcf In Brain Development And Behaviour, Adrienne Elbert

Electronic Thesis and Dissertation Repository

Chromatin architecture is an important regulator of gene expression, which dictates development. Mutations in one copy of the CTCF chromatin organizer gene cause intellectual disability and autism. Polymorphisms in CTCF have also been associated with increased risk for schizophrenia, a condition that overlaps in biological etiology with autism and intellectual disability. In this thesis, we sought to understand the role of CTCF in neurodevelopment using brain-specific conditional knockout and heterozygote mouse models. Using the Ctcf-null animals, we identify a cell-autonomous role for CTCF in regulating cortical interneuron development in the medial ganglionic eminence (MGE) through the transcriptional control of …

Chronic Clozapine Treatment Impairs Functional Activation Of Metabotropic Glutamate Receptor 2 Via An Hdac2-Depedent Mechanism, Travis M. Cuddy

Theses and Dissertations

Schizophrenia is a chronic mental disorder affecting millions worldwide. It has no known cure. Current pharmaceutical treatments have shown efficacy in only one of the three symptom clusters of schizophrenia, providing little or no benefit in the other two. Furthermore, the current standard-of-care drugs, known as atypical antipsychotics, carry risks of severe side effects affecting multiple body systems. Most patients opt to discontinue drug therapy within two years of initiation due to lack of efficacy and/or preponderance of adverse effects. Previous findings have shown that chronic usage of atypical antipsychotics causes a 5-HT_2A-dependent upregulation of histone deacetylase 2 …

Decoding The Signaling Of The D2r-2ar Heteromer: Relevance To Schizophrenia, Miao Huang

Theses and Dissertations

Schizophrenia is a severe mental disorder affecting ~1% of world population. Two G protein coupled receptors (GPCRs): Gi-coupled dopamine D2 receptor (D₂R), and Gq-coupled serotonin 2A receptor (2AR), are targeted by the typical and atypical antipsychotic drugs to treat schizophrenia. These two receptors have been shown to co-localize in brain regions relevant to schizophrenia, including the ventral tegmental area (VTA), striatum, and prefrontal cortex (PFC). Studies in our lab characterized the integrated signaling of the D₂R-2AR heteromer and found that both the Gi activity of D₂R and the Gq activity of 2AR were potentiated …