• Development of an Instrument for Assessment of Auditory Hallucinations in Schizophrenia

      Frederick, Jane A; Department of Physiological and Technological Nursing (2000-03)
      The purpose of this study was to develop and assess the psychometrics of an instrument for the assessment of auditory hallucinations in schizophrenia and other psychiatric disorders. Development of the Auditory Hallucination Assessment Scale (AHAS) was guided by Albert Ellis’ reformulated model of Rational Emotive Behavior Therapy, the ABCD model. Applied to auditory hallucinations, the ABCD model asserts that distress and maladaptive coping behaviors are consequences not of the hallucination itself, but of the individual’s beliefs about the hallucination. An initial draft of the AHAS was submitted to an expert panel for assessment of content validity. The revised version of the AHAS is a 32 item self-report. Likert scale items describe characteristics, beliefs and attitudes about hallucinations and consequences of hallucinations. The psychometric properties of the AHAS were studied in a convenience sample of 151 clients in psychosocial rehabilitation outpatient day programs in two Georgia counties. Participants also completed two other hallucination scales, and one depression scale. Exploratory factor analysis was used to determine the underlying factor structure of the items and to assess the construct validity of the AHAS. The factor analysis resulted in a three-factor model which delineated three differing clinical symptom patterns of auditory hallucinations. The factors were labeled Troublesome Voices, Dangerous Voices, and Nurturing Voices. Rather than dividing the hallucinatory experience into three cognitive components as in the theoretical model, the factors reflected connections between the characteristics, beliefs, and consequences of auditory hallucinations. Thus, each of the constructs of the theoretical model operates within each of the resulting factors. The Troublesome Voices Factor consists of items indicating distressing auditory hallucinations and attempts to cope with them. The items on this factor indicate self-awareness and reflect behavioral or emotional reactions to the voices. The items on the Dangerous Voices Factor reflect beliefs that the voices are bad, hostile and powerful. The Nurturing Voices Factor items indicate that the individual experiences soothing and comforting voices. Finally, it is clinically significant that all participants in the sample, ninety-one percent of whom had schizophrenia or schizoaffective disorder, were able to complete the AHAS without difficulty.
    • Gene-Environment Interaction Modulates Schizophrenic Endophenotypes in Heterozygous Reeler Mice

      Howell, Kristy R.; Department of Psychiatry and Health Behavior (2013-07)
      Aim 1: To determine the effect of chronic stress on the VEGF signaling pathway. Aim 2: To determine the effects of prenatal hypoxia on VEGF signaling, behavioral activities, blood flow, and brain volume in heterozygous reeler mice during early adulthood. Aim 3: To evaluate long lasting effects of prenatal hypoxia on VEGF signaling, behavioral activities, blood flow, and brain volume in heterozygous reeler mice. Aim 4: To determine the correlation between serum VEGF levels and brain volumes in schizophrenia subjects.
    • Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene ERBB4 and neuregulin-1 – ERBB4 signaling in monoamine neurons

      Bean, Jonathan C; Department of Neuroscience and Regenerative Medicine (2015)
      Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to be expressed in excitatory neurons although recent studies have disputed this view. Utilizing mice that express a fluorescent protein under the promoter of the ErbB4 gene, I determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain and hindbrain. In particular, ErbB4 was expressed in both dopamine neurons in the substantia nigra and ventral tegmental area and in serotoninergic neurons of raphe nuclei, but not in norepinephrinergic neurons of the locus coeruleus. In hypothalamus, ErbB4 was present in neurons that express oxytocin. ErbB4 was expressed in a group of cells in the subcortical areas that are positive for S100β. These results identify novel cellular targets of NRG1-ErbB4 signaling. Finally, perfusion of NRG1 into the medial prefrontal cortex enhanced both dopamine and serotonin release but with differing time courses.
    • Long-Term Continuous Corticosterone Treatment Decreases VEGF Receptor-2 Expression in Frontal Cortex

      Howell, Kristy R.; Kutiyanawalla, Ammar; Pillai, Anilkumar; Department of Psychiatry and Health Behavior (2011-05-27)
      Objective: Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated.
    • Neuregulin1 promotes excitatory synapse development specifically in GABAergic interneurons

      Tin, Kin Lai; Department of Neuroscience and Regenerative Medicine (2010-03)
      Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD- 95 puncta in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no consistent effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in postsynaptic differentiation in interneurons. Taken together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism.
    • A Variable Prenatal Stress Paradigm as a Valid Drug Discovery Platform for Cognitive Deficits Associated with Neuropsychiatric Disorders

      Wilson, Christina Ann; Department of Pharmacology and Toxicology (2012-10)
      Cognitive dysfunction is now recognized to be central to the functional disability of several neuropsychiatric disorders. However, treatment options for the management of cognitive symptoms are limited and the development of novel therapeutics has been made difficult by the lack of appropriate animal models. It has been suggested that variable prenatal stress (PNS) in rodents might be an etiologically appropriate model for some components of schizophrenia. Thus, the overall goal of this dissertation project was to conduct a comprehensive behavioral study of the model to assess face validity, and to make a preliminary assessment of its construct and predictive validity. Our results indicate that exposure to PNS results in elevated corticosterone levels following exposure to acute stress, increased aggressive behaviors, as well as increased locomotor activity and stereotypic behaviors. Further, PNS rats had altered innate fear responses to predator odor as well as impaired fear extinction. Additionally, PNS in rats was associated with impairments of sustained attention, inhibitory response control, and recognition memory all of which could be attenuated by the norepinephrine reuptake inhibitor, atomoxetine. Collectivity, these data support the premise that PNS in rodents is a valid model system for studying some behavioral components of neuropsychiatric disorders as well as their treatment.