Browsing by Subject "Prefrontal cortex"

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    Effective Disconnection of Intrinsic Networks in the Prefrontal Cortex: Convergence across Primate and Mouse Models of Schizophrenia
    (2018-09) Zick, Jennifer
    Individuals who are afflicted with schizophrenia experience a disorienting array of symptoms that include sensations of nonexistent stimuli (hallucinations), fixed beliefs not grounded in reality (delusions), emotional disturbances, and a generalized disorganization of thought. Some of the most fundamental aspects of consciousness can be disrupted in schizophrenia, such as the capacity to maintain a continuous thought process, plan and predict future actions and consequences, discern threatening from beneficial stimuli, and consciously inhibit impulsive or harmful behavior. Descriptions of the subjective experience of schizophrenia often revolve around the idea that the executive “self” of an individual is disconnected or no longer whole. Executive functions are thought to be distributed throughout cortical and subcortical networks, but to the extent that they can be localized they tend to depend on proper functioning of regions within the prefrontal cortex. In particular, the dorsolateral prefrontal cortex (DLPFC) of primates is considered to be vital in the process of organizing thought, and likewise the disorganization of thought in schizophrenia is linked to dysfunction in this region. For example, the DLPFC contains a densely interconnected circuit of pyramidal neurons that can sustain neural activity in the absence of sensory input, which is thought to underlie our ability to maintain a concept “in mind” after it has disappeared. What happens when these fundamental processes are disrupted? The manifestations can range from subtle disturbances in the integration of sensory input to a failure to distinguish reality from imagination. In this dissertation, I describe the contributions I have made to the understanding of schizophrenia during the course of my graduate school training. I was given the opportunity to begin my work on this project by analyzing preexisting neural data obtained from the DLPFC in a pharmacological primate model of schizophrenia . From there, I developed a surgical and recording protocol that allowed me to generate comparable in vivo data from the prefrontal cortex of awake Dgcr8+/- mice, an established genetic model of schizophrenia. Despite the disparities between these two animal models, I report convergent patterns indicating a disruption of neuronal correlations in the prefrontal regions of both monkeys given dissociative drugs and mice carrying a schizophrenia-associated mutation. In both studies, I found evidence that neurons in the disease state were not synchronizing their activity with each other as effectively as in the control state. Furthermore, the effective transfer of information between pairs of neighboring neurons was reduced. These results suggest that the intrinsic circuitry of the prefrontal cortex may be disconnected in schizophrenia, and that this disconnection relates to a reduction in coincident spiking activity of neighboring neurons. It is plausible that such a dissolution of local prefrontal connectivity could result in a failure to achieve the cognitively demanding task of thought organization. While much is yet to be learned about the nature of schizophrenia, my findings have the potential to motivate the development of novel approaches to the restoration of function in this devastating disease.
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    Movement sequences based on temporal interval duration and spatial position and neuronal activity in macaque dorsolateral prefrontal cortex
    (2014-11) Kerrigan, Stephen
    In neural and imaging studies the Dorsolateral Prefrontal Cortex (DLPFC) has each been shown to participate in encoding the passage of time, as well as spatial movement sequences. But we do not know how time, space, and serial order are encoded during more complex behaviors that require simultaneous control over all of these elements. In this thesis non-human primates were trained to perform a complex spatio-temporal sequence task comprised of three directional arm movements that were followed by three self-timed temporal delay intervals. We recorded single neurons in the DLPFC of two animals during performance of this task. We found evidence the single cells encoded information about the serial order, temporal interval, and direction of each movement as independent quantities as well as a joint aggregate.
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    Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats
    (2023-04) Liu, Shirelle
    Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied.In this study, Next-Generation RNA-sequencing (RNA-seq) was employed followed by quantitative chromatin immunoprecipitation to investigate changes in gene expression and their regulation in adult male and female rats’ dorsomedial prefrontal cortex (dmPFC) after a regimen of daily injection of morphine (5.0 mg/kg; 10 days). Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. A complementary behavioral study evaluated the effects of the same morphine injection regimen on locomotor activity, pain sensitivity, and somatic withdrawal signs. Behaviorally, repeated morphine injection induced locomotor hyperactivity and hyperalgesia in both sexes. 90% of differentially expressed genes (DEGs) in morphine-treated rats were upregulated in both males and females, with a 35% overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Chromatin immunoprecipitation revealed enrichment of H3 acetylation, a transcriptionally activating chromatin mark. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males. The results cohere with findings from previous studies based on a priori gene selection. This study also reveals novel genes and molecular pathways that are upregulated by repeated morphine exposure, with some common to males and females and others that are sex-specific.