{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/10583"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/10583","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Pharmacological Intervention Reduces Hippocampal Hyperactivity in a Mouse Model of Psychosis","abstract":"Psychosis is a predominant symptom domain in the conventional diagnosis of schizophrenia as well as in other psychiatric disorders. Current pharmacological treatment options abound in side effects, leading to poor patient adherence. Therefore, we are in need of novel mechanistic treatment targets. Prior research has identified the molecular and behavioral characteristics of a model in animals putatively parallel to hippocampal hyperactivity in human schizophrenia brain. A reverse-translational mouse model of psychosis has been developed based on subchronic chemogenetic inhibition of dentate gyrus (DG) during adolescence and it could become a candidate for testing antipsychotic drug activity. The subchronic DG inhibition causes a lasting downstream hippocampal hyperactivity, along with behavioral consequences. This doctoral dissertation examines the influence of antipsychotic and experimental compounds on hippocampal subfield activity as well as their influence on correcting aberrant behaviors with face validity to psychosis. The current scientific consensus in respect to psychosis and hippocampus is briefly introduced in Chapters 1 and 2. In Chapter 3, I have delineated pharmacology used in these studies. The drugs used were haloperidol - a classic antipsychotic, and levetiracetam - anticonvulsant with proven pro-cognitive effect, but experimental in the field of psychosis. In Chapter 4, I have examined the effects of subchronic Compound 21 administration one week after DG inhibition by quantifying principal cell activity in hippocampal subfields. The CA3 and CA1 were hyperactive compared to control mice. The effects of acute drug administration were assessed: all drugs tested showed robust decrease of baseline CA3 and CA1 hyperactivity (haloperidol 0.3mg/kg ip, levetiracetam 5mg/kg ip). Subsequently, in Chapter 5 I have performed Social Recognition Memory test with and without haloperidol (1.75mg/kg/day oral) or levetiracetam (100mg/kg/day oral), as well as cued and contextual fear conditioning with haloperidol (1.75mg/kg/day oral). Haloperidol, but not levetiracetam, rescued the deficit in Social Recognition Memory. However, haloperidol did not alter the increased freezing in fear conditioning paradigm. Finally, in Chapter 6, I describe how the results of this dissertation pave the way to further research of the diverse mechanisms of decreasing hippocampal hyperactivity that could lead to amelioration of psychosis-like symptoms and constitute a translational potential.","abstract_html":"Psychosis is a predominant symptom domain in the conventional diagnosis of schizophrenia as well as in other psychiatric disorders. Current pharmacological treatment options abound in side effects, leading to poor patient adherence. Therefore, we are in need of novel mechanistic treatment targets. Prior research has identified the molecular and behavioral characteristics of a model in animals putatively parallel to hippocampal hyperactivity in human schizophrenia brain. A reverse-translational mouse model of psychosis has been developed based on subchronic chemogenetic inhibition of dentate gyrus (DG) during adolescence and it could become a candidate for testing antipsychotic drug activity. The subchronic DG inhibition causes a lasting downstream hippocampal hyperactivity, along with behavioral consequences. This doctoral dissertation examines the influence of antipsychotic and experimental compounds on hippocampal subfield activity as well as their influence on correcting aberrant behaviors with face validity to psychosis. The current scientific consensus in respect to psychosis and hippocampus is briefly introduced in Chapters 1 and 2. In Chapter 3, I have delineated pharmacology used in these studies. The drugs used were haloperidol - a classic antipsychotic, and levetiracetam - anticonvulsant with proven pro-cognitive effect, but experimental in the field of psychosis. In Chapter 4, I have examined the effects of subchronic Compound 21 administration one week after DG inhibition by quantifying principal cell activity in hippocampal subfields. The CA3 and CA1 were hyperactive compared to control mice. The effects of acute drug administration were assessed: all drugs tested showed robust decrease of baseline CA3 and CA1 hyperactivity (haloperidol 0.3mg/kg ip, levetiracetam 5mg/kg ip). Subsequently, in Chapter 5 I have performed Social Recognition Memory test with and without haloperidol (1.75mg/kg/day oral) or levetiracetam (100mg/kg/day oral), as well as cued and contextual fear conditioning with haloperidol (1.75mg/kg/day oral). Haloperidol, but not levetiracetam, rescued the deficit in Social Recognition Memory. However, haloperidol did not alter the increased freezing in fear conditioning paradigm. Finally, in Chapter 6, I describe how the results of this dissertation pave the way to further research of the diverse mechanisms of decreasing hippocampal hyperactivity that could lead to amelioration of psychosis-like symptoms and constitute a translational potential.","abstract_has_math":false,"creators":["Dybowski, Filip Piotr"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Kitamura, Takashi","Tamminga, Carol","Green, Carla B.","Yamamoto, Jun","Kourrich, Said"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-06-03T19:48:23Z","date_published":"2025-06-03T19:48:23Z","updated_at":"2026-07-24T05:52:08Z","subjects":["CA1 Region, Hippocampal","Hippocampus","Psychotic Disorders","Schizophrenia","Antipsychotic Agents"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1522122345"],"render_values":[{"text":"1522122345","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/10583","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kitamura, Takashi","Tamminga, Carol","Green, Carla B.","Yamamoto, Jun","Kourrich, Said"]},{"key":"dc:creator","label":"Author","values":["Dybowski, Filip Piotr"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-06-03T19:48:23Z","2023-05","May 2023","2025-06-03T19:48:24Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["CA1 Region, Hippocampal","Hippocampus","Psychotic Disorders","Schizophrenia","Antipsychotic Agents"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/10583","1522122345"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Psychosis is a predominant symptom domain in the conventional diagnosis of schizophrenia as well as in other psychiatric disorders. Current pharmacological treatment options abound in side effects, leading to poor patient adherence. Therefore, we are in need of novel mechanistic treatment targets. Prior research has identified the molecular and behavioral characteristics of a model in animals putatively parallel to hippocampal hyperactivity in human schizophrenia brain. A reverse-translational mouse model of psychosis has been developed based on subchronic chemogenetic inhibition of dentate gyrus (DG) during adolescence and it could become a candidate for testing antipsychotic drug activity. The subchronic DG inhibition causes a lasting downstream hippocampal hyperactivity, along with behavioral consequences. This doctoral dissertation examines the influence of antipsychotic and experimental compounds on hippocampal subfield activity as well as their influence on correcting aberrant behaviors with face validity to psychosis. The current scientific consensus in respect to psychosis and hippocampus is briefly introduced in Chapters 1 and 2. In Chapter 3, I have delineated pharmacology used in these studies. The drugs used were haloperidol - a classic antipsychotic, and levetiracetam - anticonvulsant with proven pro-cognitive effect, but experimental in the field of psychosis. In Chapter 4, I have examined the effects of subchronic Compound 21 administration one week after DG inhibition by quantifying principal cell activity in hippocampal subfields. The CA3 and CA1 were hyperactive compared to control mice. The effects of acute drug administration were assessed: all drugs tested showed robust decrease of baseline CA3 and CA1 hyperactivity (haloperidol 0.3mg/kg ip, levetiracetam 5mg/kg ip). Subsequently, in Chapter 5 I have performed Social Recognition Memory test with and without haloperidol (1.75mg/kg/day oral) or levetiracetam (100mg/kg/day oral), as well as cued and contextual fear conditioning with haloperidol (1.75mg/kg/day oral). Haloperidol, but not levetiracetam, rescued the deficit in Social Recognition Memory. However, haloperidol did not alter the increased freezing in fear conditioning paradigm. Finally, in Chapter 6, I describe how the results of this dissertation pave the way to further research of the diverse mechanisms of decreasing hippocampal hyperactivity that could lead to amelioration of psychosis-like symptoms and constitute a translational potential."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Pharmacological Intervention Reduces Hippocampal Hyperactivity in a Mouse Model of Psychosis"]}]}],"canonical_facts":{"dc:contributor":["Kitamura, Takashi","Tamminga, Carol","Green, Carla B.","Yamamoto, Jun","Kourrich, Said"],"dc:creator":["Dybowski, Filip Piotr"],"dc:date":["2025-06-03T19:48:23Z","2023-05","May 2023","2025-06-03T19:48:24Z"],"dc:description":["Psychosis is a predominant symptom domain in the conventional diagnosis of schizophrenia as well as in other psychiatric disorders. Current pharmacological treatment options abound in side effects, leading to poor patient adherence. Therefore, we are in need of novel mechanistic treatment targets. Prior research has identified the molecular and behavioral characteristics of a model in animals putatively parallel to hippocampal hyperactivity in human schizophrenia brain. A reverse-translational mouse model of psychosis has been developed based on subchronic chemogenetic inhibition of dentate gyrus (DG) during adolescence and it could become a candidate for testing antipsychotic drug activity. The subchronic DG inhibition causes a lasting downstream hippocampal hyperactivity, along with behavioral consequences. This doctoral dissertation examines the influence of antipsychotic and experimental compounds on hippocampal subfield activity as well as their influence on correcting aberrant behaviors with face validity to psychosis. The current scientific consensus in respect to psychosis and hippocampus is briefly introduced in Chapters 1 and 2. In Chapter 3, I have delineated pharmacology used in these studies. The drugs used were haloperidol - a classic antipsychotic, and levetiracetam - anticonvulsant with proven pro-cognitive effect, but experimental in the field of psychosis. In Chapter 4, I have examined the effects of subchronic Compound 21 administration one week after DG inhibition by quantifying principal cell activity in hippocampal subfields. The CA3 and CA1 were hyperactive compared to control mice. The effects of acute drug administration were assessed: all drugs tested showed robust decrease of baseline CA3 and CA1 hyperactivity (haloperidol 0.3mg/kg ip, levetiracetam 5mg/kg ip). Subsequently, in Chapter 5 I have performed Social Recognition Memory test with and without haloperidol (1.75mg/kg/day oral) or levetiracetam (100mg/kg/day oral), as well as cued and contextual fear conditioning with haloperidol (1.75mg/kg/day oral). Haloperidol, but not levetiracetam, rescued the deficit in Social Recognition Memory. However, haloperidol did not alter the increased freezing in fear conditioning paradigm. Finally, in Chapter 6, I describe how the results of this dissertation pave the way to further research of the diverse mechanisms of decreasing hippocampal hyperactivity that could lead to amelioration of psychosis-like symptoms and constitute a translational potential."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/10583","1522122345"],"dc:language":["en"],"dc:subject":["CA1 Region, Hippocampal","Hippocampus","Psychotic Disorders","Schizophrenia","Antipsychotic Agents"],"dc:title":["Pharmacological Intervention Reduces Hippocampal Hyperactivity in a Mouse Model of Psychosis"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:08Z"}