Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Male Mice DOI Creative Commons

Wei-li Chang,

Karly Tegang,

Benjamin A. Samuels

et al.

Biological Psychiatry Global Open Science, Journal Year: 2024, Volume and Issue: 5(2), P. 100419 - 100419

Published: Nov. 20, 2024

Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute memory interference and overgeneralization seen many neuropsychiatric conditions, including depression, anxiety, posttraumatic stress disorder, dementia, age-related cognitive decline. Although BPS relies on the dentate gyrus is sensitive changes adult hippocampal neurogenesis, its significance as a pharmacological target has not been tested. In this study, we applied human neural stem cell high-throughput screening cascade identify compounds that increase neurogenesis. One compound with favorable profile, RO6871135, was then tested young aged mice for effects anxiety-related behaviors. Chronic treatment RO6871135 (7.5 mg/kg) increased neurogenesis improved fear discrimination task both mice. also lowered innate anxiety-like behavior, which more apparent exposed chronic corticosterone. Ablation of by irradiation supported neurogenesis-dependent mechanism RO6871135-induced improvements BPS. To possible mechanisms action, vitro vivo kinase inhibition chemical proteomics assays were performed. These tests indicated inhibited CDK8, CDK11, CaMKIIa, CaMKIIb, MAP2K6, GSK-3β. An analog demonstrated high affinity studies demonstrate method empirical identification preclinical testing novel neurogenic can improve point be interrogated development new therapies specific endophenotypes such impaired

Language: Английский

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Male Mice DOI Creative Commons

Wei-li Chang,

Karly Tegang,

Benjamin A. Samuels

et al.

Biological Psychiatry Global Open Science, Journal Year: 2024, Volume and Issue: 5(2), P. 100419 - 100419

Published: Nov. 20, 2024

Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute memory interference and overgeneralization seen many neuropsychiatric conditions, including depression, anxiety, posttraumatic stress disorder, dementia, age-related cognitive decline. Although BPS relies on the dentate gyrus is sensitive changes adult hippocampal neurogenesis, its significance as a pharmacological target has not been tested. In this study, we applied human neural stem cell high-throughput screening cascade identify compounds that increase neurogenesis. One compound with favorable profile, RO6871135, was then tested young aged mice for effects anxiety-related behaviors. Chronic treatment RO6871135 (7.5 mg/kg) increased neurogenesis improved fear discrimination task both mice. also lowered innate anxiety-like behavior, which more apparent exposed chronic corticosterone. Ablation of by irradiation supported neurogenesis-dependent mechanism RO6871135-induced improvements BPS. To possible mechanisms action, vitro vivo kinase inhibition chemical proteomics assays were performed. These tests indicated inhibited CDK8, CDK11, CaMKIIa, CaMKIIb, MAP2K6, GSK-3β. An analog demonstrated high affinity studies demonstrate method empirical identification preclinical testing novel neurogenic can improve point be interrogated development new therapies specific endophenotypes such impaired

Language: Английский

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