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Tegang, K.

Publications and source records attributed to Tegang, K..

2 recordsLinked to original sources

Distinct representations of an anxiogenic environment in different cell types of the ventral hippocampus

In addition to its role in episodic memory and spatial navigation, the hippocampus has also been found to influence mood-related disorders such as anxiety and depression. These seemingly distinct roles are consistent with a functional dissociation between the two anatomical poles of the hippocampus: whereas the dorsal portion of the hippocampus in rodents is necessary for spatial tasks, the ventral portion controls affective behaviors. We have recently found that neurons in the ventral, but not dorsal, CA1 area of mice encode anxiety-related information (i.e. are "anxiety cells") in diverse defensive and exploratory behaviors. Still it is unclear how general threat-related information is computed within the hippocampal circuit. In this work, we have examined how distinct hippocampal subregions and cell types encode anxiety-related information by imaging calcium activity in large populations of genetically-defined neurons in the ventral hippocampus while mice explore the elevated plus maze (EPM), a conflict-based anxiety test. We compared the neural encoding of task-related features within the ventral CA1 (vCA1) and ventral dentate gyrus (vDG) regions in order to examine the emergence of anxiety-related activity through the hippocampal circuit. We found that granule cells (vGCs) of the vDG represented similar valence information to neurons in vCA1 in the form of arm-type specific encoding in the EPM, which suggests that encoding of anxiety-related features is already present at this first stage of hippocampal processing. When compared with ventral granule cells (vGCs), ventral mossy cells (vMCs) underlying the DG had stronger spatial encoding and less valence encoding, suggesting that they may be more functionally connected with the highly spatially sensitive dorsal hippocampus. Together these findings will help to understand the encoding of anxiety-related information in the hippocampus and how it relates to neural circuit defects in mood-related disorders.

neuroscience↗

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice

BACKGROUNDImpairments in behavioral pattern separation (BPS)--the ability to distinguish between similar contexts or experiences--contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODSIn this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTSChronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONSThese studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

animal behavior and cognition↗