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Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

Behavioral pattern separation and cognitive flexibility are essential cognitive abilities that are disrupted in many brain disorders. A better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on the...

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Autores principales: Yun, Sanghee, Soler, Ivan, Tran, Fionya H., Haas, Harley A., Shi, Raymon, Bancroft, Grace L., Suarez, Maiko, de Santis, Christopher R., Reynolds, Ryan P., Eisch, Amelia J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267474/
https://www.ncbi.nlm.nih.gov/pubmed/37324519
http://dx.doi.org/10.3389/fnbeh.2023.1151877
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author Yun, Sanghee
Soler, Ivan
Tran, Fionya H.
Haas, Harley A.
Shi, Raymon
Bancroft, Grace L.
Suarez, Maiko
de Santis, Christopher R.
Reynolds, Ryan P.
Eisch, Amelia J.
author_facet Yun, Sanghee
Soler, Ivan
Tran, Fionya H.
Haas, Harley A.
Shi, Raymon
Bancroft, Grace L.
Suarez, Maiko
de Santis, Christopher R.
Reynolds, Ryan P.
Eisch, Amelia J.
author_sort Yun, Sanghee
collection PubMed
description Behavioral pattern separation and cognitive flexibility are essential cognitive abilities that are disrupted in many brain disorders. A better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on the integrity of the hippocampal dentate gyrus (DG) which receives glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). An inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here, we asked if the activity of LEC fan cells that directly project to the DG (LEC → DG neurons) regulates the relatively more complex hippocampal-dependent abilities of behavioral pattern separation or cognitive flexibility. C57BL/6J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA). Prior work shows that 4 weeks post-surgery, TRIP8b mice have more DG neurogenesis and greater activity of LEC → DG neurons compared to SCR shRNA mice. Here, 4 weeks post-surgery, the mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based location discrimination reversal [LDR]) and innate fear of open spaces (elevated plus maze [EPM]) followed by quantification of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). There was no effect of treatment (SCR shRNA vs. TRIP8b) on performance during general touchscreen training, LDR training, or the 1st days of LDR testing. However, in the last days of LDR testing, the TRIP8b shRNA mice had improved pattern separation (reached the first reversal more quickly and had more accurate discrimination) compared to the SCR shRNA mice, specifically when the load on pattern separation was high (lit squares close together or “small separation”). The TRIP8b shRNA mice were also more cognitively flexible (achieved more reversals) compared to the SCR shRNA mice in the last days of LDR testing. Supporting a specific influence on cognitive behavior, the SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate that the TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis compared to the SCR shRNA mice. This study advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival—behavioral pattern separation and cognitive flexibility—and suggests that the activity of LEC → DG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output.
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spelling pubmed-102674742023-06-15 Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity Yun, Sanghee Soler, Ivan Tran, Fionya H. Haas, Harley A. Shi, Raymon Bancroft, Grace L. Suarez, Maiko de Santis, Christopher R. Reynolds, Ryan P. Eisch, Amelia J. Front Behav Neurosci Behavioral Neuroscience Behavioral pattern separation and cognitive flexibility are essential cognitive abilities that are disrupted in many brain disorders. A better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on the integrity of the hippocampal dentate gyrus (DG) which receives glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). An inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here, we asked if the activity of LEC fan cells that directly project to the DG (LEC → DG neurons) regulates the relatively more complex hippocampal-dependent abilities of behavioral pattern separation or cognitive flexibility. C57BL/6J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA). Prior work shows that 4 weeks post-surgery, TRIP8b mice have more DG neurogenesis and greater activity of LEC → DG neurons compared to SCR shRNA mice. Here, 4 weeks post-surgery, the mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based location discrimination reversal [LDR]) and innate fear of open spaces (elevated plus maze [EPM]) followed by quantification of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). There was no effect of treatment (SCR shRNA vs. TRIP8b) on performance during general touchscreen training, LDR training, or the 1st days of LDR testing. However, in the last days of LDR testing, the TRIP8b shRNA mice had improved pattern separation (reached the first reversal more quickly and had more accurate discrimination) compared to the SCR shRNA mice, specifically when the load on pattern separation was high (lit squares close together or “small separation”). The TRIP8b shRNA mice were also more cognitively flexible (achieved more reversals) compared to the SCR shRNA mice in the last days of LDR testing. Supporting a specific influence on cognitive behavior, the SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate that the TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis compared to the SCR shRNA mice. This study advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival—behavioral pattern separation and cognitive flexibility—and suggests that the activity of LEC → DG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output. Frontiers Media S.A. 2023-06-01 /pmc/articles/PMC10267474/ /pubmed/37324519 http://dx.doi.org/10.3389/fnbeh.2023.1151877 Text en Copyright © 2023 Yun, Soler, Tran, Haas, Shi, Bancroft, Suarez, de Santis, Reynolds and Eisch. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Behavioral Neuroscience
Yun, Sanghee
Soler, Ivan
Tran, Fionya H.
Haas, Harley A.
Shi, Raymon
Bancroft, Grace L.
Suarez, Maiko
de Santis, Christopher R.
Reynolds, Ryan P.
Eisch, Amelia J.
Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title_full Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title_fullStr Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title_full_unstemmed Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title_short Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
title_sort behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
topic Behavioral Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267474/
https://www.ncbi.nlm.nih.gov/pubmed/37324519
http://dx.doi.org/10.3389/fnbeh.2023.1151877
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