TY - JOUR
T1 - Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
AU - Yun, Sanghee
AU - Soler, Ivan
AU - Tran, Fionya H.
AU - Haas, Harley A.
AU - Shi, Raymon
AU - Bancroft, Grace L.
AU - Suarez, Maiko
AU - de Santis, Christopher R.
AU - Reynolds, Ryan P.
AU - Eisch, Amelia J.
N1 - Funding Information:
SY support: NIH [Training Grant MH076690 (PI: Tamminga), R21MH107945 (PI: AE), R15 MH117628 (PI: Lambert) NS088555 (PI: Stowe)], a 2018 PENN McCabe Pilot grant, a 2019 IBRO travel grant, the PENN Undergraduate Research Foundation (PI: SY), a 2019 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation, a 2021 NASA HERO grant (80NSSC21K0814, PI: SY), and CHOP [Foerderer Fund for Excellence (PI: Van Batavia)], and philanthropic funds to the Eisch Lab. IS support: by the Penn Post Baccalaureate Research Education Program (PennPREP) which was supported by a grant from the NIH (R25GM071745, PI: KL Jordan-Sciutto) and additional funding from Biomedical Graduate Studies at the University of Pennsylvania. AE support: NASA [NNX07AP84G and NNX12AB55G (co-I AE) and NNX15AE09G (PI: AE)], NIH [DA007290, DA023555, DA016765, and MH107945 (PI: AE), R15 MH117628 (PI: Lambert) T, 32NS007413-25 (PI: AE and Marsh), NS088555 (PI: Stowe), and NS126279 (PI: Ahrens-Nicklas], CHOP [Foerderer Fund for Excellence (PI: Van Batavia)], Perelman School of Medicine's Department of Radiation Oncology Pilot Grant (PI: AE and Fan), and philanthropic funds to the Eisch Lab (PI: AE and Fan).
Publisher Copyright:
Copyright © 2023 Yun, Soler, Tran, Haas, Shi, Bancroft, Suarez, de Santis, Reynolds and Eisch.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - HCN
KW - TRIP8b
KW - fan cell
KW - location discrimination
KW - touchscreen based operant learning
UR - http://www.scopus.com/inward/record.url?scp=85162054244&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85162054244&partnerID=8YFLogxK
U2 - 10.3389/fnbeh.2023.1151877
DO - 10.3389/fnbeh.2023.1151877
M3 - Article
C2 - 37324519
AN - SCOPUS:85162054244
SN - 1662-5153
VL - 17
JO - Frontiers in Behavioral Neuroscience
JF - Frontiers in Behavioral Neuroscience
M1 - 1151877
ER -