Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS–FTD

Eosu Kim; Matthew A. White; Benjamin U. Phillips; Laura Lopez-Cruz; Hyunjeong Kim; Christopher J. Heath; Jong Eun Lee; Lisa M. Saksida; Jemeen Sreedharan; Timothy J. Bussey

doi:10.1038/s41398-020-01078-9

Coexistence of perseveration and apathy in the TDP-43^Q331K knock-in mouse model of ALS–FTD

Eosu Kim, Matthew A. White, Benjamin U. Phillips, Laura Lopez-Cruz, Hyunjeong Kim, Christopher J. Heath, Jong Eun Lee, Lisa M. Saksida, Jemeen Sreedharan, Timothy J. Bussey^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43^Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43^Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43^Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43^Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43^Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43^Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43^Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD.

Original language	English
Article number	377
Journal	Translational psychiatry
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41398-020-01078-9
Publication status	Published - 1 Dec 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41398-020-01078-9

Cite this

@article{e1f859b319734351ad0a94aa81bcb05c,

title = "Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS–FTD",

abstract = "Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD.",

author = "Eosu Kim and White, {Matthew A.} and Phillips, {Benjamin U.} and Laura Lopez-Cruz and Hyunjeong Kim and Heath, {Christopher J.} and Lee, {Jong Eun} and Saksida, {Lisa M.} and Jemeen Sreedharan and Bussey, {Timothy J.}",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41398-020-01078-9",

language = "English",

volume = "10",

journal = "Translational psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS–FTD

AU - Kim, Eosu

AU - White, Matthew A.

AU - Phillips, Benjamin U.

AU - Lopez-Cruz, Laura

AU - Kim, Hyunjeong

AU - Heath, Christopher J.

AU - Lee, Jong Eun

AU - Saksida, Lisa M.

AU - Sreedharan, Jemeen

AU - Bussey, Timothy J.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD.

AB - Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD.

UR - http://www.scopus.com/inward/record.url?scp=85094975400&partnerID=8YFLogxK

U2 - 10.1038/s41398-020-01078-9

DO - 10.1038/s41398-020-01078-9

M3 - Article

C2 - 33149110

AN - SCOPUS:85094975400

SN - 2158-3188

VL - 10

JO - Translational psychiatry

JF - Translational psychiatry

IS - 1

M1 - 377

ER -

Coexistence of perseveration and apathy in the TDP-43^Q331K knock-in mouse model of ALS–FTD

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this