Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Daniel Zarhin; Refaela Atsmon; Antonella Ruggiero; Halit Baeloha; Shiri Shoob; Oded Scharf; Leore R. Heim; Nadav Buchbinder; Ortal Shinikamin; Ilana Shapira; Boaz Styr; Gabriella Braun; Michal Harel; Anton Sheinin; Nitzan Geva; Yaniv Sela; Takashi Saito; Takaomi Saido; Tamar Geiger; Yuval Nir; Yaniv Ziv; Inna Slutsky

doi:10.1016/j.celrep.2021.110268

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Daniel Zarhin, Refaela Atsmon, Antonella Ruggiero, Halit Baeloha, Shiri Shoob, Oded Scharf, Leore R. Heim, Nadav Buchbinder, Ortal Shinikamin, Ilana Shapira, Boaz Styr, Gabriella Braun, Michal Harel, Anton Sheinin, Nitzan Geva, Yaniv Sela, Takashi Saito, Takaomi Saido, Tamar Geiger, Yuval NirYaniv Ziv, Inna Slutsky^*

^*Corresponding author for this work

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

15 Scopus citations

Abstract

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Original language	English
Article number	110268
Journal	Cell Reports
Volume	38
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.110268
State	Published - 18 Jan 2022

Funding

Funders	Funder number
BIRAX Regenerative Medicine Initiative	1849/17, 46BX18TKIS
MILLENNIA	51/11, ERC-2019-CoG 864353, JPMJMS2024, 1326/15
Ministry of Science and Culture of Lower Saxony	ZN3458
Sheila and Denis Cohen Charitable Trust
Horizon 2020 Framework Programme	864353, 724866
European Research Council
Rosetrees Trust	A2590
Deutsche Forschungsgemeinschaft	448865644, 440813539
Volkswagen Foundation
Ministry of Science, Technology and Space
Japan Science and Technology Agency
Israel Science Foundation	1663/18
Azrieli Foundation
Sackler Faculty of Medicine, Tel-Aviv University
Sagol School of Neuroscience, Tel Aviv University

Keywords

Alzheimer's disease
DHODH
NREM
calcium imaging
firing rate homeostasis
general anesthesia
hippocampus
hyperexcitability
single-unit recordings
sleep

Access to Document

10.1016/j.celrep.2021.110268

Cite this

Zarhin, D., Atsmon, R., Ruggiero, A., Baeloha, H., Shoob, S., Scharf, O., Heim, L. R., Buchbinder, N., Shinikamin, O., Shapira, I., Styr, B., Braun, G., Harel, M., Sheinin, A., Geva, N., Sela, Y., Saito, T., Saido, T., Geiger, T., ... Slutsky, I. (2022). Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models. Cell Reports, 38(3), Article 110268. https://doi.org/10.1016/j.celrep.2021.110268

@article{e674f1776216413fae9d707334dc2726,

title = "Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models",

abstract = "Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.",

keywords = "Alzheimer's disease, DHODH, NREM, calcium imaging, firing rate homeostasis, general anesthesia, hippocampus, hyperexcitability, single-unit recordings, sleep",

author = "Daniel Zarhin and Refaela Atsmon and Antonella Ruggiero and Halit Baeloha and Shiri Shoob and Oded Scharf and Heim, {Leore R.} and Nadav Buchbinder and Ortal Shinikamin and Ilana Shapira and Boaz Styr and Gabriella Braun and Michal Harel and Anton Sheinin and Nitzan Geva and Yaniv Sela and Takashi Saito and Takaomi Saido and Tamar Geiger and Yuval Nir and Yaniv Ziv and Inna Slutsky",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = jan,

day = "18",

doi = "10.1016/j.celrep.2021.110268",

language = "אנגלית",

volume = "38",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Zarhin, D, Atsmon, R, Ruggiero, A, Baeloha, H, Shoob, S, Scharf, O, Heim, LR, Buchbinder, N, Shinikamin, O, Shapira, I, Styr, B, Braun, G, Harel, M, Sheinin, A, Geva, N, Sela, Y, Saito, T, Saido, T, Geiger, T , Nir, Y, Ziv, Y & Slutsky, I 2022, 'Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models', Cell Reports, vol. 38, no. 3, 110268. https://doi.org/10.1016/j.celrep.2021.110268

TY - JOUR

T1 - Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

AU - Zarhin, Daniel

AU - Atsmon, Refaela

AU - Ruggiero, Antonella

AU - Baeloha, Halit

AU - Shoob, Shiri

AU - Scharf, Oded

AU - Heim, Leore R.

AU - Buchbinder, Nadav

AU - Shinikamin, Ortal

AU - Shapira, Ilana

AU - Styr, Boaz

AU - Braun, Gabriella

AU - Harel, Michal

AU - Sheinin, Anton

AU - Geva, Nitzan

AU - Sela, Yaniv

AU - Saito, Takashi

AU - Saido, Takaomi

AU - Geiger, Tamar

AU - Nir, Yuval

AU - Ziv, Yaniv

AU - Slutsky, Inna

PY - 2022/1/18

Y1 - 2022/1/18

N2 - Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

AB - Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

KW - Alzheimer's disease

KW - DHODH

KW - NREM

KW - calcium imaging

KW - firing rate homeostasis

KW - general anesthesia

KW - hippocampus

KW - hyperexcitability

KW - single-unit recordings

KW - sleep

UR - http://www.scopus.com/inward/record.url?scp=85122822103&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.110268

DO - 10.1016/j.celrep.2021.110268

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35045289

AN - SCOPUS:85122822103

SN - 2211-1247

VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 110268

ER -

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Abstract

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this