Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons

An opto-dialysis study

Janneke C. Zant, Tae Kim, Laszlo Prokai, Szabolcs Szarka, James McNally, James T. McKenna, Charu Shukla, Chun Yang, Anna V. Kalinchuk, Robert W. McCarley, Ritchie E. Brown, Radhika Basheer

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35 Citations (Scopus)

Abstract

Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that “selective” stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of “selective” optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons.

Original languageEnglish
Pages (from-to)2057-2067
Number of pages11
JournalJournal of Neuroscience
Volume36
Issue number6
DOIs
StatePublished - 10 Feb 2016

Fingerprint

Cholinergic Neurons
Wakefulness
Dialysis
Neurons
Optogenetics
GABAergic Neurons
Parvalbumins
Cholinergic Agents
Sleep
Microdialysis
Acetylcholine
Calcium-Binding Proteins
Basal Forebrain
Cholinergic Antagonists
Arousal
gamma-Aminobutyric Acid

Keywords

  • Basal forebrain
  • Cholinergic neurons
  • NREM to wake transitions
  • Opto-dialysis

Cite this

Zant, Janneke C. ; Kim, Tae ; Prokai, Laszlo ; Szarka, Szabolcs ; McNally, James ; McKenna, James T. ; Shukla, Charu ; Yang, Chun ; Kalinchuk, Anna V. ; McCarley, Robert W. ; Brown, Ritchie E. ; Basheer, Radhika. / Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons : An opto-dialysis study. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 6. pp. 2057-2067.
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abstract = "Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that “selective” stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of “selective” optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons.",
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author = "Zant, {Janneke C.} and Tae Kim and Laszlo Prokai and Szabolcs Szarka and James McNally and McKenna, {James T.} and Charu Shukla and Chun Yang and Kalinchuk, {Anna V.} and McCarley, {Robert W.} and Brown, {Ritchie E.} and Radhika Basheer",
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Zant, JC, Kim, T, Prokai, L, Szarka, S, McNally, J, McKenna, JT, Shukla, C, Yang, C, Kalinchuk, AV, McCarley, RW, Brown, RE & Basheer, R 2016, 'Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons: An opto-dialysis study', Journal of Neuroscience, vol. 36, no. 6, pp. 2057-2067. https://doi.org/10.1523/JNEUROSCI.3318-15.2016

Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons : An opto-dialysis study. / Zant, Janneke C.; Kim, Tae; Prokai, Laszlo; Szarka, Szabolcs; McNally, James; McKenna, James T.; Shukla, Charu; Yang, Chun; Kalinchuk, Anna V.; McCarley, Robert W.; Brown, Ritchie E.; Basheer, Radhika.

In: Journal of Neuroscience, Vol. 36, No. 6, 10.02.2016, p. 2057-2067.

Research output: Contribution to journalArticleResearchpeer-review

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T2 - An opto-dialysis study

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AU - Kim, Tae

AU - Prokai, Laszlo

AU - Szarka, Szabolcs

AU - McNally, James

AU - McKenna, James T.

AU - Shukla, Charu

AU - Yang, Chun

AU - Kalinchuk, Anna V.

AU - McCarley, Robert W.

AU - Brown, Ritchie E.

AU - Basheer, Radhika

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