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• W2906105621 abstract "•Optogenetic release of ACh positively modulates neocortical principal neuron excitability•Optogenetic release of ACh selectively controls dendritic excitability•Dendritic excitability is transformed by a mAChR-mediated modulation of calcium channels•Cholinergic modulation impacts behaviorally relevant dendritic integration The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output. In contrast, the synaptic release of ACh did not positively modulate axo-somatic excitability. Mechanistically, the transformation of dendritic integration was mediated by the muscarinic ACh receptor-dependent enhancement of dendritic R-type calcium channel activity, a compartment-dependent modulation which decisively controlled the associative computations executed by layer 5B pyramidal neurons. Our findings therefore reveal a biophysical mechanism by which the cholinergic system controls dendritic computations causally linked to perceptual detection. The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output. In contrast, the synaptic release of ACh did not positively modulate axo-somatic excitability. Mechanistically, the transformation of dendritic integration was mediated by the muscarinic ACh receptor-dependent enhancement of dendritic R-type calcium channel activity, a compartment-dependent modulation which decisively controlled the associative computations executed by layer 5B pyramidal neurons. Our findings therefore reveal a biophysical mechanism by which the cholinergic system controls dendritic computations causally linked to perceptual detection. The basal forebrain (BF) cholinergic system has a central role in the state-dependent control of brain function, acting to powerfully modulate cognitive processing and sensory perception (Everitt and Robbins, 1997Everitt B.J. Robbins T.W. Central cholinergic systems and cognition.Annu. Rev. Psychol. 1997; 48: 649-684Crossref PubMed Scopus (1144) Google Scholar, Goard and Dan, 2009Goard M. Dan Y. Basal forebrain activation enhances cortical coding of natural scenes.Nat. Neurosci. 2009; 12: 1444-1449Crossref PubMed Scopus (398) Google Scholar, Hasselmo and Sarter, 2011Hasselmo M.E. Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition.Neuropsychopharmacology. 2011; 36: 52-73Crossref PubMed Scopus (498) Google Scholar, Herrero et al., 2008Herrero J.L. Roberts M.J. Delicato L.S. Gieselmann M.A. Dayan P. Thiele A. Acetylcholine contributes through muscarinic receptors to attentional modulation in V1.Nature. 2008; 454: 1110-1114Crossref PubMed Scopus (338) Google Scholar, Liu et al., 2017Liu R. Crawford J. Callahan P.M. Terry Jr., A.V. Constantinidis C. Blake D.T. Intermittent stimulation of the nucleus basalis of meynert improves working memory in adult monkeys.Curr. Biol. 2017; 27: 2640-2646.e4Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, Parikh et al., 2007Parikh V. Kozak R. Martinez V. Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales.Neuron. 2007; 56: 141-154Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar, Pinto et al., 2013Pinto L. Goard M.J. Estandian D. Xu M. Kwan A.C. Lee S.H. Harrison T.C. Feng G. Dan Y. Fast modulation of visual perception by basal forebrain cholinergic neurons.Nat. Neurosci. 2013; 16: 1857-1863Crossref PubMed Scopus (332) Google Scholar, Winkler et al., 1995Winkler J. Suhr S.T. Gage F.H. Thal L.J. Fisher L.J. Essential role of neocortical acetylcholine in spatial memory.Nature. 1995; 375: 484-487Crossref PubMed Scopus (269) Google Scholar). Consistent with this, in human diseases of cognition, such as age-dependent cognitive decline and forms of dementia, the progressive degeneration of BF cholinergic nuclei correlates with the degree of cognitive impairment (Bartus et al., 1982Bartus R.T. Dean 3rd, R.L. Beer B. Lippa A.S. The cholinergic hypothesis of geriatric memory dysfunction.Science. 1982; 217: 408-414Crossref PubMed Scopus (4788) Google Scholar, Grothe et al., 2013Grothe M. Heinsen H. Teipel S. Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease.Neurobiol. Aging. 2013; 34: 1210-1220Crossref PubMed Scopus (117) Google Scholar, Whitehouse et al., 1982Whitehouse P.J. Price D.L. Struble R.G. Clark A.W. Coyle J.T. Delon M.R. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain.Science. 1982; 215: 1237-1239Crossref PubMed Scopus (2999) Google Scholar). Recent work has examined the neocortical circuit elements controlled by the synaptic release of ACh from BF cholinergic axons, which ramify throughout the neocortical layers, revealing that the activation of nicotinic ACh receptors (nAChRs) excites principal neurons and specific inhibitory interneuronal circuits (Bennett et al., 2012Bennett C. Arroyo S. Berns D. Hestrin S. Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons.J. Neurosci. 2012; 32: 17287-17296Crossref PubMed Scopus (67) Google Scholar, Chen et al., 2015Chen N. Sugihara H. Sur M. An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity.Nat. Neurosci. 2015; 18: 892-902Crossref PubMed Scopus (118) Google Scholar, Fu et al., 2014Fu Y. Tucciarone J.M. Espinosa J.S. Sheng N. Darcy D.P. Nicoll R.A. Huang Z.J. Stryker M.P. A cortical circuit for gain control by behavioral state.Cell. 2014; 156: 1139-1152Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, Hedrick and Waters, 2015Hedrick T. Waters J. Acetylcholine excites neocortical pyramidal neurons via nicotinic receptors.J. Neurophysiol. 2015; 113: 2195-2209Crossref PubMed Scopus (51) Google Scholar, Letzkus et al., 2011Letzkus J.J. Wolff S.B. Meyer E.M. Tovote P. Courtin J. Herry C. Lüthi A. A disinhibitory microcircuit for associative fear learning in the auditory cortex.Nature. 2011; 480: 331-335Crossref PubMed Scopus (570) Google Scholar, Saunders et al., 2015Saunders A. Granger A.J. Sabatini B.L. Corelease of acetylcholine and GABA from cholinergic forebrain neurons.eLife. 2015; 4: e06412Crossref Scopus (128) Google Scholar). Notably, however, the pharmacological manipulation of muscarinic AChRs (mAChRs) significantly influences human cognition, and attentive processing in animals (Everitt and Robbins, 1997Everitt B.J. Robbins T.W. Central cholinergic systems and cognition.Annu. Rev. Psychol. 1997; 48: 649-684Crossref PubMed Scopus (1144) Google Scholar, Hasselmo and Sarter, 2011Hasselmo M.E. Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition.Neuropsychopharmacology. 2011; 36: 52-73Crossref PubMed Scopus (498) Google Scholar, Herrero et al., 2008Herrero J.L. Roberts M.J. Delicato L.S. Gieselmann M.A. Dayan P. Thiele A. Acetylcholine contributes through muscarinic receptors to attentional modulation in V1.Nature. 2008; 454: 1110-1114Crossref PubMed Scopus (338) Google Scholar), by actions thought to be mediated, in part, by the direct modulation of axo-somatic ion channels and the regulation of intracellular calcium-dependent processes in principal neurons (Battefeld et al., 2014Battefeld A. Tran B.T. Gavrilis J. Cooper E.C. Kole M.H. Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.J. Neurosci. 2014; 34: 3719-3732Crossref PubMed Scopus (116) Google Scholar, Dasari et al., 2017Dasari S. Hill C. Gulledge A.T. A unifying hypothesis for M1 muscarinic receptor signalling in pyramidal neurons.J. Physiol. 2017; 595: 1711-1723Crossref PubMed Scopus (24) Google Scholar, Giessel and Sabatini, 2010Giessel A.J. Sabatini B.L. M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels.Neuron. 2010; 68: 936-947Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, Hasselmo and Sarter, 2011Hasselmo M.E. Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition.Neuropsychopharmacology. 2011; 36: 52-73Crossref PubMed Scopus (498) Google Scholar, Krnjević et al., 1971Krnjević K. Pumain R. Renaud L. The mechanism of excitation by acetylcholine in the cerebral cortex.J. Physiol. 1971; 215: 247-268Crossref PubMed Scopus (429) Google Scholar, Nicoll et al., 1990Nicoll R.A. Malenka R.C. Kauer J.A. Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system.Physiol. Rev. 1990; 70: 513-565Crossref PubMed Scopus (671) Google Scholar). Surprisingly, however, little attention has been focused on the role of the cholinergic system in the control of principal neuron dendritic excitability, despite a wealth of evidence indicating that active dendritic processing is a critical determinant of behaviorally engaged neuronal computations and sensory perception (Basu et al., 2016Basu J. Zaremba J.D. Cheung S.K. Hitti F.L. Zemelman B.V. Losonczy A. Siegelbaum S.A. Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition.Science. 2016; 351: aaa5694Crossref PubMed Scopus (125) Google Scholar, Bittner et al., 2015Bittner K.C. Grienberger C. Vaidya S.P. Milstein A.D. Macklin J.J. Suh J. Tonegawa S. Magee J.C. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons.Nat. Neurosci. 2015; 18: 1133-1142Crossref PubMed Scopus (270) Google Scholar, Gambino et al., 2014Gambino F. Pagès S. Kehayas V. Baptista D. Tatti R. Carleton A. Holtmaat A. Sensory-evoked LTP driven by dendritic plateau potentials in vivo.Nature. 2014; 515: 116-119Crossref PubMed Scopus (154) Google Scholar, Harnett et al., 2013Harnett M.T. Xu N.-L. Magee J.C. Williams S.R. Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons.Neuron. 2013; 79: 516-529Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, Murayama and Larkum, 2009Murayama M. Larkum M.E. Enhanced dendritic activity in awake rats.Proc. Natl. Acad. Sci. USA. 2009; 106: 20482-20486Crossref PubMed Scopus (48) Google Scholar, Sheffield and Dombeck, 2015Sheffield M.E. Dombeck D.A. Calcium transient prevalence across the dendritic arbour predicts place field properties.Nature. 2015; 517: 200-204Crossref PubMed Scopus (7) Google Scholar, Smith et al., 2013Smith S.L. Smith I.T. Branco T. Häusser M. Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo.Nature. 2013; 503: 115-120Crossref PubMed Scopus (239) Google Scholar, Takahashi et al., 2016Takahashi N. Oertner T.G. Hegemann P. Larkum M.E. Active cortical dendrites modulate perception.Science. 2016; 354: 1587-1590Crossref PubMed Scopus (190) Google Scholar, Xu et al., 2012Xu N.-L. Harnett M.T. Williams S.R. Huber D. O’Connor D.H. Svoboda K. Magee J.C. Nonlinear dendritic integration of sensory and motor pathways produces an object localization signal.Nature. 2012; 492: 247-251Crossref PubMed Scopus (321) Google Scholar). As the BF cholinergic system is engaged during active behavior (Eggermann et al., 2014Eggermann E. Kremer Y. Crochet S. Petersen C.C.H. Cholinergic signals in mouse barrel cortex during active whisker sensing.Cell Rep. 2014; 9: 1654-1660Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, Hangya et al., 2015Hangya B. Ranade S.P. Lorenc M. Kepecs A. Central cholinergic neurons are rapidly recruited by reinforcement feedback.Cell. 2015; 162: 1155-1168Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Parikh et al., 2007Parikh V. Kozak R. Martinez V. Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales.Neuron. 2007; 56: 141-154Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar) to regulate sensory responsiveness and perception (Fu et al., 2014Fu Y. Tucciarone J.M. Espinosa J.S. Sheng N. Darcy D.P. Nicoll R.A. Huang Z.J. Stryker M.P. A cortical circuit for gain control by behavioral state.Cell. 2014; 156: 1139-1152Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, Goard and Dan, 2009Goard M. Dan Y. Basal forebrain activation enhances cortical coding of natural scenes.Nat. Neurosci. 2009; 12: 1444-1449Crossref PubMed Scopus (398) Google Scholar, Herrero et al., 2008Herrero J.L. Roberts M.J. Delicato L.S. Gieselmann M.A. Dayan P. Thiele A. Acetylcholine contributes through muscarinic receptors to attentional modulation in V1.Nature. 2008; 454: 1110-1114Crossref PubMed Scopus (338) Google Scholar, Nuñez et al., 2012Nuñez A. Domínguez S. Buño W. Fernández de Sevilla D. Cholinergic-mediated response enhancement in barrel cortex layer V pyramidal neurons.J. Neurophysiol. 2012; 108: 1656-1668Crossref PubMed Scopus (35) Google Scholar, Pinto et al., 2013Pinto L. Goard M.J. Estandian D. Xu M. Kwan A.C. Lee S.H. Harrison T.C. Feng G. Dan Y. Fast modulation of visual perception by basal forebrain cholinergic neurons.Nat. Neurosci. 2013; 16: 1857-1863Crossref PubMed Scopus (332) Google Scholar), we investigated whether the endogenous release of ACh modulates dendritic information processing in neocortical principal neurons. To directly examine whether activation of the cholinergic system dynamically controls dendritic information processing in the principal output neurons of the neocortex, we made simultaneous whole-cell recordings from the soma and distal apical dendrites of layer 5B (L5B) pyramidal neurons in brain slices of the somatosensory neocortex prepared from mice which selectively expressed channelrhodopsin-2 (ChR2) in cholinergic neurons under the control of the cholineacetyltransferase (ChAT) promoter (Pinto et al., 2013Pinto L. Goard M.J. Estandian D. Xu M. Kwan A.C. Lee S.H. Harrison T.C. Feng G. Dan Y. Fast modulation of visual perception by basal forebrain cholinergic neurons.Nat. Neurosci. 2013; 16: 1857-1863Crossref PubMed Scopus (332) Google Scholar, Saunders et al., 2015Saunders A. Granger A.J. Sabatini B.L. Corelease of acetylcholine and GABA from cholinergic forebrain neurons.eLife. 2015; 4: e06412Crossref Scopus (128) Google Scholar) (Figures 1, S1, and S2; dendritic recording distance from soma = 515 ± 10 μm; n = 23). The optogenetic-evoked release of ACh from cholinergic axons, which ramified throughout the neocortical layers, was found to profoundly and selectively modulate the electrical excitability of apical dendrites (Figures 1A–1D and S1). In each neuron tested, a brief (4 ms) full-field photoactivation light pulse centered at the dendritic recording site transformed the output of dendritic integration from a single dendritic spike that drove a transient burst of action potential (AP) output to long-duration dendritic plateau potentials, which evoked sustained trains of AP firing (Figures 1A, 1D, S3A, and S3D; n = 66 trials, n = 13 neurons; dendritic current step: amplitude = 0.63 ± 0.04 nA, duration = 0.5 s). This transformation was apparent both immediately (50 ms) and 3.55 s after photoactivation and subsequently decayed with an exponential time course (Figures 1A, 1D, 2A–2D , S3A, and S3D; distribution significantly different from before photoactivation, Kolmogorov-Smirnov test, p < 0.0001 [50 ms], p < 0.0001 [3.55 s]; decay time constant = 23.1 s, n = 13 neurons). This cholinergic modulation of dendritic excitability was unaccompanied by changes in dendritic membrane potential, input resistance, or the area of subthreshold dendritic voltage responses, suggesting the neuromodulation of specific classes of ion channels (Figures 1A, 1D, and 2A–2D; Δ membrane potential = 0.23 ± 0.08 mV, n = 13 neurons; Δ apparent input resistance = 0.65 ± 0.21 MΩ). In contrast to the powerful control of dendritic excitability, simultaneous somatic recording demonstrated that the brief (4 ms) optogenetic-evoked release of ACh had a minimal direct influence on axo-somatic excitability, failing to significantly alter the number of APs evoked by somatic positive current steps, when full-field photoactivation was centered at somatic or dendritic sites (Figures 1C, 1D, S3B, and S3E; distributions not significantly different from before photoactivation, Kolmogorov-Smirnov test, p = 0.3359 [50 ms], p = 0.2402 [3.55 s], n = 68 trials, n = 13 neurons; somatic current step: amplitude = 0.30 ± 0.04 nA, duration = 0.5 s). Together, these data reveal that the cholinergic system acts to specifically modulate dendritic excitability in the principal output neurons of the neocortex.Figure 2The Phasic Release of Endogenous ACh Selectively and Reversibly Enhances Dendritic ExcitabilityShow full caption(A) Continuous record of voltage responses recorded from the distal apical dendrite (Vdend) of a mouse L5B pyramidal neuron evoked by supra- (upper) or sub-threshold (lower) current pulses (Idend). The optogenetic-evoked release of ACh (4 ms full-field stimuli, blue symbols) led to the enhancement of supra-, but not sub-threshold, dendritic excitability.(B) Magnification of indicated voltage responses and current steps illustrated in (A).(C) Pooled data illustrating the enhancement of the normalized area of supra-threshold dendritic voltage responses (filled blue symbols) by the optogenetic-evoked release of ACh, which recovered with an exponential time course (solid line). The open symbols show the normalized area of sub-threshold voltage responses. Dendritic recordings were made 533 ± 8 μm from soma, values represent mean ± SEM.(D) Partial reconstruction of the neuron illustrated in (A) and (B) overlain on simultaneously imaged EYFP-labeled cholinergic axons.(E) Brief optogenetic (4 ms full-field stimuli; blue trace, gating pulse) activation reliably evokes single AP firing in murine nucleus basalis (NB) magnocellular cholinergic neurons. AP firing was sequentially recorded in cell-attached (VH = 0 mV) and whole-cell modes (18 overlain traces). Tetrodotoxin (TTX, 1 μM) blocked AP firing, revealing the time course of the underlying ChR2 response.(F) Reconstruction of the neuron illustrated in (E) overlain on simultaneously imaged EYFP-labeled cholinergic somata (arrows) and neurites. The inset shows membrane-delineated EYFP staining surrounding the biocytin (purple)-filled somata in a single confocal section.(G) Peri-stimulus time histograms of AP firing recorded in cell-attached (upper) and whole-cell (lower) mode. The period of photoactivation is delineated by the blue bars. See also Figures S6 and S7.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Continuous record of voltage responses recorded from the distal apical dendrite (Vdend) of a mouse L5B pyramidal neuron evoked by supra- (upper) or sub-threshold (lower) current pulses (Idend). The optogenetic-evoked release of ACh (4 ms full-field stimuli, blue symbols) led to the enhancement of supra-, but not sub-threshold, dendritic excitability. (B) Magnification of indicated voltage responses and current steps illustrated in (A). (C) Pooled data illustrating the enhancement of the normalized area of supra-threshold dendritic voltage responses (filled blue symbols) by the optogenetic-evoked release of ACh, which recovered with an exponential time course (solid line). The open symbols show the normalized area of sub-threshold voltage responses. Dendritic recordings were made 533 ± 8 μm from soma, values represent mean ± SEM. (D) Partial reconstruction of the neuron illustrated in (A) and (B) overlain on simultaneously imaged EYFP-labeled cholinergic axons. (E) Brief optogenetic (4 ms full-field stimuli; blue trace, gating pulse) activation reliably evokes single AP firing in murine nucleus basalis (NB) magnocellular cholinergic neurons. AP firing was sequentially recorded in cell-attached (VH = 0 mV) and whole-cell modes (18 overlain traces). Tetrodotoxin (TTX, 1 μM) blocked AP firing, revealing the time course of the underlying ChR2 response. (F) Reconstruction of the neuron illustrated in (E) overlain on simultaneously imaged EYFP-labeled cholinergic somata (arrows) and neurites. The inset shows membrane-delineated EYFP staining surrounding the biocytin (purple)-filled somata in a single confocal section. (G) Peri-stimulus time histograms of AP firing recorded in cell-attached (upper) and whole-cell (lower) mode. The period of photoactivation is delineated by the blue bars. See also Figures S6 and S7. Pharmacological analysis revealed that the optogenetic-evoked cholinergic enhancement of apical dendritic excitability was abolished by the selective antagonism of M1 AChRs (Figures 1E, 1F, and S3C; number of APs after [3.55 s] photoactivation: control = 11.7 ± 1.1, telenzepine [100 nM] = 2.1 ± 0.1; t test, p = 0.0005, n = 37 trials, n = 7 neurons). In contrast, the broad-spectrum nAChR antagonist hexamethonium did not alter the cholinergic transformation of dendritic excitability (area of dendritic response; control: before = 14.2 ± 0.8 mV.s, after [3.55 s] = 26.2 ± 1.9 mV.s; hexamethonium: before = 15.4 ± 0.8 mV.s, after [3.55 s] = 25.9 ± 1.7 mV.s; t test, not significantly different, n = 5). The antagonism of nAChRs, however, blocked the small-amplitude, short-duration excitatory postsynaptic potentials (EPSPs) evoked by optogenetic activation when delivered in isolation (Hedrick and Waters, 2015Hedrick T. Waters J. Acetylcholine excites neocortical pyramidal neurons via nicotinic receptors.J. Neurophysiol. 2015; 113: 2195-2209Crossref PubMed Scopus (51) Google Scholar) to reveal a slower muscarinic AChR-mediated inhibitory component (Figures 1G–1I; EPSP control: amplitude = 1.65 ± 0.31 mV; area = 0.138 ± 0.08 mV.s, hexamethonium: amplitude = 0.18 ± 0.04 mV; area = −0.31 ± 0.11 mV.s, amplitude: t test, p = 0.0007; area: t test, p = 0.0087, n = 11 neurons; IPSP control: amplitude = −0.31 ± 0.07 mV; telenzepine = −0.03 ± 0.02 mV; t test, p = 0.017, n = 11). Consistent with previous reports, optogenetic activation also evoked short-duration nAChR-mediated EPSPs in supragranular neocortical interneurons (Arroyo et al., 2012Arroyo S. Bennett C. Aziz D. Brown S.P. Hestrin S. Prolonged disynaptic inhibition in the cortex mediated by slow, non-α7 nicotinic excitation of a specific subset of cortical interneurons.J. Neurosci. 2012; 32: 3859-3864Crossref PubMed Scopus (118) Google Scholar, Bennett et al., 2012Bennett C. Arroyo S. Berns D. Hestrin S. Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons.J. Neurosci. 2012; 32: 17287-17296Crossref PubMed Scopus (67) Google Scholar, Saunders et al., 2015Saunders A. Granger A.J. Sabatini B.L. Corelease of acetylcholine and GABA from cholinergic forebrain neurons.eLife. 2015; 4: e06412Crossref Scopus (128) Google Scholar) (Figures S4 and S5). The amplitude of nAChR-mediated EPSPs was interneuron-class-dependent (Arroyo et al., 2012Arroyo S. Bennett C. Aziz D. Brown S.P. Hestrin S. Prolonged disynaptic inhibition in the cortex mediated by slow, non-α7 nicotinic excitation of a specific subset of cortical interneurons.J. Neurosci. 2012; 32: 3859-3864Crossref PubMed Scopus (118) Google Scholar) and exhibited, in common with nAChR-mediated EPSPs recorded from L5B pyramidal neurons, prominent paired-pulse depression (Bennett et al., 2012Bennett C. Arroyo S. Berns D. Hestrin S. Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons.J. Neurosci. 2012; 32: 17287-17296Crossref PubMed Scopus (67) Google Scholar) (Figures S4 and S5; paired-pulse depression [3 s]: interneurons = 0.57 ± 0.02, n = 22; L5B = 0.59 ± 0.03, n = 20; Mann-Whitney, not significantly different, p = 0.990). In contrast to the long-lasting control of L5B pyramidal neuron apical dendritic excitability, the optogenetic-evoked release of ACh did not lead to a sustained enhancement of the excitability of interneurons (Figures S5F and S5G; number of APs evoked by current pulses: before = 6.7 ± 0.3; after [3.55 s] photoactivation = 7.0 ± 0.3; Kolmogorov-Smirnov test, not significantly different, p = 0.5996, n = 80 trials, n = 16 neurons). To explore the profile of cholinergic activation which triggered the generation of short-duration nAChR-mediated EPSPs in interneurons and L5B pyramidal neurons when evoked in isolation, and the selective longer-lasting M1 AChR-mediated enhancement of suprathreshold apical dendritic excitability in L5B pyramidal neurons, we investigated the pattern of AP firing evoked by optogenetic activation of BF cholinergic neurons (Figures 2E–2G, S4, and S6). Direct recording from identified nucleus basalis (NB) magnocellular cholinergic neurons, which widely innervate the neocortex (Kalmbach et al., 2012Kalmbach A. Hedrick T. Waters J. Selective optogenetic stimulation of cholinergic axons in neocortex.J. Neurophysiol. 2012; 107: 2008-2019Crossref PubMed Scopus (78) Google Scholar), revealed that brief (4 ms) full-field optogenetic stimuli evoked a single AP in 454 of 468 trials in cell-attached and whole-cell recordings (Figures 2E–2G; latency to AP peak = 8.42 ± 0.06 ms, n = 14 visually targeted in brain slices prepared from ChAT-Cre-ChR2-EYFP mice), a finding consistent with the time-locked and transient AP firing of this population of neurons during reinforcement behavior (Hangya et al., 2015Hangya B. Ranade S.P. Lorenc M. Kepecs A. Central cholinergic neurons are rapidly recruited by reinforcement feedback.Cell. 2015; 162: 1155-1168Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Furthermore, because of the long-lasting after-hyperpolarization potentials which followed APs (Hedrick and Waters, 2010Hedrick T. Waters J. Physiological properties of cholinergic and non-cholinergic magnocellular neurons in acute slices from adult mouse nucleus basalis.PLoS ONE. 2010; 5: e11046Crossref PubMed Scopus (21) Google Scholar), a single AP was evoked in NB magnocellular cholinergic neurons by longer-duration light stimuli (4–20 ms; n = 13), and repetitive low-frequency AP firing was only manifest in response to prolonged periods of photoactivation (Figure S6; AP firing rate [1 s photoactivation] = 3.7 ± 1.1 Hz, n = 6; rheobase step current-evoked AP threshold = −33.1 ± 1.0 mV; fast AP after-hyperpolarization potential = −26.8 ± 1.9 mV; slow AP after-hyperpolarization potential = −36.9 ± 1.2 mV, n = 14). Consistent with this, the time course of nAChR-mediated EPSPs recorded from supragranular neocortical interneurons did not change when the duration of the optogenetic activation pulse was increased from 4 to 20 ms (Figures S4H and S4I; EPSP half-width [4 ms] = 125.0 ± 7.0 ms; EPSP half-width [20 ms] = 135 ± 9.2 ms; t test, not significantly different, p = 0.193, n = 6). Furthermore, analysis of nAChR-mediated EPSPs in interneurons revealed that their onset latencies exhibited trial-to-trial temporal jitter consistent with the jitter in the timing of APs evoked in NB magnocellular cholinergic neurons in response to identical light stimuli (Figures S4A and S4D). Similarly, brief optogenetic stimuli evoked a transient, highly time-locked, burst of AP firing in a sparsely distributed population of identified cholinergic neocortical interneurons (von Engelhardt et al., 2007von Engelhardt J. Eliava M. Meyer A.H. Rozov A. Monyer H. Functional characterization of intrinsic cholinergic interneurons in the cortex.J. Neurosci. 2007; 27: 5633-5642Crossref PubMed Scopus (132) Google Scholar) (Figure S7; light stimuli [4 ms]: APs per trial = 1.86 ± 0.03; inter-spike frequency = 280.3 ± 1.7 Hz; latency to AP peak = 9.61 ± 0.07 ms; n = 576 trials, n = 12 neurons). Together, these data suggest that the brief optogenetic activation of cholinergic axons drives transient AP firing, leading to the phasic release of ACh, which in L5B pyramidal neurons evokes a long-lasting enhancement of apical dendritic excitability through the action of metabotropic AChRs. Consistent with this pharmacological profile, simultaneous dendro-somatic recordings from rat L5B pyramidal neurons revealed that the bath application of the mAChR agonist muscarine (2.5 μM) transformed the pattern of dendritic-current-evoked electrogenesis, leading to the generation of long-duration dendritic plateau potentials, which drove repetitive AP firing (Figures 3A–3C; dendritic recording distance from soma = 715 ± 17 μm; dendritic excitation, AP firing rate: control = 2.9 ± 0.3 Hz, muscarine [2.5 μM] = 22.1 ± 1.8 Hz, t test, p < 0.0001, n = 16; dendritic excitation, current step: amplitude = 1.6 nA, duration = 0.6 s). This positive modulation of dendritic signaling was unaccompanied by changes in apparent input resistance or the current threshold for dendritic spike initiation (Δ apparent input resistance = 0.78 ± 0.58 MΩ; dendritic spike rheobase: control = 1.19 ± 0.03 nA, muscarine [2.5 μM] = 1.21 ± 0.04 nA, t te" @default.
• W2906105621 created "2019-01-01" @default.
• W2906105621 creator A5043337946 @default.
• W2906105621 creator A5084043680 @default.
• W2906105621 date "2019-02-01" @default.
• W2906105621 modified "2023-10-15" @default.
• W2906105621 title "A Dendritic Substrate for the Cholinergic Control of Neocortical Output Neurons" @default.
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