When Acetylcholine Unlocks Feedback Inhibition in Cortex
Authors: Quentin Chevy, Adam Kepecs
Journal: Neuron (2018)

Acetylcholine promotes cognitive function through the regulation of cortical circuits. In this issue of Neuron, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar demonstrate how this neuromodulator can rapidly boost synapses from pyramidal to somatostatin neurons, unlocking a new computational ability in the cortical microcircuitry. Acetylcholine promotes cognitive function through the regulation of cortical circuits. In this issue of Neuron, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar demonstrate how this neuromodulator can rapidly boost synapses from pyramidal to somatostatin neurons, unlocking a new computational ability in the cortical microcircuitry. Cholinergic neurons from the basal forebrain provide dense connections to cortex and are thought to support a range of behavioral functions from attention and learning to sensory processing and memory (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, Letzkus et al., 2011Letzkus J.J. Wolff S.B.E. Meyer E.M.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, Muñoz and Rudy, 2014Muñoz W. Rudy B. Spatiotemporal specificity in cholinergic control of neocortical function.Curr. Opin. Neurobiol. 2014; 26: 149-160Crossref PubMed Scopus (80) Google Scholar). The release of acetylcholine can profoundly transform cortical processing by boosting firing rates, enhancing synaptic plasticity, and reducing network synchrony. These changes in turn can result in increased reliability of sensory responses, expansion of receptive fields, and reorganization of cortical maps. Although acetylcholine, like other neuromodulators, has been thought to act slowly via volumetric transmission and metabotropic receptors, recent data reveal a second, rapid, phasic mode of communication with point-to-point synapses and ionotropic transmission (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, Muñoz and Rudy, 2014Muñoz W. Rudy B. Spatiotemporal specificity in cholinergic control of neocortical function.Curr. Opin. Neurobiol. 2014; 26: 149-160Crossref PubMed Scopus (80) Google Scholar). Nevertheless, the relative extent and functional impact of these different types of communication remain unclear. At the cellular and synaptic levels, acetylcholine can produce a diversity of responses depending, in part, on the specific acetylcholine receptors present on the cell. Most cortical neurons express either metabotropic muscarinic or ionotropic nicotinic receptors in different complements according to neuronal subtype, cortical layer, and region (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). This heterogeneity is bound to affect the temporal dynamics of acetylcholine signals on cortical activity. In this issue of Neuron, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar use state-of-the-art techniques to examine how acetylcholine regulates the dynamics of a specific neuronal circuit ubiquitous in the superficial layers of cortex. The dendritic activity of cortical pyramidal neurons is controlled by a distinctive class of inhibitory interneurons called Martinotti cells that express somatostatin (SST), used as a marker in this study (Figure 1). In layer 5 of neocortex, pyramidal neurons can drive the activity of Martinotti cells, which in turn provide feedback inhibition to the dendrites of the same neurons (Isaacson and Scanziani, 2011Isaacson J.S. Scanziani M. How inhibition shapes cortical activity.Neuron. 2011; 72: 231-243Abstract Full Text Full Text PDF PubMed Scopus (979) Google Scholar). This disynaptic feedback inhibition forms a cortical circuit motif observed across cortical regions that is thought to gate dendritic excitation, calcium spikes, and plasticity. A similar circuit between pyramidal neurons and SST interneurons is also prevalent in layers 2/3 of the cortex. The synapses onto SST interneurons, however, are functionally weak, raising questions about their computational power. In the first set of experiments, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar show that pyramidal to SST neuron synaptic transmission fails up to 80% of the time both in brain slices in vitro and during the cortical downstate in vivo. They discovered, however, that carbachol, a cholinergic agonist, but not other neuromodulatory agonists, increases the strength of these pyramidal to SST synapses. Using a combination of bath-applied agonists and antagonists, they further demonstrate that nicotinic, but not muscarinic, receptors are involved in this enhancement. This carbachol-dependent synaptic strengthening has a presynaptic locus and is phenocopied by a PKA-activating drug, forskolin. Furthermore, the increase in pyramidal to SST neuron synaptic strength was blocked with a PKA inhibitor infused into the presynaptic pyramidal neuron, ruling out any network mechanisms. These observations are rather surprising because PKA-dependent modulation is not commonly associated with ionotropic receptors such as nicotinic receptors. Nevertheless, the results add to a handful of pioneering studies that observed nicotinic receptors creating slow and/or metabotropic dynamics. For instance, similar PKA-dependent potentiation of glutamatergic synapses through α7-containing nicotinic receptors has been described in the hippocampus (Cheng and Yakel, 2014Cheng Q. Yakel J.L. Presynaptic α7 nicotinic acetylcholine receptors enhance hippocampal mossy fiber glutamatergic transmission via PKA activation.J. Neurosci. 2014; 34: 124-133Crossref PubMed Scopus (50) Google Scholar). Interestingly, non-α7-containing nicotinic receptors can also produce an increase in pyramidal cell activity in cortex (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). Another fascinating study showed that cholinergic release can activate a subtype of cortical inhibitory neuron via unusually slow, non-α7 nicotinic receptors and in turn induce delayed disynaptic inhibition to neighboring cortical neurons (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). Common to these studies are the surprisingly slow actions of nicotinic receptor mechanisms consistent with the involvement of metabotropic pathways. Until recently, evaluating the temporal dynamics of cholinergic effects has been hindered by the paucity of alternatives to the bath application of acetylcholine agonists and antagonists. Although effective (e.g., 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), this pharmacological approach has led to somewhat confusing observations regarding which neuronal populations acetylcholine modulates and what effect it has on each (for review, see Muñoz and Rudy, 2014Muñoz W. Rudy B. Spatiotemporal specificity in cholinergic control of neocortical function.Curr. Opin. Neurobiol. 2014; 26: 149-160Crossref PubMed Scopus (80) Google Scholar). The advent of optogenetic and transgenic techniques has enabled the field to investigate with temporal precision and circuit specificity the effects of acetylcholine release. Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar asked whether optogenetically induced acetylcholine release can produce a rapid enhancement of the pyramidal to SST synapse. To precisely control the timing of acetylcholine release, they expressed channelrhodopsin in basal forebrain cholinergic neurons and delivered brief (10 ms) light flashes. They show that a single and rather brief pulse of endogenous acetylcholine is sufficient to reproduce the effects of bath-applied cholinergic agonists. Intriguingly, the synaptic potentiation is temporally restricted and peaks about 200 ms after acetylcholine delivery, a relatively long delay but comparable to those reported by the previous studies discussed above. What are the consequences of this delayed cholinergic boosting of pyramidal-SST synapses? To address this question, we need to consider the dynamics of the circuit in which the pyramidal-SST motif is embedded. Recall that SST neurons tend to inhibit the distal dendrites of pyramidal cells, precisely where top-down, long-range inputs arrive. SST neurons, in turn, are inhibited by VIP-expressing neurons, specializing in disinhibition (Kepecs and Fishell, 2014Kepecs A. Fishell G. Interneuron cell types are fit to function.Nature. 2014; 505: 318-326Crossref PubMed Scopus (641) Google Scholar). Phasic cholinergic activity can recruit disinhibition either through inhibitory neurons in layer 1 (Letzkus et al., 2011Letzkus J.J. Wolff S.B.E. Meyer E.M.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) or likely through VIP neurons in layers 2/3 (although this has not yet been directly demonstrated; Figure 1). Hence, acetylcholine-mediated disinhibition could open a gate for long-range feedback to influence pyramidal neuron activity. In the ensuing time window of pyramidal disinhibition, local and long-range cortical inputs would be integrated into the output of pyramidal cells. Then, the window would be closed shut by feedback inhibition due to the delayed enhancement of pyramidal-SST neuron synapses described in this study. The same burst of acetylcholine could thereby drive both the opening and the closing of a brief plasticity window: pyramidal cell disinhibition acting immediately and feedback inhibition occurring after some time delay. This disinhibition/feedback inhibition balance could therefore create a temporal frame for associative plasticity in cortex (Figure 1). Finally, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar asked whether this enhancement is specific to the pyramidal to SST neuron synapses or more generally observed in other synapses of the cortical microcircuit. Synapses between pyramidal cells showed no sign of potentiation after either bath application of the cholinergic agonist carbachol or release of endogenous acetylcholine by optogenetic activation of cholinergic fibers. Testing the synapse between pyramidal cells and parvalbumin (PV)-expressing interneurons, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar noted an interesting discrepancy between bath application of the cholinergic agonist and optogenetically evoked endogenous acetylcholine. While carbachol application potentiated pyramidal to PV synapses, this was not observed using optogenetic activation of cholinergic fibers. These contrasting results concerning the pyramidal to PV synapses could reflect the difference between tonic and phasic modes of the cholinergic system. Optogenetic techniques generate precisely timed acetylcholine pulses, likely specific to synaptic receptors. Bath-applied carbachol, on the other hand, likely activates extrasynaptic receptors as well and produces receptor desensitization. The increase in pyramidal to PV synapses by carbachol might be due the recruitment of extrasynaptic receptors. The involvement of these receptors under physiological conditions remains unknown. The synapse specificity of cholinergic enhancement at the pyramidal-SST connection suggests an intriguing possibility: a triadic synapse with cholinergic presynaptic boutons regulating a glutamatergic synapse onto SST interneurons. Although the anatomical basis of this remains to be determined, Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar provide compelling evidence that phasic cholinergic activity can reconfigure specific circuit elements, in this case, boosting pyramidal-SST feedback inhibition. This impressive study by Urban-Ciecko et al., 2018Urban-Ciecko J. Jouhanneau J.-S. Myal S.E. Poulet J.F.A. Barth A.L. Neuron precisely timed nicotinic activation drives SST inhibition in neocortical circuits.Neuron. 2018; 97 (this issue): 611-625Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar sets the stage for understanding how the phasic release of acetylcholine can reconfigure specific cortical circuits in potentially complex ways. At the circuit level, the feedback inhibition mechanism they have discovered may support desynchronization of cortex (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, 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) and the enhancement of cortical neuron tuning. During behavior, reinforcers can drive brief cholinergic bursts and VIP neuron activation, thereby creating a circuit configuration for associative plasticity (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). Although somewhat speculative, these possibilities show that the highly-specific boosting of pyramidal-SST synapses could have important consequences for cortical circuit operation during behavior. We would like to thank the National Institutes of Health for support and Elizabeth T. Gibson for help in preparing this manuscript. Precisely Timed Nicotinic Activation Drives SST Inhibition in Neocortical CircuitsUrban-Ciecko et al.NeuronFebruary 07, 2018In BriefUsing in vitro and in vivo dual patch-clamp recordings and optogenetics, Urban-Ciecko et al. demonstrate endogenous acetylcholine release in the neocortex selectively enhances synaptic transmission between pyramidal neurons and SST interneurons through presynaptic nicotinic receptors Full-Text PDF Open Archive