Preferential cholinergic excitation of corticopontine neurons

Baker, Arielle L.; O’Toole, Ryan J.; Gulledge, Allan T.

doi:10.1113/jp275194

Cited by 36 publications

(65 citation statements)

References 56 publications

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“…Classically, G q -coupled excitation in pyramidal neurons is associated with suppression of potassium conductances, including those mediating the “M” (muscarine-suppressed) current and those responsible for afterhyperpolarizations (AHPs) in pyramidal neurons following bouts of action potential generation ( Krnjevic et al, 1971 ; Schwindt et al, 1988 ; McCormick and Williamson, 1989 ; Araneda and Andrade, 1991 ; Wang and McCormick, 1993 ; Villalobos et al, 2005 , 2011 ). However, reduction of potassium conductances does not fully account for G q -mediated excitation in neocortical pyramidal neurons ( Andrade, 1991 ; Haj-Dahmane and Andrade, 1996 ), as G q -coupled muscarinic ACh and 5-HT receptors also engage inward currents generated by calcium-dependent ( Haj-Dahmane and Andrade, 1998 ; Yan et al, 2009 ; Lei et al, 2014 ) and independent ( Haj-Dahmane and Andrade, 1996 ; Shalinsky et al, 2002 ; Egorov et al, 2003 ; Magistretti et al, 2004 ; Baker et al, 2018 ) non-specific cation channels.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex

Stephens

Baker

Gulledge

2018

Front. Neural Circuits

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Serotonin (5-HT) selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A) receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current), or activation of non-specific cation conductances that underlie calcium-dependent afterdepolarizations (ADPs). However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s) involved. In layer 5 of the mouse medial prefrontal cortex, we tested potential mechanisms of serotonergic excitation in commissural/callosal (COM) projection neurons, a subpopulation of pyramidal neurons that exhibits 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh) receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%), rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances gated by 2A receptors. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50%, when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a non-specific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third ionic effector, as blockade of KV7 channels with XE991 (10 μM) reduced serotonergic excitation by ∼50% in control conditions, and by ∼30% with intracellular BAPTA present. Together, these findings demonstrate a role for at least three distinct ionic effectors, including KV7 channels, a calcium-sensitive and calcium-permeable non-specific cation conductance, and the calcium-dependent ADP conductance, in mediating serotonergic excitation of COM neurons.

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Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex

Stephens

Baker

Gulledge

2018

Front. Neural Circuits

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“…Indeed, in this first-draft implementation, we assumed that the dose-dependent activation profile of ACh is homogeneous on excitatory and inhibitory cell-types and their synaptic connections, which is a gross generalization. For example, recent work reports that ACh inhibits L4 spiny neurons through muscarnic receptors, as against persistent excitation of L23 and L5 PCs (Eggermann and Feldmeyer, 2009 ; Dasgupta et al, 2018 ) and could have contrasting effects on sub-types of PCs located in the same neocortical layer and region (Joshi et al, 2016 ; Baker et al, 2018 ). As the next step to refine the biological accuracy and specificity of our framework, we plan to systematically incorporate physiological data on cholinergic varicosities, receptor localization and kinetics of ACh receptors, and specific ACh-induced effects on neuronal and synaptic function of an assortment of neocortical cell-types.…”

Section: Discussionmentioning

confidence: 99%

Data-Driven Modeling of Cholinergic Modulation of Neural Microcircuits: Bridging Neurons, Synapses and Network Activity

Ramaswamy

Colangelo

Markram

2018

Front. Neural Circuits

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Neuromodulators, such as acetylcholine (ACh), control information processing in neural microcircuits by regulating neuronal and synaptic physiology. Computational models and simulations enable predictions on the potential role of ACh in reconfiguring network activity. As a prelude into investigating how the cellular and synaptic effects of ACh collectively influence emergent network dynamics, we developed a data-driven framework incorporating phenomenological models of the physiology of cholinergic modulation of neocortical cells and synapses. The first-draft models were integrated into a biologically detailed tissue model of neocortical microcircuitry to investigate the effects of levels of ACh on diverse neuron types and synapses, and consequently on emergent network activity. Preliminary simulations from the framework, which was not tuned to reproduce any specific ACh-induced network effects, not only corroborate the long-standing notion that ACh desynchronizes spontaneous network activity, but also predict that a dose-dependent activation of ACh gives rise to a spectrum of neocortical network activity. We show that low levels of ACh, such as during non-rapid eye movement (nREM) sleep, drive microcircuit activity into slow oscillations and network synchrony, whereas high ACh concentrations, such as during wakefulness and REM sleep, govern fast oscillations and network asynchrony. In addition, spontaneous network activity modulated by ACh levels shape spike-time cross-correlations across distinct neuronal populations in strikingly different ways. These effects are likely due to the regulation of neurons and synapses caused by increasing levels of ACh, which enhances cellular excitability and decreases the efficacy of local synaptic transmission. We conclude by discussing future directions to refine the biological accuracy of the framework, which will extend its utility and foster the development of hypotheses to investigate the role of neuromodulators in neural information processing.

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“…A wealth of evidence supports a role for fast ACh release in promoting increased attention to stimuli and in subsequent plasticity [Sarter et al, 2016]. In addition, ACh excites the response network and suppresses the internal networks [Baker et al, 2018]. Second, ACh is the agent used in motoneuronmuscle connections, i.e., the means by which neurons induce strong muscle contractions.…”

Section: Response Execution Attention: Acetylcholine (Ach)mentioning

confidence: 99%

The Brain, Explained: A Comprehensive Theory of Brain Function

Rappoport¹

2018

Preprint

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Understanding brain function is one of the most important problems in human history. At present, there is no concrete theory for how the brain works. Here, a theory is presented that provides a detailed mechanistic biological account of the brain's capacities, including motor control, functional states, language, and thinking. Brain function is managed by a well-defined r e sponse ( R ) p r ocess t h at i s generally similar to the process underlying the immune system. The R process is strongly reflected in the brain's anatomy, physiology, and external i n teractions. Different R process stages are supported by distinct excitatory networks located in different cortical layers, hippocampal fields, and bagal ganglia paths, by distinct coordination networks comprised of GABAergic interneurons, and by distinct molecular agents. The roles of norepinephrine, serotonin, dopamine and acetylcholine is to promote the alert, planning, goal-setting and execution R process modes, respectively. Opioids and oxytocin promote termination by success, failure, fight o r r un, w hile g lucocorticoids and cannabinoids suppress acute responses to protect cells. The R process has two instances occurring at different time scales. The millisecondscale Quax process implements the execution of hierarchical sequences of movements and thoughts, in which the selection of the next action is determined via interaction between top-down predictions and sensory inputs. The slower Need process controls the satisfaction of internal and external needs. The theory differs from the existing standard accounts in many of the major topics (e.g., the basal ganglia, dopamine, language), and shows how cognition results from biological processes.

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Preferential cholinergic excitation of corticopontine neurons

Cited by 36 publications

References 56 publications

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex

Data-Driven Modeling of Cholinergic Modulation of Neural Microcircuits: Bridging Neurons, Synapses and Network Activity

The Brain, Explained: A Comprehensive Theory of Brain Function

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