Adrenergic Modulation Regulates the Dendritic Excitability of Layer 5 Pyramidal Neurons In Vivo.

The excitability of the apical tuft of layer 5 pyramidal neurons is thought to play a crucial role in behavioral performance and synaptic plasticity. We show that the excitability of the apical tuft is sensitive to adrenergic neuromodulation. Using two-photon dendritic Ca2+ imaging and in vivo whole-cell and extracellular recordings in awake mice, we show that application of the α2A-adrenoceptor agonist guanfacine increases the probability of dendritic Ca2+ events in the tuft and lowers the threshold for dendritic Ca2+ spikes. We further show that these effects are likely to be mediated by the dendritic current Ih. Modulation of Ih in a realistic compartmental model controlled both the generation and magnitude of dendritic calcium spikes in the apical tuft. These findings suggest that adrenergic neuromodulation may affect cognitive processes such as sensory integration, attention, and working memory by regulating the sensitivity of layer 5 pyramidal neurons to top-down inputs.

[1]  S. Siegelbaum,et al.  HCN1 Channels Constrain Synaptically Evoked Ca2+ Spikes in Distal Dendrites of CA1 Pyramidal Neurons , 2007, Neuron.

[2]  M. Biel,et al.  A family of hyperpolarization-activated mammalian cation channels , 1998, Nature.

[3]  Walter Senn,et al.  Hyperpolarization-activated current Ih disconnects somatic and dendritic spike initiation zones in layer V pyramidal neurons. , 2003, Journal of neurophysiology.

[4]  Randy M. Bruno,et al.  Effects and Mechanisms of Wakefulness on Local Cortical Networks , 2011, Neuron.

[5]  P. Golshani,et al.  Cellular mechanisms of brain-state-dependent gain modulation in visual cortex , 2013, Nature Neuroscience.

[6]  M. Häusser,et al.  Dendritic Discrimination of Temporal Input Sequences in Cortical Neurons , 2010, Science.

[7]  Rafael Yuste,et al.  moco: Fast Motion Correction for Calcium Imaging , 2015, Front. Neuroinform..

[8]  Mark T. Harnett,et al.  Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical Pyramidal Neurons , 2015, The Journal of Neuroscience.

[9]  U. Kaupp,et al.  Molecular identification of a hyperpolarization-activated channel in sea urchin sperm , 1998, Nature.

[10]  W. Rall.  Branching dendritic trees and motoneuron membrane resistivity. , 1959, Experimental neurology.

[11]  T. Robbins,et al.  Noradrenergic modulation of cognition: Therapeutic implications , 2013, Journal of psychopharmacology.

[12]  Hongdian Yang,et al.  Origins of choice-related activity in mouse somatosensory cortex , 2015, Nature Neuroscience.

[13]  Mark T. Harnett,et al.  Nonlinear dendritic integration of sensory and motor input during an active sensing task , 2012, Nature.

[14]  D. Johnston,et al.  The h Channel Mediates Location Dependence and Plasticity of Intrinsic Phase Response in Rat Hippocampal Neurons , 2008, The Journal of Neuroscience.

[15]  Christof Koch,et al.  Physiology of Layer 5 Pyramidal Neurons in Mouse Primary Visual Cortex: Coincidence Detection through Bursting , 2015, PLoS Comput. Biol..

[16]  H. Brown,et al.  How does adrenaline accelerate the heart? , 1979, Nature.

[17]  M. Carandini,et al.  Inhibition dominates sensory responses in awake cortex , 2012, Nature.

[18]  Masanori Murayama,et al.  Inhibitory Regulation of Dendritic Activity in vivo , 2012, Front. Neural Circuits.

[19]  S. Sara,et al.  Orienting and Reorienting: The Locus Coeruleus Mediates Cognition through Arousal , 2012, Neuron.

[20]  Matthew E Larkum,et al.  Effect of common anesthetics on dendritic properties in layer 5 neocortical pyramidal neurons. , 2008, Journal of neurophysiology.

[21]  Rajeevan T. Narayanan,et al.  Layer-specific high-frequency action potential spiking in the prefrontal cortex of awake rats , 2013, Front. Cell. Neurosci..

[22]  Matthew E Larkum,et al.  Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o‐βγ‐subunit interaction with Cav1 channels , 2013, The Journal of physiology.

[23]  B. Sakmann,et al.  Active propagation of somatic action potentials into neocortical pyramidal cell dendrites , 1994, Nature.

[24]  Taro Kiritani,et al.  Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control. , 2011, Journal of neurophysiology.

[25]  D. Johnston,et al.  Dopaminergic Regulation of Neuronal Excitability through Modulation of Ih in Layer V Entorhinal Cortex , 2006, The Journal of Neuroscience.

[26]  M. Larkum,et al.  High I(h) channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. , 2001, Journal of neurophysiology.

[27]  G. Stuart,et al.  Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model , 2007, The Journal of physiology.

[28]  B. Connors,et al.  Regenerative activity in apical dendrites of pyramidal cells in neocortex. , 1993, Cerebral cortex.

[29]  D. McCormick,et al.  α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex , 2007, Cell.

[30]  Idan Segev,et al.  The morphoelectrotonic transform: a graphical approach to dendritic function , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  S. Sara.  The locus coeruleus and noradrenergic modulation of cognition , 2009, Nature Reviews Neuroscience.

[32]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[33]  B. Sakmann,et al.  In vivo, low-resistance, whole-cell recordings from neurons in the anaesthetized and awake mammalian brain , 2002, Pflügers Archiv.

[34]  Nelson Spruston,et al.  Dendritic integration: 60 years of progress , 2015, Nature Neuroscience.

[35]  Michiel W. H. Remme,et al.  Different levels of Ih determine distinct temporal integration in bursting and regular‐spiking neurons in rat subiculum , 2006, The Journal of physiology.

[36]  Gábor Tamás,et al.  Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites , 2002, Nature Neuroscience.

[37]  Henry Markram,et al.  Models of Neocortical Layer 5b Pyramidal Cells Capturing a Wide Range of Dendritic and Perisomatic Active Properties , 2011, PLoS Comput. Biol..

[38]  R. Miura,et al.  Quantification of membrane properties of trigeminal root ganglion neurons in guinea pigs. , 1986, Journal of neurophysiology.

[39]  M. Larkum,et al.  Active cortical dendrites modulate perception , 2016, Science.

[40]  B. Sakmann,et al.  Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Santello,et al.  Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation , 2015, Neuron.

[42]  Daniel Johnston,et al.  Projection-Specific Neuromodulation of Medial Prefrontal Cortex Neurons , 2010, The Journal of Neuroscience.

[43]  Jonathan D. Cohen,et al.  Adaptive gain and the role of the locus coeruleus–norepinephrine system in optimal performance , 2005, The Journal of comparative neurology.

[44]  J. Magee.  Dendritic Hyperpolarization-Activated Currents Modify the Integrative Properties of Hippocampal CA1 Pyramidal Neurons , 1998, The Journal of Neuroscience.

[45]  W. Gan,et al.  REM sleep selectively prunes and maintains new synapses in development and learning , 2017, Nature Neuroscience.

[46]  Zizhen Zhang,et al.  Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors , 2013, PloS one.

[47]  I. Lampl,et al.  Subthreshold oscillations and resonant behavior: two manifestations of the same mechanism , 1997, Neuroscience.

[48]  Zhian Hu,et al.  Neurophysiology of HCN channels: From cellular functions to multiple regulations , 2014, Progress in Neurobiology.

[49]  LM Hurley,et al.  A matter of focus: monoaminergic modulation of stimulus coding in mammalian sensory networks , 2004, Current Opinion in Neurobiology.

[50]  M. Sarter,et al.  Modulators in concert for cognition: Modulator interactions in the prefrontal cortex , 2007, Progress in Neurobiology.

[51]  Idan Segev,et al.  Principles Governing the Operation of Synaptic Inhibition in Dendrites , 2012, Neuron.

[52]  S. Siegelbaum,et al.  Molecular mechanism of cAMP modulation of HCN pacemaker channels , 2001, Nature.

[53]  Andreas T. Schaefer,et al.  Coincidence detection in pyramidal neurons is tuned by their dendritic branching pattern. , 2003, Journal of neurophysiology.

[54]  S. Manita,et al.  A Top-Down Cortical Circuit for Accurate Sensory Perception , 2015, Neuron.

[55]  Michael T. Lippert,et al.  Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task , 2015, Front. Behav. Neurosci..

[56]  G. Stuart,et al.  Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. , 2000, Journal of neurophysiology.

[57]  B. Sakmann,et al.  A new cellular mechanism for coupling inputs arriving at different cortical layers , 1999, Nature.

[58]  Nathalie L Rochefort,et al.  Dendritic organization of sensory input to cortical neurons in vivo , 2010, Nature.

[59]  S. Foote,et al.  Extrathalamic modulation of cortical function. , 1987, Annual review of neuroscience.

[60]  A. Lavin,et al.  α2‐Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents , 2007, The Journal of physiology.

[61]  A. Polsky,et al.  Synaptic Integration in Tuft Dendrites of Layer 5 Pyramidal Neurons: A New Unifying Principle , 2009, Science.

[62]  Spencer L. Smith,et al.  Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo , 2013, Nature.

[63]  Nicholas T. Carnevale,et al.  The NEURON Simulation Environment , 1997, Neural Computation.

[64]  C. Wahl-Schott,et al.  Hyperpolarization-activated cation channels: from genes to function. , 2009, Physiological reviews.

[65]  Idan Segev,et al.  Subthreshold oscillations and resonant frequency in guinea‐pig cortical neurons: physiology and modelling. , 1995, The Journal of physiology.

[66]  W. Gan,et al.  Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity , 2015, Nature.

[67]  C. Wahl-Schott,et al.  HCN channels: Structure, cellular regulation and physiological function , 2009, Cellular and Molecular Life Sciences.

[68]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[69]  D. Johnston,et al.  Subcircuit-specific neuromodulation in the prefrontal cortex , 2014, Front. Neural Circuits.

[70]  Mark T. Harnett,et al.  Potassium Channels Control the Interaction between Active Dendritic Integration Compartments in Layer 5 Cortical Pyramidal Neurons , 2013, Neuron.

[71]  B. Sakmann,et al.  Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons , 1997, The Journal of physiology.

[72]  Mark C. W. van Rossum,et al.  Cellular Mechanisms Underlying Behavioral State-Dependent Bidirectional Modulation of Motor Cortex Output , 2015, Cell reports.

[73]  A. Arnsten,et al.  Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions , 2004, Biological Psychiatry.

[74]  Y. Yarom,et al.  Resonance, oscillation and the intrinsic frequency preferences of neurons , 2000, Trends in Neurosciences.

[75]  G. Stuart,et al.  Single Ih Channels in Pyramidal Neuron Dendrites: Properties, Distribution, and Impact on Action Potential Output , 2006, The Journal of Neuroscience.

[76]  E. Vizi,et al.  Alpha2-adrenergic receptors modify dendritic spike generation via HCN channels in the prefrontal cortex. , 2008, Journal of neurophysiology.