Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

[1]  K. Krnjević,et al.  The mechanism of excitation by acetylcholine in the cerebral cortex , 1971, The Journal of physiology.

[2]  G. E. Alexander,et al.  Neuron Activity Related to Short-Term Memory , 1971, Science.

[3]  J M Fuster,et al.  Firing changes in cells of the nucleus medialis dorsalis associated with delayed response behavior. , 1973, Brain research.

[4]  F. Bloom,et al.  Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[5]  F. Bloom,et al.  Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  P. Goldman-Rakic,et al.  Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. , 1985, Science.

[7]  I. Creese,et al.  Characterization of alpha 1-adrenergic receptor subtypes in rat brain: a reevaluation of [3H]WB4104 and [3H]prazosin binding. , 1986, Molecular pharmacology.

[8]  P. Schwindt,et al.  Slow conductances in neurons from cat sensorimotor cortex in vitro and their role in slow excitability changes. , 1988, Journal of neurophysiology.

[9]  P. Goldman-Rakic,et al.  Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. , 1989, Journal of neurophysiology.

[10]  J. Morrison,et al.  Noradrenergic innervation of monkey prefrontal cortex: A dopamine‐β‐hydroxylase immunohistochemical study , 1989, The Journal of comparative neurology.

[11]  L. Descarries,et al.  Noradrenaline axon terminals in adult rat neocortex: An immunocytochemical analysis in serial thin sections , 1990, Neuroscience.

[12]  A. Constanti,et al.  Muscarinic receptor activation induces a prolonged post-stimulus afterdepolarization with a conductance decrease in guinea-pig olfactory cortex neurones in vitro , 1991, Neuroscience Letters.

[13]  Rodrigo Andrade,et al.  Cell excitation enhances muscarinic cholinergic responses in rat association cortex , 1991, Brain Research.

[14]  J. Glowinski,et al.  Contribution of an α1-adrenergic receptor subtype to the expression of the “ventral tegmental area syndrome” , 1992, Neuroscience.

[15]  P. Schwindt,et al.  Properties and ionic mechanisms of a metabotropic glutamate receptor-mediated slow afterdepolarization in neocortical neurons. , 1994, Journal of neurophysiology.

[16]  Bao-Ming Li,et al.  Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. , 1994, Behavioral and neural biology.

[17]  T. Hökfelt,et al.  Distribution of alpha 1 adrenoceptors in rat brain revealed by in situ hybridization experiments utilizing subtype-specific probes , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  M. J. Zigmond,et al.  Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Effects of diazepam , 1995, Neuroscience.

[19]  P. Goldman-Rakic.  Cellular basis of working memory , 1995, Neuron.

[20]  B. Moghaddam,et al.  Effect of a pharmacological stressor on glutamate efflux in the prefrontal cortex , 1996, Brain Research.

[21]  J. Krystal,et al.  The biological basis of panic disorder. , 1996, The Journal of clinical psychiatry.

[22]  R. Roth,et al.  Role of the Amygdala in the Coordination of Behavioral, Neuroendocrine, and Prefrontal Cortical Monoamine Responses to Psychological Stress in the Rat , 1996 .

[23]  C. A. Morgan,et al.  Noradrenergic Alterations in Posttraumatic Stress Disorder , 1997, Annals of the New York Academy of Sciences.

[24]  H. Akil,et al.  Distribution of α 1a-, α 1b- and α 1d-adrenergic receptor mRNA in the rat brain and spinal cord , 1997, Journal of Chemical Neuroanatomy.

[25]  G. Teuchert-Noodt,et al.  Social environment alters both ontogeny of dopamine innervation of the medial prefrontal cortex and maturation of working memory in gerbils (Meriones unguiculatus) , 1998, Journal of neuroscience research.

[26]  Leslie G. Ungerleider,et al.  An area specialized for spatial working memory in human frontal cortex. , 1998, Science.

[27]  M. D’Esposito,et al.  Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI. , 1999, Brain research. Cognitive brain research.

[28]  Bao-Ming Li,et al.  Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys , 1999, Neuropsychopharmacology.

[29]  G. Aghajanian,et al.  5-HT2A receptor or alpha1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. , 1999, European journal of pharmacology.

[30]  JaneR . Taylor,et al.  α-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function , 1999, Biological Psychiatry.

[31]  JaneR . Taylor,et al.  A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in the prefrontal cortex , 1999, Biological Psychiatry.

[32]  B. Postle,et al.  Activity in Human Frontal Cortex Associated with Spatial Working Memory and Saccadic Behavior , 2000, Journal of Cognitive Neuroscience.

[33]  A. Arnsten,et al.  Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats , 2000, Pharmacology Biochemistry and Behavior.

[34]  M. Hasselmo,et al.  Graded persistent activity in entorhinal cortex neurons , 2002, Nature.

[35]  M. Raskind,et al.  The α1-Adrenergic Antagonist Prazosin Improves Sleep and Nightmares in Civilian Trauma Posttraumatic Stress Disorder , 2002 .

[36]  M. Raskind,et al.  The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. , 2002, Journal of clinical psychopharmacology.

[37]  S. Siegelbaum,et al.  Hyperpolarization-activated cation currents: from molecules to physiological function. , 2003, Annual review of physiology.

[38]  K. Venkatachalam,et al.  Regulation of Canonical Transient Receptor Potential (TRPC) Channel Function by Diacylglycerol and Protein Kinase C* , 2003, Journal of Biological Chemistry.

[39]  E. Peskind,et al.  Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. , 2003, The American journal of psychiatry.

[40]  S. Di,et al.  Presynaptic Noradrenergic Regulation of Glutamate Inputs to Hypothalamic Magnocellular Neurones , 2003, Journal of neuroendocrinology.

[41]  J. Bains,et al.  Priming of Excitatory Synapses by α1 Adrenoceptor-Mediated Inhibition of Group III Metabotropic Glutamate Receptors , 2003, The Journal of Neuroscience.

[42]  J. Sweatt,et al.  Protein Kinase C Overactivity Impairs Prefrontal Cortical Regulation of Working Memory , 2004, Science.

[43]  H. Bengtsson,et al.  Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus , 2004, Genesis.

[44]  B. Moghaddam,et al.  Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release , 2004, Neuropsychopharmacology.

[45]  P. Kalivas,et al.  Impoverished Rearing Environment Alters Metabotropic Glutamate Receptor Expression and Function in the Prefrontal Cortex , 2004, Neuropsychopharmacology.

[46]  C. E. Rodríguez-Pérez,et al.  Human alpha1D-adrenoceptor phosphorylation and desensitization. , 2004, Biochemical pharmacology.

[47]  C. E. Rodríguez-Pérez,et al.  Human α1D-adrenoceptor phosphorylation and desensitization , 2004 .

[48]  D. Kullmann,et al.  Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why? , 2005, Progress in biophysics and molecular biology.

[49]  J. Bains,et al.  Noradrenaline Triggers Multivesicular Release at Glutamatergic Synapses in the Hypothalamus , 2005, The Journal of Neuroscience.

[50]  D. Surmeier,et al.  Dendritic Excitability of Mouse Frontal Cortex Pyramidal Neurons Is Shaped by the Interaction among HCN, Kir2, and Kleak Channels , 2005, The Journal of Neuroscience.

[51]  R. Andrade,et al.  Serotonergic regulation of calcium‐activated potassium currents in rodent prefrontal cortex , 2005, The European journal of neuroscience.

[52]  T. Akaike,et al.  Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons , 2005, Neuroscience Research.

[53]  A. Arnsten,et al.  The Beta-1 Adrenergic Antagonist, Betaxolol, Improves Working Memory Performance in Rats and Monkeys , 2005, Biological Psychiatry.

[54]  I. So,et al.  Desensitization of canonical transient receptor potential channel 5 by protein kinase C. , 2005, American journal of physiology. Cell physiology.

[55]  A. Arnsten,et al.  Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. , 2006, Learning & memory.

[56]  Y. Watanabe,et al.  Cellular and subcellular localization of alpha-1 adrenoceptors in the rat visual cortex , 2006, Neuroscience.

[57]  D. Morilak,et al.  Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability , 2006, Neuroscience.

[58]  A. Arnsten,et al.  Adrenergic pharmacology and cognition: focus on the prefrontal cortex. , 2007, Pharmacology & therapeutics.

[59]  R. Rimondini,et al.  Water T-maze, an improved method to assess spatial working memory in rats: Pharmacological validation , 2007, Neuroscience Letters.

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

[62]  Kyriaki Sidiropoulou,et al.  Corticolimbic Expression of TRPC4 and TRPC5 Channels in the Rodent Brain , 2007, PloS one.

[63]  D. Surmeier,et al.  M1 muscarinic receptor modulation of Kir2 channels enhances temporal summation of excitatory synaptic potentials in prefrontal cortex pyramidal neurons. , 2007, Journal of neurophysiology.

[64]  B. Stell,et al.  Axonal GABAA receptors , 2008, The European journal of neuroscience.

[65]  Michael E Hasselmo,et al.  Mglur-dependent Persistent Firing in Entorhinal Cortex Layer Iii Neurons , 2022 .

[66]  S. Sternson,et al.  A FLEX Switch Targets Channelrhodopsin-2 to Multiple Cell Types for Imaging and Long-Range Circuit Mapping , 2008, The Journal of Neuroscience.

[67]  Z. J. Huang,et al.  High-Resolution Labeling and Functional Manipulation of Specific Neuron Types in Mouse Brain by Cre-Activated Viral Gene Expression , 2008, PloS one.

[68]  A. Arnsten,et al.  β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals , 2008, Neurobiology of Aging.

[69]  Michael E Hasselmo,et al.  Persistent Firing Supported by an Intrinsic Cellular Mechanism in a Component of the Head Direction System , 2009, The Journal of Neuroscience.

[70]  Y. Smith,et al.  Light and electron microscopic localization of alpha-1 adrenergic receptor immunoreactivity in the rat striatum and ventral midbrain , 2009, Neuroscience.

[71]  R. Andrade,et al.  TRPC Channels Mediate a Muscarinic Receptor-Induced Afterdepolarization in Cerebral Cortex , 2009, The Journal of Neuroscience.

[72]  T. Simpson,et al.  A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. , 2009, Alcoholism, clinical and experimental research.

[73]  K. Deisseroth,et al.  Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning , 2009, Science.

[74]  L. Matzel,et al.  Selective attention, working memory, and animal intelligence , 2010, Neuroscience & Biobehavioral Reviews.

[75]  A. Arnsten,et al.  Dynamic Network Connectivity: A new form of neuroplasticity , 2010, Trends in Cognitive Sciences.

[76]  Philippe Séguéla,et al.  Metabotropic induction of persistent activity in layers II/III of anterior cingulate cortex. , 2010, Cerebral cortex.

[77]  Dmitri A Rusakov,et al.  Presynaptic GABAA receptors enhance transmission and LTP induction at hippocampal mossy fiber synapses , 2010, Nature Neuroscience.

[78]  D. Morilak,et al.  Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[79]  T. Sakaba,et al.  Multivesicular Release Differentiates the Reliability of Synaptic Transmission between the Visual Cortex and the Somatosensory Cortex , 2010, The Journal of Neuroscience.

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

[81]  K. Deisseroth,et al.  Tuning arousal with optogenetic modulation of locus coeruleus neurons , 2010, Nature Neuroscience.

[82]  A. Alonso,et al.  TRPC channels underlie cholinergic plateau potentials and persistent activity in entorhinal cortex , 2011, Hippocampus.

[83]  Mark F Bear,et al.  Toward fulfilling the promise of molecular medicine in fragile X syndrome. , 2011, Annual review of medicine.

[84]  J. Renger,et al.  Presynaptic HCN1 channels regulate CaV3.2 activity and neurotransmission at select cortical synapses , 2011, Nature Neuroscience.

[85]  T. Berger,et al.  Persistent activity in layer 5 pyramidal neurons following cholinergic activation of mouse primary cortices , 2011, The European journal of neuroscience.

[86]  A. Arnsten.  Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia , 2011, International Journal of Developmental Neuroscience.

[87]  P. Piazza,et al.  Glucocorticoids Can Induce PTSD-Like Memory Impairments in Mice , 2012, Science.

[88]  T. H. Brown,et al.  Muscarinic receptor activation enables persistent firing in pyramidal neurons from superficial layers of dorsal perirhinal cortex , 2012, Hippocampus.