Elsevier

Brain Research

Volume 1229, 10 September 2008, Pages 47-60
Brain Research

Research Report
Individual and additive effects of neuromodulators on the slow components of afterhyperpolarization currents in layer V pyramidal cells of the rat medial prefrontal cortex

https://doi.org/10.1016/j.brainres.2008.06.098Get rights and content

Abstract

The effects of 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine (DA) and the muscarinic receptor agonist carbachol (CCh) on the voltage step-induced outward currents underlying afterhyperpolarization (AHP), consisting of a medium (ImAHP) and slow (IsAHP) component, were investigated in layer V pyramidal cells of the rat medial prefrontal cortex (mPFC). Whole-cell voltage clamp recordings were performed in vitro to quantitatively measure ImAHP and IsAHP and to examine their functional link to spike-frequency adaptation in the presence of agonists. CCh, 5-HT and NA all reduced the IsAHP and the spike adaptation, and, in some cells, replaced the IsAHP by the slow inward currents (IsADP) underlying the slow afterdepolarization (sADP). DA, however, failed to increase the frequency despite its comparable inhibition of the IsAHP over a range of concentrations. In order to test the neuromodulator agonists to see if they have additive actions on the IsAHP, the effects of co-application of two agonists that increased spike-frequency, 5-HT+NA, 5-HT+CCh and CCh+NA, all at the concentration 30 μM were examined. Specific combinations that included CCh showed additive effects on the slow afterpolarization currents, possibly via both inhibition of IsAHP and generation of IsADP. These findings suggest that neuromodulators have differential effects on the link between the IsAHP modulation and spike-frequency adaptation, and that they could exert additive effects on the slow aftercurrents following a strong excitation and, therefore, regulate the repetitive firing properties of the output cells of the rat mPFC.

Introduction

Most ascending neuromodulatory systems, including those of serotonin (5-HT) (O'Hearn and Molliver, 1984), acetylcholine (ACh) (Mesulam et al., 1983), noradrenaline (NA) (Jones and Moore, 1977) and dopamine (DA) (Lindvall and Björklund, 1974), innervate the medial prefrontal cortex (mPFC) of mammalian brain and exhibit overlapping terminal fields (Lewis et al., 1992). Virtually all the original nuclei of these corticopetal systems in the brainstem or the basal forebrain receive reciprocal inputs, either directly or indirectly, from the PFC (for a review, see Briand et al., 2007). Except for 5-HT, they show the two distinct patterns of activity, tonic and phasic ones, which are evident in the pattern of either firing activity or neurotransmitter release. Tonic activity is state-specific and regulates arousal (Pribram and McGuinness, 1975), reflecting alterations in the activity over several minutes. On the contrary, phasic components are evoked by defined cognitive activity lasting for several seconds (Briand et al., 2007).

These systems affect the excitability of neurons in cortical local circuits, which mainly consist of pyramidal and nonpyramidal neurons. Each agonist exerts a depolarizing action on a specific subpopulation of GABAergic interneurons depending on the cell type, and makes them discharge a train of action potentials (Kawaguchi, 1997, Férézou et al., 2002, Gorelova et al., 2002). Although the effects on the membrane potential of pyramidal cells appear less prominent than those on nonpyramidal cells, two remarkable effects on the intrinsic membrane properties of these cells have been established. One is the potent inhibition of slow afterhyperpolarization potentials (sAHP), and the other is the replacement of sAHP by slow afterdepolarization (sADP) (Schwindt et al., 1988b, Haj-Dahmane and Andrade, 1998). sAHP arises from activation of calcium-activated potassium currents triggered by calcium influx during a train of action potentials, lasts for seconds (for a review, see Vogalis et al., 2003), causes spike-frequency adaptation, and is thus a major determinant of cellular excitability (Madison and Nicoll, 1982). Medium AHP (mAHP), which decays faster than sAHP (Stocker et al., 1999), has also been shown to follow a burst of action potentials, to be caused by calcium-activated potassium currents, and to affect early interspike interval (Faber and Sah, 2002). These two afterpolarizations could be separable on pharmacological grounds: mAHP is sensitive to the blockade by apamin, a bee toxin, whereas sAHP is not (Faber and Sah, 2002). Unlike sAHP and mAHP, sADP emerges solely in the presence of agonists (Schwindt et al., 1988b). The sADP temporally overlaps with the sAHP and only appear when the inward currents mediating the sADP exceed the outward current underlying sAHP (IsAHP) (Schwindt et al., 1988b).

Strong inhibition of sAHP has been shown for a range of neuromodulatory agonists including NA (Madison and Nicoll, 1982), the muscarinic agonist carbachol (CCh) (Schwindt et al., 1988b), and 5-HT (Pedarzani and Storm, 1993). This inhibition results in raised firing rate due to reduced spike-frequency adaptation (Madison and Nicoll, 1982, Pedarzani and Storm, 1993). The effects of DA on the sAHP of the pyramidal cells, however, are rarely addressed in the PFC despite its importance in PFC-related cognition (Sawaguchi and Goldman-Rakic, 1991). Moreover, given the enormous complexity of the effects of DA on current-evoked spike firing (Gorelova and Yang, 2000, Gulledge and Jaffe, 1998, Gulledge and Jaffe, 2001, Yang and Seamans, 1996), it is difficult to deduce the effects of DA on the sAHP.

Several lines of evidence indicate a concomitant increase in the release of multiple neuromodulator systems in the rat PFC that is induced by behavioral task or exposure to stress. Visual attention tasks enhance temporally overlapping efflux of NA and ACh in the mPFC (Dalley et al., 2001). Stress due to conditioned fear increases both 5-HT (Yoshioka et al., 1995) and ACh (Acquas et al., 1996) release in the PFC. Thus it is possible that interaction could take place between these systems at a cellular level, because neuromodulators released concomitantly in the overlapping target regions might exert their actions partly via the convergence of signaling pathways on the sAHP, that is, the usual inhibition of sAHP and the less frequent generation of sADP. Evidence describing such interaction between these systems at a cellular level, however, has remained scarce.

The purpose of the present study is two-fold. First, the difference in the individual effects of four neuromodulator agonists, 5-HT, CCh, NA and DA, on the mAHP and sAHP of layer V pyramidal neurons of the rat mPFC was examined. In particular, the link between their modulation of the IsAHP and the change in spike-frequency was tested, because very little is known about such a link for DA, whereas it has been established for the other three agonists (Madison and Nicoll, 1982, Schwindt et al., 1988b, Pedarzani and Storm, 1993). Second, the question of whether co-application of two distinct agonists, that have been shown to increase the spike-frequency, also show measurable additive effects on the currents underlying slow afterpotentials was examined. The inhibition of IsAHP and the generation of IsADP were considered collectively as an index to assess repetitive firing properties.

Section snippets

Results

Recordings were made from visually identified large pyramidal neurons (n=95) in layer V of the rat medial prefrontal cortex (mPFC). The primary focus of this study is to examine both the individual and additive effects of distinct neuromodulators on the IsAHP and the repetitive firing properties of layer V pyramidal cells. The number of cells tested for the actions of individual agonists and their combinations (all at 30 μM) was as follows: serotonin (5-HT), n = 13; noradrenaline (NA), n = 6;

Discussion

The major findings of the present study in the layer V pyramidal neurons of the rat mPFC are summarized as follows. (1) Inhibitory effects on the Ca2+-activated IsAHP were comparable among the four neuromodulator agonists, 5-HT, CCh, NA and DA, and the influences of these agents on ImAHP were much smaller than those on IsAHP. However, their effects on repetitive action potential firing properties were different because 5-HT, CCh and NA all increased the frequency of action potential firing by

Experimental procedures

Animal-use procedures were in accordance with the Tottori University Guide for the Care and Use of Laboratory Animals and were approved by the Tottori University Animal Care and Use Committee. All the experiments conformed to international guidelines on the ethical use of animals.

Acknowledgments

The authors thank Dr. M.Brown for critical reading the manuscript. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

References (55)

  • PedarzaniP. et al.

    PKA mediates the effects of monoamine transmitter on the K+ current underlying the slow spike frequency adaptation in hippocampal neurons

    Neuron

    (1993)
  • RamosB.P. et al.

    Adrenergic pharmacology and cognition: focus on the prefrontal cortex

    Pharmacol. Ther.

    (2007)
  • SarterM. et al.

    Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection

    Brain Res. Rev.

    (2005)
  • SmithD.G. et al.

    Esposure to predator odor stress increases efflux of frontal cortex acetylcholine and monoamines in mice: comparisons wit immobilization stress and reversal by chlordiazepoxide

    Brain Res.

    (2006)
  • YoshiokaM. et al.

    Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex

    Pharmacol. Biochem. Behav.

    (1995)
  • AmatJ. et al.

    Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

    Nat. Neurosci.

    (2005)
  • AcquasE. et al.

    Conditioned and unconditioned stimuli increase frontal cortical and hippocampal acetylcholine release: effects of novelty, habituation, and fear

    J. Neurosci.

    (1996)
  • Aston-JonesG. et al.

    Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli

    J. Neurosci.

    (1981)
  • BlandS.T. et al.

    Stressor controllability modoulates stress-induced dopamine and serotonin efflux and morphine-induced serotonin efflux in the medial prefrontal cortex

    Neuropsychopharmacology

    (2003)
  • DalleyJ.F. et al.

    Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task

    J. Neurosci.

    (2001)
  • DongY. et al.

    Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons

    J. Neurosci.

    (2003)
  • FaberE.S.L. et al.

    Physiological role of calcium-activated potassium currents in the rat lateral amygdala

    J. Neurosci.

    (2002)
  • FaberE.S.L. et al.

    Independent roles of calcium and voltage-dependent potassium currents in controlling spike frequency adaptation in lateral amygdala pyramidal neurons

    Eur. J. Neurosci.

    (2005)
  • FérézouI. et al.

    5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons

    J. Neurosci.

    (2002)
  • FoehringR.C. et al.

    Norepinephrine selectively reduces slow Ca2+- and Na+-mediated K+ currents in cat neocortical neurons

    J. Neurophysiol.

    (1989)
  • GillT.M. et al.

    Sustained visual attention performance-associated prefrontal neuronal activity: evidence for cholinergic modulation

    J. Neurosci.

    (2000)
  • GorelovaN. et al.

    Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex

    J. Neurophysiol.

    (2002)
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