C.D. B<irnes and O. Pompeiano (Eds.
)
Progress m Brain Research, Vol. 88
<fl 1991 Elsevier Science Publishers B.V.
CHAPTER22
Actions of norepinephrine in the cerebral cortex
and thalarnus: irnplications for function
of the central noradrenergic systern
D.A. McCorrnick, H.-C. Pape and A. Williarnson
Section of Neurobio/ogy, Ya/e Uníversity School of Medicine, Cedar Street, New Haven, CT, U.S.A.
Norepinephrine (NE) has poten! and long-lasting ionic effects
on cortical and thalamic neurons. In cortical pyramidal cells,
activation of j3-adrenergic receptors results in an enhanced
excitability and responsiveness to depolarizing inputs. This
enhanced excitability is expressed as a reduction in spike
frequency adaptation and is mediated by a marked suppres-
sion of a slow Ca+ +-activated potassium current known as
IAHP· In the thalamus, application of NE results in the
suppression of ongoing rhythmic burst activity and a switch to
the single spike firing mode of action potential generation.
Key words: noradrenaline, neocortex, arousal, sleep, neuromodulation
Introduction
The mammalian cerebral cortex and thalamus are
densely innervated by noradrenergic fibers arising
almost exclusively from the brainstem nucleus,
the locus coeruleus (LC) (Lindvall et al., 1974;
Foote et al., 1983; Hughes and Mullikin, 1984;
Morrison and Foote, 1986). In addition, {3, a 1,
and a 2-adrenoceptors have been localized within
both the cerebral cortex and thalamus (Rainbow
et al., 1984; Jones et al., 1985; Palacios et al.,
1987). Stimulation of the LC modulates, through
293
This effect is mediated through an a 1-adrenergic suppression
of a resting leak potassium curren!, IKL' and through a
j3-adrenoceptor-mediated enhancement of the hyperpolariza-
tion activated cation current 1 h· Together with the actions of
other neuromodulatory neurotransmitters (i.e., acetylcholine,
histamine, serotonin) these effects facilitate the switch of
these neurons from a state of rhythmic oscillation and low
excitability during drowsiness and slow-wave sleep to a state
of increased excitability and responsiveness during periods of
waking, attentiveness and cognition.
the activation of adrenoceptors, the electrical ac-
tivity generated by neurons in the cortex and
thalamus (Rogawski and Aghajanian, 1980;
Kayama et al., 1982; Sato et al., 1989). These,
and other findings indicate that the central nor-
adrenergic system is intimately involved in deter-
mining both the leve! of neuronal excitability and
the pattern of activity generated by neurons in
thalamocortical systems. Postsynaptic actions of
norepinephrine (NE) have been determined in a
number of CNS regions. In the brainstem, hy-
pothalamus, and spinal cord, activation of a 1
294
adrenoceptors is associated with a slow depolar-
ization mediated by a decrease in a K + conduc-
tance (Aghajanian, 1984, 1985; Ma and Duo, 1985;
Randle et al., 1986; reviewed by Supranant, 1990).
In contrast, activation of {3-adrenergic receptors
in the hippocampus is associated with an increase
in excitability through a reduction in spike fre-
quency adaptation (Haas and Konnerth, 1983;
Madison and Nicoll, 1986; Nicoll et al., 1990).
The response to activation of aradrenoceptors
has been extensively studied in the LC and is
associated with inhibition mediated by an in-
crease in membrane K + conductance (Williams
et al., 1985; North, 1989). The precise ionic mech-
anisms by which NE modulates the pattern of
activity generated by thalamic and cortical neu-
rons is the subject of this chapter.
Actions of NE in the cerebral cortex
Iontophoretic applications of NE to cerebral cor-
tical neurons recorded extracellularly in vivo have
revealed a wide variety of postsynaptic responses
including weak inhibition, slow excitation and
"modulation" (Bevan et al., 1977; Waterhouse et
al., 1981; Waterhouse et al., 1988; Sato et al.,
1989). In general, the weak inhibitory responses
are localized throughout al! layers and are medi-
ated by {3-adrenergic receptors while the slow
excitatory responses are more prominent in the
middle or deeper layers and are mediated by
a-adrenoceptors, probably of the a 1 subtype (see
below; Bevan et al., 1977; Waterhouse et al.,
1981; Armstrong-James and Fox, 1983). Modula-
tory responses to NE have been reported to take
the form of increases in the so-called "signal-to-
noise" ratio; in other words, an increase in the
ratio between the stimulus-specific response to
baseline firing rate. These modulatory responses
appear to be mediated by both a- and ,B-adren-
ergic receptors.
Intracellular investigations of the actions of
NE on cortical pyramidal cells have so far only
revealed an ionic action in response to stimula-
tion of {3-adrenoceptors (McCormick and Wil-
liamson, 1989; Foehring et al., 1989); the specific
ionic responses mediated by a 1 and a 2 adreno-
ceptors remain to be investigated. Activation of
/3-adrenergic receptors on cortical pyramidal cells
results in a marked reduction in spike frequency
adaptation through a block of the Ca++ _activated
potassium current known as I AHP (McCormick
and Williamson, 1989; Foehring et al., 1989). In
the absence of agonists, intracellular injection of
a constant depolarizing current pulse into a corti-
cal pyramidal cell results in the generation of a
train of action potentials which slow down in
frequency over time, a process known as spike
frequency adaptation (Fig. 1, control). Spike fre-
quency adaptation appears to result from the
activation of a number of different potassium
currents, of which two, IAHP and IM, play a majar
role (Madison and Nicoll, 1984). IAHP is a potas-
sium current which is activated by increases in
the intracellular concentration of Ca++ into the
micromolar range (Pennefather et al., 1985). It
was named IAHP because its activation by Ca++
entry, occurring during a train of action poten-
tials, results in an afterhyperpolarization of the
membrane potential following the train. I M, in
contrast, is not activated by Ca++, but rather is
sensitive to the membrane potential of the cell
(Brown and Adams, 1980). Depolarization of the
membrane above approximately - 75 mV results
in increasing activation of IM, which subsequently
reduces the firing rate of the neuron. Together,
these two potassium currents slow down the rate
of action potential generation during a constant
depolarizing current pulse (Fig. 1, control).
Examination of the effects of NE, or other
neurotransmitters, on I AHP can be performed with
a technique known as hybrid voltage clamp. In
this technique, the cell is first induced to gener-
ate a train of action potentials with intracellular
injection of a depolarizing current pulse. At the
end of the pulse, the microelectrode amplifier is
switched to voltage clamp mode and the voltage
is "clamped" at the desired holding potential
(typically - 60 mV). The resulting current which
the amplifier must supply in order to keep the
 295

A Control Histamine Recovery E

n- Current Pulse

i l-300 msec -1
1~1~~
L"~ci 1-- 2 sec -1

B Methacholine F

e Norepinephrine

G(lL
D Serotonin
JillJl 1

H , \
\

NE
J------~
~
~

~· .

5.~~
Fig. l. Histamine (HA), methacholine (MCh), norepinephrine (NE), and serotonin (5-HT) all reduce spike frequency adaptation
and IAHP in human neocortical neurons. A-D. Intracellular injection of a depolarizing current pulse results in the generation of a
train of action potentials which shows spike frequency adaptation (Control). Application of HA (A; 500 µ,M in pipette), MCh (B; 1
mM), NE (C; 500 µ,M) or 5-HT (D; 300-500 µ,M) results in a reversible reduction of adaptation. E-H. Intracellular injection of a
curren! pulse was used to generate from 6 to 10 action potentials (curren! trace only shown). After the cessation of the pulse, the
cell was switched to voltage clamp mode (held at - 60 mV) and the after curren! examined. Application of all four agents reduced
a slow outward component (IAHP) of this after current. HA and MCh both caused, in addition, an apparent inward curren! and
therefore the traces in E and F were offset to match the pre-drug baseline for illustrative purposes. I AHP became progressively
smaller throughout the course of the experiment due in part to repeated applications of the four agents. AH data, except C, were
obtained from the same !ayer III human cortical neuron from the anterior temporal lobe. Although this cell displayed spike
frequency adaptation to NE, this data was not suitable for illustration due to filtering (cutoff at 100 Hz) for examination of IAHP·
Data in C was obtained from another anterior temporal human cortical neuron. (From McCormick and Williamson, 1989.)

membrane potential at this leve! is equal to that
which is flowing through the ionic channels acti-
vated by the train of action potentials (Fig. lE-H).
A majar component of this current is IAHP (Fig.
lE). Application of NE, or the f3-adrenoceptor
agonist isoprenaline, results in the complete sup-
pression of IAHP (Fig. lG) and a marked reduc-
tion in spike frequency adaptation (Fig. lC). This
response appears to be a very general mechanism
underlying noradrenergic influence on cortical
pyramidal cells for it has been found in nearly
every cortical pyramidal cell exhibiting spike fre-
296
quency adaptation in widely diverse regions of
the cortex, including the cingulate, sensorimotor,
and visual areas, and within CA 1 pyramidal cells
and dentate granule cells of the hippocampus
(Madison and Nicoll, 1986; Haas and Rose 1987;
McCormick and Williamson, 1989; Foehring et
al., 1989). Similarly, this response has been
demonstrated in cortical pyramidal cells from a
number of different species including rat, guinea
pig, cat and human (Madison and Nicoll, 1986;
McCormick and Williamson, 1989; Foehring et
al., 1989).
The exact cellular mechanisms by which NE
reduces IAHP are not yet completely known, al-
though the work by Madison and Nicoll in the
hippocampus reveal that it probably involves the
f3-adrenergic stimulation of adenylyl cyclase
(Madison and Nicoll, 1986). Presumably, activa-
tion of f3-adrenergic receptors increases the pro-
duction of cAMP through stimulation of adenylyl
cyclase. This increase in intracellular concentra-
tions of cAMP may then result in a decrease in
the arnplitude of I AHP through a cAMP-depen-
dent protein kinase. One possibility is that this
A-kinase phosphorylates sorne critica! portian of
the IAHP channel and results in a decrease in
their sensitivity to the intracellular levels of Ca++.
Interestingly, NE is not the only neurotrans-
rnitter which can reduce IAHP, and therefore re-
duce spike frequency adaptation. For exarnple,
we have shown in the human neocortical pyrarni-
dal cells that histarnine, acetylcholine, and sero-
tonin are also capable of reducing IAHP' even
when examined in the same neuron (Fig. 1). This
result indicates a rernarkable convergence of neu-
rotransrnitter action between the various neuro-
rnodulatory transrnitter agents, a property which
is now known to be widespread in the central and
peripheral nervous system (North, 1989; Mc-
Corrnick and Williarnson, 1989; Nicoll et al.,
1990).
The ability of NE to block spike frequency
adaptation in cortical pyramidal cells would be
expected to have very specific consequences for
action potential generation in vivo. If the neuron
were silent, blocking of I AHP by NE rnay have no
effect at ali, since this current will rnost likely not
be active. However, if the neuron were to be
suddenly depolarized while {3-adrenoceptors were
activated, then the resulting train of action poten-
tials will occur at a rate higher than that which
would be generated in the absence of NE, partic-
ularly after the first 50 msec or so. Indeed, the
longer the cell is depolarized, the greater the
enhancement of spike firing resulting frorn sup-
pression of IAHP· If the neuron were tonically
active, reduction of I AHP will result in an increase
in firing rate of the neuron, due to the reduction
of tonic activation of this potassiurn current. In
this rnanner, NE, acting through f3-receptors, will
selectively and potently enhance the response of
cortical pyramidal cells to prolonged depolariza-
tions, such as those associated with stimulation of
a sensory receptive field.
Although this ability to enhance the response
of cortical pyrarnidal cells to trains of excitatory
inputs rnay underlie the apparent ability of NE to
enhance the response to stimulation of peripheral
receptive fields in sorne neurons (e.g., Water-
house et al., 1988), it does not explain two other
findings: (1) the apparent weak inhibitory effects
of NE in the cerebral cortex; and (2) the a-adren-
oceptor-rnediated slow, excitatory responses (Be-
van et al., 1977; Waterhouse et al., 1981; Arrn-
strong-Jarnes and Fox, 1983). Unfortunately, the
cellular mechanisrns underlying either of these
effects are not yet known. However, the re-
sponses known to occur to NE in other regions of
the central and peripheral nervous system suggest
sorne possibilities. Madison and Nicoll found in
hippocarnpal pyrarnidal cells that application of
NE occasionally resulted in a hyperpolarization
of the rnernbrane potential in addition to the
reduction in spike frequency adaptation. This
srnall hyperpolarization was suggested to underlie
the weak inhibitory influence of NE previously
dernonstrated in vivo (Madison and Nicoll, 1986).
The hyperpolarization was associated with an in-
crease in mernbrane conductance suggesting that
it was rnediated by opening of either K + or Cl -
 297

channels, although the specific ionic mechanisms
have not yet been determined. A second possibil-
ity is suggested by the actions of NE in smooth
muscle cells. In these cells, activation of /3-adren-
oceptors results in a selective enhancement of the
M-current (Sims et al., 1988). If a similar re-
sponse occurred in the cerebral cortex, it would
be expected to reduce the ability of the neuron to
genera te ongoing activity (i.e., inhibition of spike
activity). However, the voltage-dependent nature
of 1M would predict that the resulting inhibitory
effects should be larger far large depolarizations
than far spontaneous activity, a prediction which
is opposite to that reported in vivo. Finally, a
third possibility is that NE reduces the effective-
ness of excitatory neurotransmission, either post-
Cerebral Cortex
synaptically or presynaptically, in the cerebral
cortex.
The ability of NE to excite cortical pyramidal
cells through a-adrenoceptors probably results
from a reduction of a resting potassium current,
distinct from IM or IAHP, since this response has
been demonstrated in a variety of other central
neurons, including thalamic relay cells (see be-
low; reviewed by Nicoll et al., 1990). This hypo-
thesis remains to be tested thoroughly.
Actions of NE in the thalamus
Extracellular iontophoretic applications of NE
onto thalamocortical relay neurons in the rodent
LGNd or nucleus reticularis result in a potent

A Normal NE

m
Pyramidal Cell

Jtl~
lnterneuron

B
C tgK

~-----
A
NE -d.c.

Retina
Fig. 2. Postsynaptic actions of NE in the thalamus and cerebral cortex. A. Application of NE to a human cortical pyramidal cell in
uitro greatly reduces spike frequency adaptation and results in an enhanced discharge. This effect is associated with a block of IAHP
(see Fig. 1). B. Application of NE to a thalamic neuron during the periodic injection of depolarizing current pulses (top trace). NE
application results in a slow depolarization due to a reduction in membrane potassium conductance. The slow depolarization shifts
the neuron from the burst firing mode (pre; expanded for detail) to the single spike mode (post). The cell in (B) is a relay cell from
the parataenial thalamic nucleus. Similar results were obtained in LGNd relay neurons. C. NE causes the same response in
thalamic reticular (nRt) cells. The ionic actions of NE on cortical and thalamic interneurons are not known. (From McCormick,
1989.)
298
and prolonged excitation or increase in neuronal
excitability (Rogawski and Aghajanian, 1980;
Kayama et al., 1982). This response appears to be
mediated though a 1-adrenoceptors and can be
activated by electrical stimulation of the LC
(Rogawski and Aghajanian, 1980; Kayama et al.,
1982). Stimulation of the LC in the cat also
results in prolonged excitation of LGNd relay
cells (Nakai and Takaori, 1974), although sorne
authors report that iontophoretic application of
NE to these neurons results in weak inhibition
(Phillis et al., 1967). The reasons for these species
differences are not known. The lack of significant
species differences in cat and rodent LGNd in
vitro (McCormick and Prince, 1988), indicates
that the observed differences in vivo may result
from differences in methodology.
Application of NE to thalamocortical relay
neurons in vitro results in two main effects, de-
pending upon the pharmacological subtype of
receptor stimulated. Activation of a 1-adrenocep-
tors results in a marked slow depolarization re-
sulting from the reduction of a resting "leak"
potassium current which we have termed IKL
(Fig. 2B). This slow depolarization can be 10-20
mV in amplitude and up to 2 min in duration,
even after a single pulse application of NE (Fig.
2B). The widespread presence of a¡-adrenocep-
tors in the thalamus (Janes et al., 1985) parallels
the presence of this slow depolarizing response
throughout the thalamus including the lateral and
medial geniculate nuclei, the nucleus reticularis,
the anteroventral nucleus, and the parataenial
nucleus (McCormick and Prince, 1988). The slow
depolarizing response to NE appears to be medi-
ated by a G-protein, since the intracellular injec-
tion of a non-hydrolyzable GTP analogue, GTP-
y-S, results in responses which do not return to
baseline, (e.g., they do not recover once acti-
vated). However, this slow depolarizing response
is not blocked by pertussis toxin, indicating that
this G-protein is not pertussis toxin sensitive and
therefore not G¡ or G 0 (McCormick, unpublished
observations). (The effectiveness of pertussis toxin
treatment was confirmed in these cells by the
B
A mm1111111mm111111111111mmmmmmm11111111111nmmm11muu11111111 ~11111~111111mlllll~llllllmlllll~llllllmlllll~llllll~lllll~llllll~llllll~lllll~llllll~lllll~llllll11111111
11illll
•
NE 40 s
5HT •
e D
-100 -100
V (mlll V (mVl
Control
Control
-0.5
' '
'SHT
-NE
-1.5 -1.5
Fig. 3. Responses of thalamic neurons to NE and 5-HT after
pharmacological block of a 1 and a 2 adrenoceptors. A. Appli-
cation of NE to a dorsal lateral geniculate neuron during the
injection of hyperpolarizing constan! current pulses (top trace)
results in a small depolarizing and a large increase in appar-
ent input conductance (bottom trace). Upward going lines
represen! rebound Ca++ spikes (indicated by asterisk). B.
Application of 5-HT to a medial geniculate neuron has a
similar effect. C,D. The I-V relationships obtained in voltage
clamp before and after application of NE and 5-HT show a
progressive increase in inward curren! at membrane poten-
tials negative to approximately -60 mV. (From Pape and
McCormick, 1989.)
finding that it had blocked responses to the
GABA 8 agonist baclofen.) The second messen-
ger system (if any) through which NE results in a
reduction in 1KL is not known, although it does
not appear to involve cAMP (see below). Interest-
ingly, we have found that stimulation of mus-
carinic or histaminergic H 1 receptors on thalamo-
cortical neurons can also result in reduction of
IKL (McCormick and Prince, 1987; McCormick
and Feeser, unpublished results). Thus, as in cor-
tical pyramidal cells, there appears to be a re-
markable convergence of transmitter action in
thalamic neurons.
Activation of ~-adrenoceptors on thalamocor-
tical relay cells results in a novel and interesting
response: the membrane potential appears to
change only slightly while the responsiveness of
the cell to a hyperpolarizing current pulse is
markedly reduced (Fig. 3A). Examination of this
effect in voltage clamp revealed that stimulation
 299

of ¡3-adrenoceptors results in an enhancement of active at resting membrane potential results in an

inward rectification at membrane potentials neg-
ative to approximately - 60 m V (Fig. 3C). Fur-
ther examination of this ¡3-adrenoceptor effect
revealed that it was mediated by an enhancement
of the hyperpolarization-activated cation current
Ih (Fig. 4). Hyperpolarization of thalamic relay
neurons (and practically all principal neurons in
the CNS and PNS) results in the activation of a
current, 1h, which is carried by both Na+ and K +
ions (Pape and McCormick, 1989). The activation
of this current depolarizes the membrane poten-
tial back towards the reversa! potential of 1h
( - 43 mV). Subsequently, the activation of this
current results in a depolarizing "sag" of hyper-
polarizing responses, a feature which has previ-
ously been referred to as "anomalous rectifica-
tion." The ¡3-adrenergic enhancement of Ih, sub-
sequently, partially offsets the ability of the neu-
ron to hyperpolarize in response to other inputs.
Activation of ¡3-adrenergic receptors on thala-
mocortical relay neurons results in a shift of the
activation curve for Ih such that at any given
voltage, a larger percentage of Ih is active (Fig.
4). The resulting increase in the amount of Ih
overall increase in the "leak" conductance of the
membrane, thereby resulting in a decrease in the
response of the cell to hyperpolarizing current
pulses (Fig. 3A). In contrast, the response of the
neuron to depolarizing current pulses appears to
be largely unaltered, or in sorne cases, even
slightly potentiated (unpublished observations).
Interestingly, we have also found that stimulation
of serotonergic receptors of an, as yet, unknown
subtype can also result in an enhancement of Ih
(Fig. 38, D), as can activation of H 2 histaminer-
gic receptors (McCormick and Feeser, unpub-
lished observations). These results indicate that
Ih is under the control of at least three different
neurotransmitter systems in thalamocortical relay
neurons.
Enhancement of 1h by NE, 5-HT and HA may
occur through the activation of adenylyl cyclase
since this response is mimicked by applicatbn of
the membrane permeable cAMP analogue 8-
bromo-cAMP, by activation of adenylyl cyclase
directly with applications of forskolin (application
of the inactive forskolin analogue 1,9-dideoxy-for-
skolin is without effect), or by inhibition of phos-

B -53 mV

~
1~

-1
'~
'~
1 \nA)
-2

-3
O~ Control
._..NE
4'lw-
~:: t.

.
_J 70 mV
1.5 nA

1s

Fig. 4. NE enhances a curren! activated by hyperpolarization. A Graph of the instantaneous (circles) and steady-state (triangles)
currents in response to a hyperpolarizing voltage step before (open symbols) and after (filled symbols) application of NE. Original
traces are shown in B. Application of NE results in a marked enhancement of the inward curren! activated by hyperpolarization
with only a small increase in instantaneous conductance. (From Pape and McCormick, 1989.)
300
phodiesterase activity with IBMX (Pape and Mc-
Cormick, 1989). The possibility that these recep-
tors may couple to adenylyl cyclase through Gs
remains to be tested.
These results suggest that the sensitivity of 1h
to the voltage across the membrane is constantly
under the control of the intracellular concentra-
tion of cAMP, which itself is under the control of
stimulatory, and presumably inhibitory, G-pro-
teins which are coupled to neurotransmitter re-
ceptors. Exactly how increases in intracellular
concentrations of cAMP Iead to an increase in
the voltage sensitivity of Ih is not known. How-
ever, one can easily imagine a process by which
cAMP activates a protein kinase which phospho-
rylates sorne critica! portian of Ih channels, re-
sulting in a shift in the electrical dipole of the
voltage-sensing portian of the channel, and there-
fore an increase in sensitivity to the charge across
the membrane. This ongoing equilibrium between
phosphorylation and de-phosphorylation (con-
trolled by the state of stimulation of ¡3-adrenergic
and other receptors and intracellular biochemical
processes) would then result in the constant ad-
justment of the amplitude of lh.
Functional consequences of noradrenergic
actions in the thalamus
Thalamic neurons display two very distinct states
of action potential generation both in vivo and in
vitro. During periods of slow-wave sleep and EEG
synchronization, thalamocortical relay neurons
display high-frequency (200-500 Hz) burst dis-
charges, while during periods of waking and at-
tentiveness, thalamic relay neurons display activ-
ity characterized by the occurrence of single spikes
(see Fig. 5) (McCarley et al., 1983; Steriade and
Deschenes, 1984; Steriade and Llinás, 1988).
Burst firing in thalamic neurons is due to the
presence of a large, low-threshold Ca++ current
(Jahnsen and Llinás, 1984a,b; Coulter et al., 1989;
Hernandez-Cruz and Pape, 1989). The voltage-
dependent properties of this current are such
that when the membrane potential is negative to
A
B
S sleep •
2JDJJl~li
P sleep 100 msec
Fig. 5. Firing properties of thalamic neurons and their alter-
ation with shifts in sleep-wake cycle. A. At - 75 mV, thalamic
cells respond to a depolarizing curren! pulse with a slow
Ca++ spike (arrow) that triggers a burst of three Na+-depen-
dent action potentials. This type of cellular activity is known
as burst firing. Depolarizing the cell to - 63 mV inhibits burst
firing by inactivating the low threshold Ca++ curren!. The
response of the cell is now entirely passive,. Upan depolariza-
tion to -53 mV, the same amplitude curren! pulse generated
a train of four action potentials. This latter pattern of spike
activity is known as the single spike or transfer mode of action
potential generation. Decreasing resting membrane potassium
conductance (gK), as with NE stimulation of a 1 adrenocep-
tors, is very effective in shifting the neuron from the burst to
single spike firing mode. B. Intracellular recording from an
LGNd neuron during transition from slow-wave sleep (S-sleep)
to paradoxical sleep (P-sleep) and vice versa. SPOL (sommeil
phasique a andes lentes) is an intermediary stage between
S-sleep and P-sleep and is characterized by ponto-geniculate-
occipital (PGO) waves (Hirsch et al., 1983). Slow-wave sleep is
characterized by the presence of rhythmic burst discharges
(expanded in Cl) and a relatively hyperpolarized membrane
potential. Paradoxical sleep is characterized by single spike
activity (C2) and a relatively depolarized membrane potential.
Similar shifts in membrane potential are found in the transi-
tion from slow-wave sleep to waking. Depolarization of the
membrane potential in paradoxical sleep may represen! the
influence of increased activity of brainstem cholinergic neu-
rons while the depolarizing influence upan waking may be
due to a mixture of cholinergic, noradrenergic, serotonergic
and histaminergic influences. (B and C from Hirsch et al.,
1983, with permission.)

- 65 mV, thalamic neurons can exhibit a low-
threshold Ca++ spike that generates a high-
frequency burst of fast Na+ /K+-mediated action
potentials (Fig. 5A, - 75 mV). If the neuron is
tonically depolarized positive to - 65 mV, then
the more traditional single spike, or transfer,
mode of neuronal activity is generated (Fig. 5A,
- 53 mV). These two firing modes have very
different functional consequences for the transfer
of synaptic inputs to the cerebral cortex. The
burst firing mode appears to be ideally suited for
the generation of intrathalamic and thalamocorti-
cal rhythms, while the single spike firing mode is
ideally suited for the faithful transmittal of fast
synaptic inputs arriving as a consequence of the
activation of peripheral receptive fields. For ex-
ample, in the burst firing mode, the output of the
relay neuron is highly non-linear in relation to
the input that triggers it, while in the single spike
firing mode, input and output are much more
linearly related (McCormick and Feeser, 1990).
The transfer of information through the thalamus
to the cerebral cortex is accurate only when the
thalamic neuron is in the transfer mode and not
in the burst firing mode (Livingstone and Hube!,
1981; Steriade and Llinás, 1988). The high corre-
lation between the mode of action potential gen-
eration in single thalamic neurons and the state
of the EEG in the animal gives rise to the excit-
ing possibility that observations on thalamic neu-
ronal membrane properties in vitro can be di-
rectly related to behavioral observations. The
ability of neurotransmitters to change the firing
mode of thalamic neurons from one state to the
other is of particular interest because it may
underlie, in part, the animal's shift from a state of
EEG synchronization (e.g., drowsiness, inatten-
tiveness or slow-wave sleep) to one of EEG-de-
synchronization (e.g., arousal, alertness, and
paradoxical sleep).
Indeed, application of NE to thalamocortical
relay neurons results in a potent and prolonged
shift of the firing mode of these cells from burst
firing to the generation of tonic activity (Fig. 2B).
Intracellular recordings indicate that this shift in
301
firing mode is generated in large part by a large
depolarization of the membrane potential result-
ing from reduction of I KL (McCormick, unpub-
lished observations). In addition, we have also
found that enhancement of I h alone, either
through the activation of ,8-adrenoceptors or
serotonergic receptors, also results in a decrease
in the ability of the cell to oscillate. However,
although this ,8-receptor-mediated effect may
suppress ongoing rhythmic activity, it only mildly
promotes the generation of single-spike activity
(Pape and McCormick, 1989; unpublished obser-
vations).
Functional implications of noradrenergic
responses
Based upon this and other information we would
like to propose the following scenario for the
contribution of the ascending noradrenergic sys-
tem in activation of the thalamus and cortex. The
transition from synchronized, rhythmic thalamo-
cortical activity during slow-wave sleep to desyn-
chronized, high-frequency activity during arousal
and attentiveness is associated with an average
increase in firing rate of noradrenergic, as well as
cholinergic, serotonergic, and histaminergic, neu-
rons (Trulson and Jacobs, 1979; Aston-Jones and
Bloom, 1981; Vanni-Mercier et al., 1984; Lamour
et al., 1986). The increased release of NE (as well
as by ACh, 5-HT, and HA) will have numerous
and complex actions on forebrain neurons (e.g.,
see McCormick, 1989; Nicoll et al., 1990).
In the thalamus, the increased release of NE
will cause a slow depolarization of thalamocorti-
cal relay cells as well as neurons in the nucleus
reticularis (Fig. 2). In addition, increases in the
release of ACh and HA onto thalamocortical
relay neurons will also add to this slow depolariz-
ing influence (McCormick and Prince, 1987; Mc-
Cormick and Feeser, unpublished observations).
The resulting slow depolarization will inactivate
the low-threshold Ca++ spike and move the
membrane potential out of the voltage range in
which Ih is active. Consequently, the depolariza-
302
tion towards single spike firing threshold, the
increase in specific membrane resistance, and the
reduced responsiveness to hyperpolarizations
(through enhancement of Ih), will all increase the
likelihood that phasic EPSPs will trigger action
potentials in a one-to-one manner (McCormick
and Feeser, 1990) and thus result in an increase
in the faithful transfer of incoming spike trains to
the cerebral cortex.
The actions of NE, and other modulatory neu-·
rotransmitters, in the cerebral cortex will con-
tribute to the determination of the fate of these
synaptic potentials arriving from the thalamus. In
cortical pyramidal cells, the reduction of the
ca++_activated K+ current, IAHP' by NE (as well
as by ACh, 5-HT, and HA) and the voltage-
activated potassium current I M by ACh and 5-HT
(McCormick and Williamson, 1989) will enable
these cells to respond faithfully to the incoming
trains of EPSPs. Selective activation of individual
NE fibers may allow for activation of localized
regions of the cerebral cortex, or functionally
related groups of cells, which may correspond to
those which are activated in the thalamus. To-
gether, these modulatory actions in both thalamic
and cortical neurons may facilitate the pattern of
neuronal processing which is associated with cog-
nition.
Evidence for and against a role of the central
noradrenergic system in arousal
Anatomical, electrophysiological, and pharmaco-
logical data indicate that the central noradrener-
gic system arising from the LC operates by modu-
Iating the excitability and "state" of neurons in
divergent regions of the CNS, probably in a coor-
dinated and unified fashion, in arder to achieve
sorne goal. The question then becomes, what
goal? The most accurate answer to this question
would entail a complete detailing of all features
of this neurotransmitter system including the pre-
cise anatomical, pharmacological and physiologi-
cal properties of every synapse which it makes
and receives, as well as the interactions of these
synapses with the physiological properties of each
of the pre- and post-synaptic elements involved.
Barring such a comprehensive knowledge of this
system, we are forced to resort to forming gener-
alizations, sometimes using vague and potentially
inaccurate terms. One such term is "arousal."
The normal nervous system appears to exist within
a continuum of three broad states: aroused, syn-
chronized sleep, and desynchronized (also known
as REM or paradoxical) sleep. Arousal and rapid
eye movement (REM) sleep are associated with
an EEG which exhibits a preponderance of higher
frequencies, while synchronized sleep is charac-
terized by the preponderance of slower (1-12 Hz)
frequencies in the EEG. These two states of the
EEG, in turn, correspond to a preponderance of
neuronal activity associated with the ongoing in-
teractions of large number of synapses, neurons,
and neuronal circuits during arousal and REM
sleep, or to the relatively slow, synchronous firing
of groups of neurons in thalamocortical circuits
during slow-wave sleep. Here we use the term
arousal to indicate a state in which the nervous
system is activated and the animal is awake and is
either directly interacting with the world around
it, or has the potential to quickly do so in re-
sponse to sorne stimulus. Thus, we do not refer to
the desynchronization of the EEG which occurs
during REM sleep as arousal, per se, but rather
as EEG activation. Although specific exceptions
to this generalization can be raised, these terms
are useful linguistic tools for discussion.
A role of the central noradrenergic system in
"arousal" is suggested largely upan the findings
of physiological and pharmacological studies. The
activity of central noradrenergic neurons are
known to increase in anticipation of increases in
"arousal" (Aston-Jones, 1985; Jacobs, 1986). In
addition, presentation of a novel stimulus which
attracts the animal's attention is associated with a
strong burst of action potentials in LC neurons
(Aston-Jones, 1985). Intraventricular injections of
NE have a potent "activating" influence upan the
EEG and "arousing" influence upon the animal's
behavior (Matsuda, 1968, 1969; Cordeau et al.,

1971), while central administration of antagonists
facilitate the appearance of EEG-synchronization
and behavioral sleep (Matsuda, 1968, 1969). The
specific ionic actions of NE on thalamic and
cortical neurons also suggest a role in "arousal"
since these actions result in a shift in the respon-
siveness and firing properties of these neurons
similar to those which occur during the shift from
synchronized s!eep to waking (see above).
The arguments against a role for the central
NE pathways in arousal typically center around
two findings: (1) noradrenergic neurons in the LC
are specifically inactive during REM sleep even
though the EEG is desynchronized (Aston-Jones,
1985) and (2) extensive lesions of the LC do not
impair the animal's ability to exhibit relatively
normal sleep-wake cycles (Iones et al., 1977).
Although a lack of a role for the central NE-sys-
tem in "arousal" is one possible interpretation of
these results, a more parsimonious explanation is
suggested by the finding that there are at least
five other systems which also contribute to activa-
tion of the nervous system: (1) brainstem cholin-
ergic projections to thalamus; (2) basal forebrain
cholinergic projections to cortex and thalamus;
(3) brainstem 5-HT system; (4) hypothalamic his-
taminergic projections to thalamus and cortex; (5)
hypothalamic projections to cortex which contain
an a-MSH-like peptide.
During REM sleep, extracellular recordings
indicate that brainstem cholinergic neurons be-
come markedly active, while NE, 5-HT and per-
haps HA neurons fall silent (Trulson and Jacobs,
1979; Vanni-Mercier et al., 1984; Aston-Jones,
1985; Jacobs, 1986; Lamour et al., 1986). Thus,
the activation of the EEG in this state may result
largely from the central actions of ACh, although
it is unlikely that this transmitter is solely respon-
sible for this state. Similarly, the lack of pro-
nounced alterations in the sleep-wake cycle after
large lesions of the LC is probably due to the
presence of the five other systems which are
capable of generating activation of the nervous
system and behavioral arousal in the absence of
the noradrenergic system. In this general sense,
303
the lesion results do not revea! any evidence as to
whether or not the LC is involved in inducing the
cellular phenomena which underlie arousal, but
rather merely state that it is probably not essen-
tial for it to occur when ali of the other systems
are left intact.
Conclusions
The anatomical and physiological features of the
central noradrenergic system suggest that it con-
tributes to the control of the "processing state"
of the central nervous system. The postsynaptic
actions of NE in the thalamus and cerebral cortex
are consistent with a role in the control of neu-
ronal excitability and responsiveness to other,
more phasic, postsynaptic potentials. These nor-
adrenergic actions suggest that activation of the
LC will lead to an abolition of slow rhythmic
oscillations in thalamocortical systems and an in-
crease in responsiveness of these neurons to in-
puts from peripheral sensory receptors. In this
manner, the central noradrenergic system, with
the other modulatory transmitter systems, may
control the leve! of "arousal" and readiness of
the CNS.
Acknowledgements
Supported by NIH, the Klingenstein Fund, Patti-
son Fund, the Sloan Foundation, and a fellowship
from the Deutsche Forschungemeinschaft.
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