Upload
truongdang
View
242
Download
4
Embed Size (px)
Citation preview
ME.6200
Cholinergic Neuromodulation II
Prof. Gregor Rainer
LC; locus ceruleus (NE)
ldt, laterodorsal tegmental nucleus
LH, lateral hypothalamus
ms, medial septal nucleus
ppt, pedunculopontine nucleus
si, substantia innominata
SN, substantia nigra
vdb, vertical diagonal band nucleus
bas, nucleus basalis
BLA, basolateral amygdala
DR, dorsal raphe (5-HT)
EC, entorhinal cortex
hdb, horizontal diagonal band nucleus
Icj, islands of Cajella
IPN, interpeduncular nucleus
Cholinergic CNS projections
Cholinergic CNS effects: Septo-Hippocampal pathway
bas, nucleus basalis
BLA, basolateral amygdala
DR, dorsal raphe
EC, entorhinal cortex
hdb, horizontal diagonal band nucleus
Icj, islands of Cajella
IPN, interpeduncular nucleus
LC; locus ceruleus
ldt, laterodorsal tegmental nucleus
LH, lateral hypothalamus
ms, medial septal nucleus
ppt, pedunculopontine nucleus
si, substantia innominata
SN, substantia nigra
vdb, vertical diagonal band nucleus
The hippocampal theta (4-8Hz) rhythm
LIA
LIA: Large irregular activity
The hippocampal theta (4-8Hz) rhythm
The hippocampal theta rhythm in rat is probably the most well-studied biological rhythms. We
distinguish type I (non-cholinergic, movement-related) and type II (cholinergic, not movement-
related) theta. Type I theta has higher peak frequency and greater amplitude than type II theta.
Type I theta is observed during exploratory behavior associated with voluntary movements such as
walking, hopping, head movements and manipulatory paw movements.
Type II theta is observed during periods of alert immobility, during the delivery of sensory stimuli in
the auditory, visual and somatosensory modality.
Outside of theta, the hippocampus shows LIA (large irregular activity) that does not have a clear
theta peak, and is associated with automated behaviors such as grooming. LIA often includes
«sharp waves», large amplitude broad band frequency events.
Infusion of Carbachol into the medial
septum (MS) region produces robust
theta activity, during behavioral
states not or weakly associated with
theta oscillatory activity.
Behaviorally, Carbachol application
in the MS elicits exploratory behavior
including walking, sniffing, rearing
followed later by an extended period
of alert immobility.
Infusion Atropine reduces type II
theta rhythm and associated
behaviors, while not affecting type I
theta.
Exploratory behavior
Automated motor behavior
Alert immobility
In vivo behavioral pharmacology of the theta rhythm
Type I theta is not cholinergically controlled
• The two types of Hippocampal theta rhythm are associated with
exploratory behavior and alert immobility respectively. Type II theta
has a lower peak frequency and is controlled by the Cholinergic
system.
• Delivering Carbachol to the medial septum induces theta in the
hippocampus and elicits theta-associated behaviors.
Take Home Message
Two components of Acetylcholine response to exploration of novel environment
Neuroscience. 2001;106(1):43-53. http://dx.doi.org/10.1016/S0306-4522(01)00266-4
o Control animals (kept in home cage, no exploration)
I Expl
II Expl
Exploration of novel environment: strong enhancement in Ach, not
correlated with motor exploration. >> Other mechansims (type I theta)
control behavior here.
Exploration of familiar environment:weaker enhancement in Ach,
correlated with motor exploration. >> type II theta regime.
The Journal of Physiology, 562, 81-88. January 1, 2005
In vitro activation of CA3 pyramidal cell by medial septum stimulation
Electrical microstimulation in the presence of AMPA/kainate,
NMDA, GABAA and GABAB receptor antagonists in the slice
medium.
50 ms
100 μ
V
Induction of fast oscillations in field CA3 of hippocampal slices by Carbachol (CCh)
PNAS March 4, 2003 vol. 100 no. 5 2872-2877
Note: CCh is a mAChR agonist that does not cross the
BBB. It activates both nAChR and mAChRs.
Nature Neuroscience 4, 1259 - 1264 (2001)
Human hippocampal-rhinal cortex gamma range (32−48 Hz) oscillatory synchronization
predicts subsequent memory
doi:10.1038/nn759
PNAS February 8, 2005 vol. 102 no. 6 2158-2161
ACh lesion Control
delay lengths [s] list lengths [N. items]
Rhinal cortex cholinergic deafferentation produces severe memory impairment
AChE staining
http://dx.doi.org/10.1073/pnas.0409708102
Local infusion of cholinergic immunotoxin
severly disrupts memory in a delayed-non-
matching-to-sample task. Effects are
similar in magnitude to complete ablation of
this cortex.
Rhinal cortex is essential for storing the
representations of new visual stimuli,
thereby enabling their later recognition.
ACh
Current theory of rhinal cortex
function as „gatekeeper for
declarative memory“
The more familiar an item is, the
less rhinal processing it requires
and the less vigorously it is
encoded into memory.
Rhinal cortex cholinergic deafferentation produces severe memory impairment
http://dx.doi.org/10.1016/j.tics.2006.06.003 Trends in Cognitive Sciences Volume 10, Issue 8, August 2006, Pages 358-362
Muscarinic prefrontal or temporal cortex blockade impairs object/place task performance
Learn. Mem. 2009. 16: 8-11 http://dx.doi.org/10.1101/lm.1121309
Bilateral Muscarinic blockade
(scopolamine) in rhinal or the
prefrontal cortex impairs object/place
test performance.
This test does not involve any specific
training, but relies on the innate
tendency of animals to explore novel
objects or places more than familiar
ones.
Unilateral Scopalamine infusion in
rhinal cortex together with prefrontal
cortex of the opposite hemisphere has
the same effecs as bilateral infusions
in each structure.
Object-in-place associative memory
depends upon cholinergic modulation
of neurones within the PRH-PFC
circuit
• The two types of Hippocampal theta rhythm are associated with
exploratory behavior and alert immobility respectively. Type II theta
has a lower peak frequency and is controlled by the Cholinergic
system.
• Delivering Carbachol to the medial septum induces theta in the
hippocampus and elicits theta-associated behaviors.
• In vitro work has shown that cholinergic agonists can also induce
higher frequency oscillations (including gamma oscillations).
• Synchronization of oscillations between hippocampus and rhinal
cortex predicts memory encoding.
• Impaired oscillatory interaction between hippocampus and
adjacent cortex may underlie amnesia and learning impairments.
Take Home Message
bas, nucleus basalis
BLA, basolateral amygdala
DR, dorsal raphe
EC, entorhinal cortex
hdb, horizontal diagonal band nucleus
Icj, islands of Cajella
IPN, interpeduncular nucleus
LC; locus ceruleus
ldt, laterodorsal tegmental nucleus
LH, lateral hypothalamus
ms, medial septal nucleus
ppt, pedunculopontine nucleus
si, substantia innominata
SN, substantia nigra
vdb, vertical diagonal band nucleus
Cholinergic CNS effects: Visual System
Neuroscience 132 (2005) 501–510
Acetylcholine is increased in visual cortex during visual stimulation
hdb, horizontal diagonal band nucleus
Prefrontal Visual
Visual Visual
Blue: Visual projection
Yellow: Prefrontal projection
Red: ChAT
• Acetylcholine release in the cortex is regionally specific. Increases are
observed in the visual cortex, but not in the prefrontal cortex, during visual
stimulation. Basal forebrain cholinergic projections to the visual system
originate mainly in the NBM/HDB region.
Take Home Message
Orientation selectivity in primary visual cortex (V1)
Neuron Volume 56, Issue 4, 21 November 2007, Pages 701-713
NIC: nicotine
MEC: mecamylamine (an nAChR antagonist)
Nicotine enhances visual response gain of layer 4 visual cortex neurons
nAChRs are expressed presynaptically at thalamic
synapses onto excitatory, but not inhibitory, neurons
in the primary thalamorecipient layer 4c.
Psychophysical effect of Nicotine on grating detection in humans
with Nicotine
Response threshold
Nicotine boosts neural signals at low contrast
0 .1 .5 1 0
20
40
60
Contrast Level
Sp
ike R
ate
[H
z]
V1 Neuron contrast response function
nAChR Agonist
Recovery
Control
Rmaxcontrol
RmaxnAChR
C50control
C50nAChR
C50…. Semi-saturation contrast
Rmax…. Responsivity
Naka-Rushton function
Drifting sinusoidal gratings were presented at 3 different contrast levels (0.1, 0.5, 1) and at 8 different directions with and without iontophoretic cholinergic drug application.
Nicotine enhances contrast response in tree shrew V1
Bhattacharyya et al Eur J Neurosci 35(8): 1270-1280 (2012)
Rmax but not C50 affected by cholinergic agonists
0 20 40 60 80 100 0
20
40
60
80
100
Control R max
[Hz]
Dru
g R
max [H
z]
0 0.2 0.4 0.6 0.8 1 0
0.2
0.4
0.6
0.8
1
Control C 50
Dru
g C
50
nAChR
mAChR nAChR
mAChR
200 400 600 800 1000 1200 1400
-100
0
100
200
300
nAChR Agonist
D C
RF
A [H
z]
Depth [ m m]
200 400 600 800 1000 1200 1400
-100
0
100
200
300
mAChR Agonist D
CR
FA
[H
z]
Depth [ m m]
Supragranular Granular Infragranular 0
20
40
60
D C
RF
A [H
z]
mAChR Agonist
nAChR Agonist
Laminar differences in nicotinic and muscarinic modulation
P<0.05
Nicotine enhances thalamocortical activation
cortex
LGN
thalamus
fro
m r
etin
a
nAChR
mAChR
Glutamatergic
GABAergic
Cholinergic
Muscarinic stimulation mostly affects non-granular layers
Diffusion Tensor Imaging of
the BF to V1 projection
Courtesy Dr. David Leopold, NIH, Bethesda (USA)
Basal forebrain (BF) projections to primary visual cortex (V1)
Experimental Setup
BF stimulation elicits -band oscillations and reduces D-band activity
Peaked and broad -band spectral changes following BF stimulation
DOI: 10.1111/j.1460-9568.2010.07171.x
in vitro rat visual cortex
kainate / carbachol application
BF DBS increases responsivity and contrast sensitivity in V1: example
MUA site
BF DDBS
BF DBS
CONTROL
C50control
C50bf dbs
Rmaxcontrol
Rmaxbf dbs
C50…. Semi-saturation contrast
Rmax…. Responsivity
Naka-Rushton function
Drifting sinusoidal gratings were presented at 3 different contrast levels (0.1, 0.5, 1) and at 8 different directions with and without BF stimulation.
BF DBS increases responsivity and contrast sensitivity in V1:
population
Rmax and C50 changes in previous Literature
Study Manipulation Area Rmax C50
Bhattacharyya et al 2012 nAChR, mAChR activation V1 =
Soma et al 2011 mAChR activation V1 =
Disney et al 2012 ACh application V1 =
Atallah 2012 GABA interneuron activation V1 =
Katzner et al 2011 GABA-A blockade V1 =
Alitto et al 2010 Anaesthesia LGN =
Wilson et al 2012 SOM interneuron activation V1
DOI
10.1111/j.1460-9568.2012.08052.x
10.1152/jn.00188.2012
10.1152/jn.00330.2011
10.1016/j.neuron.2011.12.013
10.1523/jneurosci.5753-10.2011
10.1113/jphysiol.2010.190538
10.1038/nature11347
Multiple pathways of BF influence on cortical activity
RN
basal forebrain
cortex
LGN
thalamus
fro
m r
etin
a
NBM
from
laye
r VI
nAChR
mAChR
Glutamatergic
GABAergic
Cholinergic
SOMATOSTATIN
PARVALBUMIN
V1 Interneuron stimulation
Wilson et al 2012
• Nicotinic AChR agonist application has largest effects on the contrast
response in the granular layer, targeting presynaptic nAChR on the
thalamocortical projections and up-regulating Glutamate release.
• Muscarnic AChR agonist application has largest effects on contrast responses
outside the granular cortical input layer.
• Both nAChR and mAChR agonists enhance contrast responsivity (Rmax) while
not afffecting contrast sensitivity (C50).
• The signature of basal forebrain activitation in cortex is enhanced gamma
range oscillations, which can take a broad band or peaked form. The peaked
form is likely cholinergic in origin.
• Basal forebrain deep brain stimulation results in enhanced contrast
responsivity, as well as greater sensitivity to contrast corresponding to reduced
C50 values. GABAergic projections from the basal forebrain to cortex that
target somatostatin-positive interneurons are likely to be the pathway
mediating these changes.
Take Home Message
Single object Object pairs
Basal forebrain neural ensembles exhibit -Frequency oscillations
during visual-reward learning
• Rats were trained with 3 LEGO objects, each of which was associated with a
specific reward value (high positive, low positive, mild aversive).
• They were then exposed to pairs of objects, and had to choose one of them to
receive the associated reward (decision task). Animals needed 2-3 days to
learn this decision task.
• Frequency oscillation bursts tended to occur around the time of the
decision, prior to object encounter, in the basal forebrain local field potential
(LFP). These bursts showed a tendency to be larger during the first day of the
visual-reward learning, linking basal forebrain activation to visual learning
processes.
Take Home Message
Nature 454, 1110-1114 (28 August 2008)
release bar reward
Acetylcholine contributes to attention in primary visual cortex through mAChR
Drug: Ach applied locally by Iontophoresis,
ACh application enhances neural tuning for bar length in V1, and
upregulates attentional modulation.
Ach Attentional Effects are reduced by mAChR blocker Scopolamine,
Acetylcholine biases processing in favour of sensory (subcortical) over lateral
(intracortical) inputs
Brain Research Volume 880, Issues 1-2, 13 October 2000, Pages 51-64
IC intracortical
SC subcortical
AC auditory cortex
Slice preparation
su
bco
rtic
al
intr
acort
ica
l
fast slow
fast slow
Layer 4 responses in
Auditory Cortex (AC)
CCh attenuates IC
fast potential more
than SC fast
potential
fast potential -> AMPA sensitive monosynaptic
slow potential -> polysynaptic
LOW CCh: strong reduction in slow potentials, fast potentials unaffected
• Acetylcholine contributes to attentional modulation in the primary visual
cortex through mAChR.
• Acetylcholine can bias cortical processing in favour of sub- or intracortical
inputs. High ACh is associated with domination of subcortical (thalamocortical)
inputs and perception of parts, whereas low ACh favors intracortical inputs and
holistic perception.
Take Home Message
bas, nucleus basalis
BLA, basolateral amygdala
DR, dorsal raphe
EC, entorhinal cortex
hdb, horizontal diagonal band nucleus
Icj, islands of Cajella
IPN, interpeduncular nucleus
LC; locus ceruleus
ldt, laterodorsal tegmental nucleus
LH, lateral hypothalamus
ms, medial septal nucleus
ppt, pedunculopontine nucleus
si, substantia innominata
SN, substantia nigra
vdb, vertical diagonal band nucleus
Cholinergic CNS effects: Cholinergic Striatum Interneurons
Nucleus Accumbens (NAcc)
NAcc connects Putamen and Nucleus Caudatus of the Striatum
MSN (Medium Spiny Neuron) are the main neuron type in the Striatum
NAcc is major target of ventral tegmental area (VTA), involved in
reward/motivation pathway
Cholinergic Interneurons only account for 1-2% of Neurons.
Cholinergic CNS effects: Striatum Interneurons
Nucleus Accumbens (NAcc)
MSN
Cholinergic Interneuron activation (mostly) inhibits MSN neurons
Cholinergic CNS effects: Striatum Interneurons
Nucleus Accumbens (NAcc)
Cocaine-induced Place preference is abolished by silencing Cholinergic NAcc interneurorns.
• Cholinergic interneurons in the Nucleus Accumbens play an important role in
the motivation / reward network
• Optogenetic activation of these neurons mostly reduces firing rates of
medium spiny neurons, that make up the majority of NAcc neurons.
Conversely, inhibition of cholinergic neurons increases MSN activity.
• Silencing NAcc Cholinergic interneurons abolishes conditioned place
preference induced by Cocaine administration.
Take Home Message
Cholinergic CNS effects: LDT/PPT Thalamic pathway
bas, nucleus basalis
BLA, basolateral amygdala
DR, dorsal raphe
EC, entorhinal cortex
hdb, horizontal diagonal band nucleus
Icj, islands of Cajella
IPN, interpeduncular nucleus
LC; locus ceruleus
ldt, laterodorsal tegmental nucleus
LH, lateral hypothalamus
ms, medial septal nucleus
ppt, pedunculopontine nucleus
si, substantia innominata
SN, substantia nigra
vdb, vertical diagonal band nucleus
Encephalitis Lethargica: Viral brain infection pandemic in early 1900s
In 1917, the Viennese Neurologist von Economo
observed large number of patients suffering from a
novel sleep disorder.
While they were able to stand, walk or communicate
normally, they would spontaneously fall asleep when
left alone. Many slept for 20hours per day. The
disease progresses quickly and could lead to death
within a period of a few weeks. Von Economo
observed, that a specific region in the brain stem
tended to show lesions in these patients.
Interestingly, he also described a small number of
patients suffering from insomnia. These patients
were found to have lesions confined to a small
region anterior to the other patients‘ lesion.
The disease turned out to be a viral pandemic,
which disappeared again as spontaneously as it had
appeared.
Based on these observations, von Economo
postulated the existence of a sleep center, which
inhibits neurons in a brain stem target region
responsible for arousal and wakefullness, thereby
inducing sleep.
VLPO, ventrolateral preoptic nucleus (lacks Ox receptors)
TMN, tubermomamillary nucleus
BF, basal forebrain
LC, locus coeruleus
LDT, laterodorsal tegmental nucleus
PPT, peduncopontine nucleus
PeF, perifornical area
Involvement of Cholinergic Centers in wake/sleep regulation
Nature 437, 1257-1263 (27 October 2005)
The Ascending Arousal System The VLPO Sleep Promotion System
The VLPO and the ascending arousal
systems form mutually inhibitory circuits that
prevent intermediate states between waking
and sleep.
Orexin acts to stabilize the system in the
awake or the sleep state, and prevents
intermediate states (Both humans and
animals spend only a small part of each day
(typically <1–2%) in transitional states)
A lack of orexins or their type 2 receptor can
cause symptoms of narcolepsy in
experimental animals, by destabilizing the
wake/sleep regulation mediated by Orexin.
(REM only) LDT / PPT
LDT / PPT
The flip/flop circuit of sleep regulation
Behavioural Brain Research Volume 115, Issue 2, November 2000, Pages 183-204
Adenosine promotes sleep by inhibiting Cholinergic activity
Caffeine, the most widely
used psychoactive drug is
an adenosine A1 and A2A
receptor antagonist
be
ha
vio
ral sta
te [%
]
Adenosine injection into
Cholinergic brainstem centers
cause sleep.
Adenosine builds up in parts of
the brain because the energy
supply (ATP) runs low. (ATP is
degraded to ADP, AMP and
eventually Adenosine)
NEJM Volume 348:2110-2124 May 22, 2003
The nicotinic ACh Receptor is a major target of general Anesthetics such as Isoflurane
• The wake/sleep cycle is governed by a brain stem circuit that
includes the VLPO (sleep center), which inhibits brain stem
centers controlling release of Acetylcholine and other
neuromodulators to the cortex.
• Caffeine is an Adenosine receptor antagonist. By blocking
Adenosine, Caffeine reduces Adenosine´s inhibitory influence
on Cholinergic neurons, leading to increased release of ACh and
arousal. Adenosine tends to build up during periods of
extended wakefullness, when ATP is running low. It returns to
normal levels after sleep.
• The nAChR is a major target of volatile anesthetics used
during general Anesthesia. It is an allosteric modulator of the
nAChR receptor, causing a strong reduction in excitatory
membrane currents mediated by nAChR. Other major targets are
the GABA-A and the glycine receptor.
Take Home Message