of AMPA Receptor Subtypes in Pavlovian Fear Conditioning
Pavlovian fear conditioning is one of the most powerful paradigms
to study associative learning. A proposed mechanism for the underlying
plasticity of fear conditioning is long-term potentiation (LTP) carried
out through glutamatergic neurotransmission. The present proposal
would investigate the nature of synaptic plasticity in glutamate receptor
targeted transgenic mice and assess their ability for fear learning.
The study would test the specific hypothesis that AMPA-dependent alterations
in synaptic strength are necessary for fear learning. The project
will also evaluate the function of dopaminergic modulation of plasticity
in the amygdala. We expect that the triangulation of genetics, electrophysiology
and behavioural research will serve to elucidate the function of AMPA-receptor
subtypes at specific synaptic connections in the amygdala during learning.
Fear and fear disorders, including depression, anxiety and chronic
stress, have a major impact on quality of life. Currently, depression
is ranked fourth among all diseases of the global burden of disease.
Depression is the leading cause of mental disability and the burden
of depressive illness is rising. The World Health Organisation (WHO,
2001) has estimated that by the year 2020, depression will be the
second most common cause of disability in the developed world and
the number one cause of disability in the developing world.
for a role for the amygdala in emotional learning has grown considerably
in the last decade. In particular, many studies have focused on the
contribution of the amygdala to fear learning. The amygdala-centric
fear conditioning system is arguably the best understood cognitive
learning system in the brain. The amygdala is anatomically situated
to integrate information from a variety of sensory domains and within
the amygdala, the lateral nucleus projects to the basolateral receive
convergent inputs from the cortex, thalamus and basal nuclei. To a
great extent, progress in the study of amygdala-based learning has
occurred because of three factors: (1) Advances in memory research;
(2) Psychologically well-defined model system; (3) Genetic manipulation
research spanning the last 30 years has advanced our understanding
of how the fear learning occurs. Using a highly successful model of
memory called long-term potentiation (LTP), glutamatergic neurons
have been shown to be sensitive to the history of previous neuronal
activity (Bliss and Lømo, 1973). In the first pioneering experiment,
Tim Bliss and Terje Lømo, working in Per Andersen’s laboratory
in Oslo, showed that brief high-frequency trains of stimuli (a tetanus)
increased the amplitude of the excitatory postsynaptic potential (EPSP)
in target neurons. Such an electrophysiological property had long
been sought as a potential neural substrate of memory formation. Subsequent
pharmacological manipulations indicated that treatments that prevent
the neuronal populations from showing LTP (Collingridge et al., 1983)
also prevent the normal formation of spatial memories (Morris et al,
1986). Successful LTP induction requires synaptic activation on a
sufficiently depolarised dendritic spine, leading to local calcium
influx that initiates LTP expression. However, the nature of the expression
mechanism of LTP is still largely unknown.
In the last decade, much research on the amygdala has focused on a
psychologically well-defined aspect of emotion, Pavlovian fear conditioning.
Fear conditioning is an experimental approach that simplifies the
problem of fear learning in such as way as to make it tractable. Crucially,
Pavlovian fear conditioning involves rapid, one-trial learning, which
makes the study of the exact point of acquisition more easily defined.
Pavlovian fear conditioning usually entails learning the associating
a conditional stimulus (CS) with an aversive unconditional stimulus
(US). In the most common form of fear conditioning the animal learns
to associate a tone-CS with an aversive US – usually a foot shock.
Subsequent presentation of the CS alone is sufficient to cause a species-typical
fear reaction. In rodents this can be measured as an increase in freezing
relative to a pre-conditioning baseline levels of activity.
introduction of genetic manipulation techniques to delete or modify
genes that code for particular proteins has brought a new level of
precision to bear on the problem of how memory is formed. By manipulating
the right targets, experimenters can analyse the neural substrates
of behaviour and cognition more exactly than ever before. The present
project will use genetic engineering techniques to evaluate the roles
of specific ionotropic glutamate receptor subtypes. At the majority
of cortical synapses the glutamate binds to two ionotropic receptors,
AMPA and NMDA. While AMPA receptors mediate the standard impulse traffic
between neurones, the NMDA receptors have special roles during development
and other situations, effected through their ability to let calcium
ions into specific postsynaptic sites. Both receptors are large, multi-component
protein molecules that can be assembled in various ways to give variants
with different properties. The AMPA receptor is a tetramer, a combination
of four monomer molecules. Four different monomer types or GluR1–4
subunits, each coded for by a separate gene, are available for the
assembly. Increased synaptic efficacy may be due to an enhanced current
through AMPA receptors. If we can manipulate the AMPA receptor at
the molecular level, we can interfere with the processes underlying
changes in synaptic efficacy. This will enable us to understand how
LTP is expressed, and to identify its functional significance.
behavioural and in vivo electrophysiological experiments suggest that
plastic changes in neuronal connections in the amygdala might underlie
Pavlovian fear conditioning (LeDoux, 2000; Maren, 2001). However,
molecular mechanisms modulating synaptic transmission in the amygdala
during conditioning are not understood. By using mouse mutants with
gene targeted deletions of AMPA-receptor subtypes – the principal
glutamate-gated ion channels for fast chemical synaptic transmission
in the brain – we revealed in preliminary studies that some receptor
subtypes are essential for activity induced, enhanced synaptic transmission
in lateral and/or basal nuclei of the amygdala. The deficits in associative
plasticity found in AMPA-receptor subtype deficient mice were sometimes,
but not in all cases, accompanied by impaired fear learning. This
indicates that some forms of amygdalar LTP are involved in Pavlovian
conditioning. At all inputs, both AMPA/kainate and NMDA-type receptors
are active and colocalise in the postsynaptic density (Mahanty and
Sah, 1999). The amygdala is a locus of sensory convergence and a site
for CS–US association. Intra-amygdaloid circuitry conveys the association
to the central nucleus, where projections to the hypothalamus and
brainstem mediate fear responses such as freezing (periaqueductal
gray), potentiated acoustic startle (nucleus reticularis pontis caudalis),
increased heart rate and blood pressure (lateral hypothalamus), increased
respiration (parabrachial nucleus) and glucocorticoid release (paraventricular
nucleus of the hypothalamus).
changes in anatomical structures, connectivity and wiring of functional
neuronal circuits in the CNS seem to be important for development
of the CNS. Intensive studies on the hippocampus, however, provide
evidence that long-term changes in synaptic connectivity are one of
the principle mechanisms necessary for memory formation. The ionotropic
glutamate receptor channels of the NMDA- and AMPA-receptor family
were found to be key players in induction and expression of long term
changes of synaptic transmission (Morris et al. 1986; Zamanillo et
al. 1999), and the picture arises that different ionotropic glutamate
receptor subtypes can produce different and, perhaps, specific forms
of plasticity (Köhr et al. 2003, Fleischmann et al. 2003, Jensen
et al. 2003), which are linked to its distinct behavioural readouts
(Reisel, et al, 2002; Schmitt et al, 2003). In the associative synaptic
plasticity of the amygdala there is also converging evidence that
during Pavlovian conditioning plasticity mechanisms are operative,
which are akin to NMDA-receptor dependent hippocampal LTP (LeDoux,
2000; Maren, 2001; Blair et al. 2001). LTP can be induced in the lateral
amygdala - the primary input nucleus of the amygdala - by tetanic
stimulation of excitatory afferents in vivo and in vitro (Huang &
Kandel 1998, Bauer et al. 2002) or by pairing afferent stimulation
with postsynaptic depolarisation in vitro (Huang & Kandel 1998,
Weisskopf et al. 1998, Tsvetkov et al. 2002, Bissière et al.
hippocampal LTP at Schaffer collateral-CA1 synapses compelling evidence
for the involvement of postsynaptic AMPAR modification and trafficking
has been provided by several studies (Song and Huganir, 2003). Virus
mediated gene transfer studies in hippocampal slice preparations suggested
that heterodimeric AMPA-receptors containing GluR1/2 subunits are
added to synapses upon induction of LTP whereas heterodimeric GluR2/3
AMPA-receptors are thought to replace existing synaptic receptors
during normal receptor turnover (Shi et al. 2001). A number of studies
have demonstrated that phosphorylation of GluR1 subunits can modulate
AMPA-receptor channel properties as well as their synaptic targeting.
Both mechanisms are thought to be crucial for long-term changes of
synaptic transmission (Barria et al. 1997, Benke et al. 1998, Derkach
et al. 1999, Lee et al. 2000).
In contrast to the hippocampus, in the amygdala the role of AMPA receptor
subtypes in synaptic transmission and plasticity has so far not been
addressed. Preliminary results obtained by the applicant show that
GluR3 deficient mice exhibit deficits in fear learning that were accompanied
by a selective lack of LTP in the lateral amygdala, but not in the
basal nucleus. This raises the possibility that different forms of
associative plasticity involving distinct AMPA-receptor subtypes might
coexist within the amygdaloid complex. Understanding the molecular
mechanisms underlying LTP in distinct amygdaloid nuclei will provide
means to assess the role of these nuclei in specific aspects of amygdala
dependent learning tasks.
The aim of this research proposal is to reveal the function of AMPA
receptor subtypes in amygdala-dependent synaptic transmission and
to link that to their role in fear learning.
Genetic mouse models. The project will test
mice with global GluR1 and GluR3 deletions. We will attempt to identify
the AMPA-receptor subtypes and nerve cell connections that modulate
synaptic transmission and participate in Pavlovian fear conditioning
in the mouse. The project will also have access to GFP-tagged GluR1
and GluR3 mice. In these strains, the global AMPA-receptor subunit
knockout will be rescued by expression of green fluorescent protein
(GFP)-tagged AMPA-receptor subunits using transgenic mouse lines.
In this transgenic system the expression of GFP-tagged subunits can
be controlled by doxycycline (dox) (Krestel et al. 2001; Mack et al.
2001). Hippocampus and amygdala mediated phenotypes of global AMPA-receptor
knockouts can be dissected through careful dox regulation. First,
GluR1 knockout mice with transgenic GFP-tagged AMPA-receptor subunits
are kept in the absence of dox. The GFP-tagged subunit is expressed
in the forebrain including hippocampus and amygdala and will rescue
the global GluR1 depletion in both regions (Mack et al. 2001). The
induced GFP-tagged subunit expression can be restricted to hippocampal
CA1 and dentate gyrus granular cells. The expression is negligible
in the amygdala and other areas of the forebrain. Comparing the learning
behaviour of dox-suppressed and unsuppressed mice will enable us to
identify the hippocampal-mediated contribution to the phenotypes.
GluR1-deficient mice show impaired spatial memory formation in the
T-maze (Reisel et al. 2002) and impairments in cued fear conditioning
(preliminary data, not shown). We expect that GluR1 deficient mice
with GFP-GluR1 expression will show a rescue of both behavioural phenotypes
whereas dox-suppressed mice should rescue at least the hippocampal-mediated
memory in the T-maze. Since mice with conditional expression of GFP-tagged
GluR1 and GluR3 are already generated and are partially analysed in
the laboratory of Rolf Sprengel, we can use this methodology for AMPA
receptor subtypes of principal neurons in the amygdala.
Fear Conditioning and Complimentary Behavioural Tests.
Fear conditioning is a behavioural paradigm that has been employed
as a model for emotional learning in animals. During fear conditioning,
a neutral conditioned stimulus (the CS; for example, a tone) is followed
by an unconditioned stimulus (the US; for example, a foot shock),
which routinely elicits a stereotypic response — the behavioural correlates
of fear. Examples of species-typical defensive responses that are
brought under the control of the CS include defensive behaviours (such
as freezing) and autonomic (e.g. heart rate, blood pressure) and endocrine
(hormone release) responses, as well as alterations in pain sensitivity
(analgesia) and reflex expression (fear-potentiated startle and eye
blink responses). The acquisition of conditioning fear behaviour in
rodents is usually evaluated by measuring 'freezing', a characteristic
defensive posture expressed in the presence of stimuli that predict
danger. The amount of time accounted for by freezing is measured during
the presentation of the CS as well as during the 20 seconds immediately
before CS onset (pre-CS period). The latter is a measure of the acquisition
of aversive conditioning to the experimental context in which the
US is delivered (such as the conditioning chamber); freezing to the
experimental context is independent of the presence or absence of
an explicit CS, and is typically seen with both paired and unpaired
important objective within the behavioural analyses will be to separate
the effects of memory formation mediated by the hippocampus, on the
one hand, and the amygdala, on the other. Methods to deal with the
potential confound of the hippocampal phenotype in the GluR1 mutants
(Reisel et al, 2002) will be developed and evaluated. Fear-potentiated
startle may be the preferred way to test for fear related learning
in these animals. In the fear-potentiated startle paradigm, the movements
of the animal are recorded in a custom-built startle chamber, using
an oscillometer to monitor the animal’s behaviour in response to an
aversively paired CS (Cassella and Davis, 1986). Fear conditioning
measured with fear-potentiated startle is effective in rodents using
both auditory and visual conditioned stimuli (Campeau and Davis, 1995).
Importantly, cued fear conditioning has been shown to be hippocampus-independent
in rats (Phillips and LeDoux, 1992). An important general aim in the
current project will be to validate tasks that are effective for rats,
and to adapt and modify these so that the can be used to test mice
of different strains.
testing will also include a number of additional emotional and cognitive
tests. Any programme intended to identify cognitive effects of genetic
manipulations must investigate not only performance on the crucial
cognitive tasks, but also more basic aspects of behaviour, whose dysfunction
may affect performance not by changing cognition, but as a result
of changing motor, motivational or perceptual functions. In order
to draw clear inferences about cognition, it is essential to demonstrate
a clean bill of health on these other behavioural assays. The tasks
we have chosen reflect this need. Planned experiments include tasks
known to have varying sensitivities to hippocampal dysfunction, including
T-maze, water maze, active and passive avoidance test, motor-coordination
on the rotarod, navigation in the open field, and dark-light box preference.
synaptic transmission in the lateral and basal amygdala in GluR deficient
Previous electrophysiological studies have confirmed that excitatory
afferents to projection neurons and interneurons in the lateral and
basal amygdala form glutamatergic synapses (Weisskopf and LeDoux 1999;
Szinyei et al. 2003). Dual-component analysis of evoked and spontaneous
synaptic currents has shown that AMPA- and NMDA-receptors are present
at individual synapses in these neurons. Projection neurons in the
lateral and basal amygdala will be recorded in the whole cell voltage
clamp configuration (Bissière et al. 2003). Both thalamic and
cortical afferents to the lateral nucleus will be tested, as well
as thalamic afferents to the basal nucleus. Spontaneous synaptic currents,
miniature synaptic currents, evoked EPSCs and short-term facilitation
or depression will be analysed and compared to wild-type mice and
mice deficient for specific AMPA-receptor subunits.
properties of AMPA receptors. Preliminary data obtained
by the applicant indicate that miniature EPSCs recorded in the lateral
amygdala of GluR3 deficient mice show a slower rise time compared
to wild-type mice. Therefore, special emphasis will be put on this
subunit. Experiments will be performed to investigate if that change
is caused by altered AMPA-receptor channel properties. Outside- out
patches will be pulled from neurons in the lateral and basal nucleus
and exposed to AMPA-receptor agonists (a GluR1/3 agonist is available
to the project through the laboratory of Rolf Sprengel). Single channel
activity will be recorded and analysed using a time course fitting
procedure (Colquhoun and Sigworth 1995).
and inhibitory circuits in GluR-deficient mice. Given
that inhibitory synaptic transmission strongly regulates the induction
of LTP in the lateral amygdala (Bissière et al. 2003), and
that LTP of excitatory transmission onto interneurons has been shown
to depend on calcium-permeable AMPA-receptors (Mahanty and Sah, 1998),
excitatory inputs onto interneurons will be investigated. Interneurons
in the lateral and basal amygdala will be recorded in the whole cell
voltage clamp configuration. Interneurons will be identified by their
morphology and non-accommodating spiking pattern upon depolarising
current injection (Mahanty & Sah 1998, Bissière et al.
2003). During whole cell recordings interneurons will be filled with
biocytin for subsequent histochemical analysis. At the moment it is
not clear if our conditional mouse models will show direct changes
of interneuronal responses and it has to be investigated whether GFP-tagged
AMPA-receptors are expressed in interneurons of the amygdala.
imaging of GFP-tagged AMPA receptors. Once synaptic
connections have been identified at which AMPA-receptor subtypes play
important roles in synaptic transmission or plasticity, two-photon
confocal imaging methods will be applied to study the regulation and
trafficking of these subunits at those synapses. These experiments
will be performed in Heidelberg by the applicant using mice expressing
and the amygdala. There is growing evidence that the
neurotransmitter dopamine plays an important role in the modulation
of LTP in the amygdala. Evidence suggests that Pavlovian fear conditioning
depends of dopaminergic gating of amygdaloid LTP (Bissiere et al,
2003), and inactivation of the D1 receptor (Guerracci et al, 2000)
and the D2 receptor (Greba et al, 2001) impair emotional learning.
The project will also benefit greatly from the inclusion of two mice
mutant provided by collaborators of active partner Ivar Walaas. Over
the last 20 years, Walaas has worked together with the internationally
recognised laboratory of Paul Greengaard at Rockefeller University,
NY, USA. Part of this work was acknowledged in the award of the 2000
Nobel Prize in Physiology or Medicine to Paul Greengaard. DARPP (dopamine-and
adenosine 3':5'-monophosphate-regulated phosphoprotein) has been identified
and cloned. Available to the project will be two mutant lines (DARPP-32
and DARPP-21). The regional distribution of DARPP follows the pattern
of dopaminergic innervation, particularly in the basal ganglia (Walaas,
1983c). DARPP is a critical mediating factor in the function of D1
containing dopaminergic cells (Walaas and Greeengard, 1984). Cells
expressing D1 receptor mRNA are heterogeneously expressed in the amygdaloid
complex, with the most intense hybridisation in the basolateral amygdala
(Fremaeu et al, 1990). This suggests a potential role for DARPP in
amygdala modulation, an area of research that has not been investigated
in these mutants to date. We will test this directly through a combination
of electrophysiological and behavioural tests.
The principal objective of the current proposal is to establish whether
AMPA molecules change to execute critical changes at synapses that
support Pavlovian fear conditioning. The project has four sub-goals:
(1) To examine the electrophysiological function of GluR1 and GluR3
subunits in the lateral and basolateral amygdala circuits. (2) To
test to what extent the mutant mice lines are able to undergo Pavlovian
fear conditioning. (3) To ascertain whether the impairments associated
with lack of amygdalar LTP can be related to performance in other
cognitive and affective behavioural tasks. (4) To test for amygdalar
LTP and fear conditioning in DARPP-32 and -21 mutants.
Achievements. At the end of the project period, we expect
to have definite answers to some of the key questions outlined above.
Most significantly, we expect to have a systematic profile of the
necessary or sufficient molecular mechanisms of AMPA-dependent amygdalar
plasticity. Moreover, we expect that the project will further elucidate
the respective roles of the lateral and the basolateral nucleus of
the amygdala and their roles in Pavlovian fear conditioning. Finally,
we expect that our results should prove of value for learning about
the general properties of LTP and learning.
The behavioural experiments detailed in the project proposal include
several conditioning experiments using aversive conditioning (mild
foot shock or load noise). It is unfortunately not possible to study
fear conditioning without the use of aversive conditioning, and so
every effort has to be made in order to minimise the stress experienced
by the animal, whilst still being able to assess learning. The applicant
will devote significant efforts to the careful calibration of tests
for the type of mice used in the project. Because the project relies
on specific molecular deletions that can be activated in the adult
animal, the risk of developmental abnormalities for the animal is
minimal. Selective mutations of this kind represent a dramatic methodological
refinement, as it permits the neural substrate or mechanism under
investigation to be studied while minimising the likelihood that the
animal will experience potentially aversive or distressing side effects.
For behavioural analyses to be interpretable, it is essential that
the experimental animals be in a good overall condition. Thus, on
ethical grounds, but also for pragmatic scientific reasons, the general
behaviour of the animals used in the present project will be monitored
FOR MEDICINE AND HEALTH IN SOCIETY
Fear and fear-related disorders are a major, and growing, socio-economic
problem. The potential for treating such impairments depends on understanding
the underlying processes from which they arise, and identifying effective
points at which it could be feasible to intervene when normal performance
is compromised. Identifying the changes in memory that result from
specific gene manipulations provides critical information on which
therapeutic steps will depend. Insights derived from such basic research
will form the basis for pharmacological approaches to reduce mental
disability. Thus, the improved understanding of molecular and cellular
mechanisms underlying learning and memory processes may, beyond its
purely scientific aspect, aid the design of procedures to treat and
alleviate the most debilitating mental disorders in humans.
The results of the project will be disseminated primarily through
publications in highly ranked international scientific journals. In
the project timetable (see Appendix, p. 10), points at which it would
be natural to summarise and possibly publish the data obtained are
indicated with the ! symbol. The results will also be presented at
scientific meetings as abstracts, posters and lectures.
The main resources and equipment required for the successful completion
of the project are available from the collaborator laboratories.
POSITION AND COLLABORATORS
The candidate will divide his time between the Institute of Physiology
at the University of Oslo and the laboratories of Rolf Sprengel and
Peter Seeburg at the Molecular Neurobiology Department at the Max
Planck Institute in Heidelberg, Germany. In addition, the project
will extend the collaboration with Andreas Lüthi at the Friedrich
Miescher Institute in Basel, Switzerland and with Mark Good at Cardiff
University in Wales, UK. The project will maintain the highly successful
existing collaboration with Ivar Walaas, Øivind Hvalby and
Vidar Jensen and at the Institute of Physiology, UiO, and with the
group of Nick Rawlins and David Bannerman at the Department of Experimental
Psychology, Oxford, UK. Thus, the project will bring together the
strengths of several excellent European laboratories: the electrophysiological
skills of Oslo, the molecular manipulative skills of Heidelberg, the
behaviour technology skills of Oxford. This work builds on the successful
collaboration of these groups under Framework V (QLG3-1999-01022).
Together, the planned experiments and the excellent collaborators
involved means that the project should be well placed to make significant
scientific advances in understanding the molecular mechanisms of fear
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