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in-cites, May 2007
http://www.in-cites.com/papers/KPLesch.html |
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An
interview with:
Prof. Dr. K.P. Lesch |
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 his
month, in-cites talks with Dr. Klaus-Peter Lesch about his
paper, "Association of anxiety-related traits with a
polymorphism in the serotonin transporter gene regulatory
region," (Science
274[5292]: 1527-31, 29 November 1996), as well as his related
research. This paper has been named a Highly Cited Paper in the
field of Neuroscience & Behavior by
Essential
Science Indicators ,
and currently has a total of 1,160 citations to its credit. Dr.
Lesch’s record in our database includes 181 original articles
and review papers cited a total of 6,593 times to date. Dr.
Lesch is Professor and Vice Chair of Molecular and Clinical
Psychobiology as well as Director of the
ADHD Program at the
University of Würzburg in Germany. |
Would you give us some background on your education and research
interests?
I am a clinical psychiatrist, and have been affiliated with the
Department of Psychiatry and Psychotherapy at the University of
Würzburg, Germany, for more than two decades. Since the early days
of my clinical training I have developed a strong interest in the
neurobiological foundation of personality traits, behavior, and
related disorders. In the 1990s this fascination was further shaped
by applying molecular-neurobiological and genetic modification
strategies to my approach to psychobiology, psychopathology, and
psychopharmacology.
As my personal development as a scientist advanced, I considered
myself privileged to contribute to the neuroscience initiative of
the University of Würzburg, which provided me with the framework of
an excellent interdisciplinary research environment. The focus of my
group’s research has long been on the serotonin (5-HT) system of the
brain and its impact on a wide spectrum of psychiatric illness,
including disorders of attention, cognition, and emotion regulation,
as well as their treatment.
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“As analyses of the genomes of humans,
nonhuman primates and other species has
contributed fundamentally to understanding
how humans have evolved, the next level of
complexity concerns the nature of genetic
variation among humans and its influence on
interindividual differences as well as the
relative impact of genetic and environmental
determinants on social competence and
behavior” |
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Apart from my dedication to basic and clinical
psychopharmacology, the extent of my work ranges from studies on
neurotransmitter dysregulation in depression and the role of
postreceptor signal transduction in therapeutic drug action to
investigations on the neurobiology of the 5-HT receptor subtype 1A
(5-HT1A), 5-HT transporter (5-HTT), monoamine oxidase A (MAOA)
in anxiety and aggression.
In my approach to science I consider myself as an interface and I
continue to be committed to bridging the sizeable gap between basic
molecular and clinically applicable research. My group’s work
attempts to integrate pertinent research strategies to elucidate
mechanisms of altered intra- and interneuronal communication and
their impact on the pathophysiology of psychiatric disorders with
the long-term aim to identify final common pathways which could be
targeted by novel treatments. This integration spans the application
of a wide spectrum of neuroscience techniques involving genetics,
neurobiology, morphology, physiology, psychology, and multimodal
imaging in humans and animal models, such as rodent and non-human
primates, in order to arrive at a better understanding of the
relations among functional genomics, proteomics, and cellomics as
well as the interaction of the environment with the brain’s
plasticity, connectivity, and ultimately, function.
Would you please sum up your 1996 Science
paper, "Association of anxiety-related traits with a polymorphism in
the serotonin transporter gene regulatory region?"
The rationale and starting point for our collaborative effort was
that the 5-HT transporter (5-HTT)—the master controller in the
fine-tuning of 5-HT signaling—was thought to be involved in emotion
regulation and related disorders. In the wake of the groundbreaking
discovery of presynaptic neurotransmitter uptake by Hertting &
Axelrod 45 years ago and shortly after its identification as the
initial target of antidepressant drug action, the 5-HTT was first
linked to the etiology and pathophysiology of depression 25 years
ago by S. Langer, M. Briley, and associates. Following
characterization of the rat 5-HTT gene (Slc6a4) 15 years ago,
a decade of extensive molecular genetic studies was launched with
our report of association between 5-HTT variation and
anxiety-related traits in 1996.
Our work took the field a step further by indicating that a
length variation of a repetitive sequence in the upstream regulatory
region (5-HTT-linked polymorphic region, 5-HTTLPR) not only
regulates transcriptional efficiency of the human 5-HTT (SLC6A4)
resulting in variable 5-HT uptake function of the transport protein,
but also differentially moderates anxiety- and aggression-related
personality dimensions—traits that had long been implicated in the
risk scenario of depression and suicidal behavior. In a subsequent
study D. Collier’s, M. Catalano’s, and our groups confirmed that
allelic variation of 5-HTT function also modifies the risk to
develop depression and comorbid disorders, such alcohol dependence.
What was the significance of this paper for your field?
In the decade ensuing the first report linking 5-HTT
variation to anxiety-related traits, numerous clinical cohorts have
been studied for association with disorders of emotion regulation,
including depression, substance abuse, eating disorders, and autism
or disorders related to morphogenic actions of 5-HT in other organ
systems apart from the brain, such as the heart, blood vessels,
bowel, and bone. However, modest effect sizes typical of non-Mendelian
traits, polygenic patterns of inheritance, epistatic and epigenetic
interactions, and heterogeneity between studies led to inconsistent
success in replication and considerably confounded attempts to reach
agreement regarding the role of 5-HTT in the pathophysiology of
these diseases.
The connection between 5-HTT and emotion regulation
reached the next level of fascination when we discovered that the 5-HTT-linked polymorphic region (5-HTTLPR) is unique to humans
and simian primates. In hominoids (humans and great apes) short and
long alleles originate from variation at a specific site, whereas an
alternative location for a variation within the 5-HTTLPR was found
in rhesus macaques. Somewhat surprising, yet evocatively paralleling
the human condition and likely based on an independent molecular
event, the length variation of the rh5-HTTLPR is once more basically
biallelic—short and long variants. The presence of the rh5-HTTTLPR
and resulting allelic variation of 5-HTT activity in rhesus macaques
provides a unique model to dissect the relative contribution of
genes and environmental stressors to central 5-HT function and
related behavioral outcomes.
The demonstration that early life stress and other modes of gene
x environmental interaction uniquely reinforce or even uncover links
between 5-HTT variation, behavior, and psychopathology in
both humans and non-human primates is particularly outstanding and
heralded a new era of behavioral genetics. Several recent studies
suggest that 5-HTT variation interacts with deleterious early
rearing experience in rhesus monkeys to influence attentional and
emotional resources, sensitivity to ethanol, and stress response.
While the neural and molecular mechanisms underlying gene x
environment interaction are still poorly understood, the
identification of 5-HTT as a susceptibility gene for
depression is a first step en route for an explanation of the
molecular dimension of personality and behavior at risk, outlining
strategies to identify physiologic pathways and mechanisms that lead
to other disorders of cognitive function and emotion regulation,
providing tools to dissect the interactive effects of genes and
environment in the development of affective disorders, and holding
the potential to predict response to antidepressant therapy and
other treatments.
Where is this work today – have you and your colleagues developed it
further?
Early small steps of behavioral genetics are contrasted by giant
leaps in a postgenomic era still in its infancy. The application of
paradigms novel to neurogenetic approaches including
neurophysiology, neuropsychology, and functional neuroimaging as
well as inclusion of a more extensive phenotypic spectrum (e.g.,
higher cognitive functions, communication skills, social competence,
longevity, etc.) have strengthened the connection between 5-HTT,
social cognition and emotionality, and continue to enable a more
profound understanding of how common genetic variation modulates
human behavior. Finally, studies in genetically modified mice have
begun to underscore the central role of 5-HT and its fine-tuning by
5-HTT function in embryonic patterning events, brain development,
and synaptic plasticity, particularly in neurocircuitries related to
social cognitive and emotional processes.
Potential relevance of 5-HTT variation in social
cognition, the construct comprising processes employed to conform to
essential norms and procedures of the social world, is currently
transcending the borders of behavioral genetics to embrace biosocial
science. As analyses of the genomes of humans, nonhuman primates and
other species has contributed fundamentally to understanding how
humans have evolved, the next level of complexity concerns the
nature of genetic variation among humans and its influence on
interindividual differences as well as the relative impact of
genetic and environmental determinants on social competence and
behavior.
Although the 5-HTT has become a model molecule par excellence in
cognitive, biosocial, and psychiatric neurosciences, we are faced
with a new wealth of genomic data and the potential for manipulating
genes, and the question arises, "What are the future challenges and
limitations for determining the genetic influence on behavioral
traits?" While it is obvious that certain genes play a pre-eminent
role in the encoding of particular behaviors and that the
individual’s current environment and past life events have major
impact on expression patterns and epigenetic programming, neither
genes nor environment act alone in determining development and
patterns of behavior. An as-yet little-explored level of complexity
comes from the interactions between genetic and epigenetic
mechanisms involving DNA methylation and histone acetylation in
determining gene expression.
The future challenge for behavioral genetics applied to the
elucidation of neurocircuitries of cognition, emotionality, and
related brain pathology associated with depression will the shift
from the analysis of gene sequence and protein structure to the
understanding of neural mechanisms. The sequel to the gene knowledge
spiral will therefore be extraction and integration of experimental
data, construction of gene and protein networks, and the creation of
functional information by feedback from simulation to empirical
approaches.
If you are free to talk about it, what are your current projects?
As a consequence of the unsolved issues outlined above, my group
is currently pursuing three lines of research: we are looking at the
impact of variation of serotonin signaling on social organization of
different macaque species; we are attempting to develop methods for
the imaging of neural mechanisms of epigenetic processes at the
level of brain systems; and we would like to learn more about
molecular mechanisms of epigenetics.
First, a particularly intriguing question is whether social
cognition is moderated by the serotonin transporter, the master
controller of serotonin function. Macaques exhibit exceptional
inter-species variation in aggression-related behavior, as
illustrated by recent studies showing overlapping patterns of
aggression-based social organization grades and macaque phylogeny.
For macaques, like humans, survival depends on effective social
functioning. Social skills facilitate access to sustenance,
protection, and mates. Socially adept individuals tend to be
healthier and live longer.
To search for the molecular basis for this hypothesis, variation
of the 5-HTT (5-HTTLPR) and monoamine oxidase A gene (MAOALPR),
another key regulator of serotonin signaling, was determined in
seven macaque species representing the entire spectrum of different
social organization grades (Wendland et al., 2006). Macaque
species displaying tolerant societies, with relaxed dominance and
high levels of conciliatory tendency, were monomorphic at the
5-HTTLPR (and the MAOALPR). In contrast, those species known to
exhibit intolerant, hierarchical, and nepotistic societies were
polymorphic at one or more of these loci. Rhesus monkeys, the most
intolerant and hierarchical species of macaques, showed the greatest
degree of allelic variation in both genes. These findings suggest
that genetically variable 5-HT neurotransmission affects critical
elements of macaque social behavior, in particular the exceptional
level of interspecies variation in aggression-related behavior.
Second, although clinical evaluation and self-report of life
events revealed that the effect of psychosocial stress on depression
risk is modified by allelic variation of 5-HTT function, the neural
mechanisms underlying this moderator effect is poorly understood. As
a first approximation toward identification of neurocircuits in
control of these epigenetic processes, individuals with
self-reported life stress but no history of depression were
investigated with multimodal MRI imaging. Based on fMRI and
perfusion data, support was found for a model by which life stress
interacts with the effect of 5-HTTLPR genotype on amygdala and
hippocampal resting activation which may provoke a chronic state of
negative cognitive bias including increased vigilance, threat, or
rumination (Canli et al. 2006). Life events also
differentially affected, as a function of 5-HTTLPR genotype,
functional connectivity of the amygdala and medial prefrontal cortex
in response to emotional stimuli with a wide network of other
regions, as well as gray matter structural features. These
interactions may constitute a neural mechanism for epigenetic
vulnerability for depression.
Intriguingly, whole-brain analyses of activation, functional
connectivity, and gray matter density and volume revealed additional
regions that were moderated by the interaction of 5-HTTLPR genotype
and life stress. The remarkable fact about these regions is that
they belong to circuits that integrate imitation-related behavior,
from which social cognition and the behavior in a social world has
evolved. Social cognition comprises representations of internal
somatic states, interpersonal knowledge, and motivations, as well as
procedures used to decode and encode the self relative to other
people. This complex set of processes, which is carefully
orchestrated to support skilled social functioning and
communication-facilitated networking, has recently been associated
with activity in distinct neurocircuits of the brain. Regions
involved in imitation, imitative learning, social cognition, and
communication skills, and affected by 5-HTT x life stress,
include the superior parietal lobule, superior temporal gyrus,
inferior frontal gyrus, precentral gyrus, insula, anterior cingulate,
and amygdala (Canli et al. 2005, 2006). Some of these regions
contain mirror neurons, which are activated during goal-directed
behavior or the observation of such behavior in others, and Von
Economo neurons, which are believed to play a role in social
bonding.
These findings suggest that social competence and behavior may be
subject to an interaction between psychosocial stress and 5-HTTLPR
genotype, while mirror or Von Economo neurons are targets of
epigenesis. Future electrophysiological and imaging studies will
have address whether interaction of 5-HTTLPR and life stress
moderates neural activation during imitation or social processing
tasks.
Finally, 5-HTT deficient mice seem to represent an indispensable
tool for studying molecular and neural mechanisms of epigenetics.
Investigations in rodents have demonstrated that maternal behavior
has long-lasting consequences on anxiety-like behavior of the
offspring and that intra- and extra-uterine maternal signals can
synergistically induce enduring plastic changes in neurocircuits
involved in depression.
This epigenetic inheritance of anxiety-like behavior underscores
the view that environmental influences can persistently remodel
neuronal units during early development, rendering 5-HTT
modified mice indispensable for the dissection of the molecular and
neural mechanisms of epigenetic programming at the
neurodevelopmental-behavioral interface.
Papers cited
Canli T, Omura
K,
Haas B, Constable RT, Lesch KP, "Beyond
affect: a role for genetic variation of the serotonin
transporter in neural activation during a cognitive attention
task," Proc. Natl. Acad. Sci. USA 102:12224-12229. 2005.
Canli T, Qiu M, Omura K, Congdon E,
Haas BW, Amin Z, Herrmann MJ, Constable RT, Lesch KP, "Neural
correlates of epigenesis," Proc. Natl. Acad. Sci. USA
103:16033-16038, 2006.
Wendland JR, Lesch KP, Newman TK, Timme
A, Gachot-Neveu H, Thierry B, Suomi SJ, "Differential functional
variability of serotonin transporter and monoamine oxidase A
genes in macaque species displaying contrasting levels of
aggression-related behavior," Behav. Genet. 36:163-72,
2006. 
K.P. Lesch, M.D.
Professor and Vice Chair
Director ADHD Program
Molecular and Clinical Psychobiology
Department of Psychiatry and Psychotherapy
University of Würzburg
Würzburg, Germany
| Prof. Dr. K.P. Lesch's
most-cited paper with 1,160 cites to date: |
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Lesch KP,
et al., "Association of anxiety-related traits with a
polymorphism in the serotonin transporter gene regulatory
region," Science 274(5292): 1527-31, 1996. |
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Source:
Essential Science Indicators |
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in-cites, May 2007
http://www.in-cites.com/papers/KPLesch.html |
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cites
