ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Developmental programming of anxiety
Cornelius Gross
PhD 1995, Yale University.
Postdoctoral research at
Columbia University.
Group leader at EMBL
Monterotondo since 2003.
Senior Scientist since 2009.
Previous and current research
Anxiety disorders are debilitating mental illnesses characterised by excessive worry and exaggerated
responses to threatening stimuli. Epidemiological studies suggest that both genetic and environmental
factors contribute to the prevalence of these disorders. For example, exposure to
adverse events such as trauma, maltreatment or negligence during childhood is known to result
in an increased risk for anxiety disorders during adulthood. However, not all persons subjected to
such events develop anxiety, and genetic factors are thought to influence the long-term outcome
of such experiences. Recently a number of specific genetic polymorphisms have been identified
that moderate susceptibility to mental illness following exposure to childhood adversity. However,
we know little about the neural circuits and molecular substrates that underlie such gene-byenvironment
risk factors. A better understanding of the molecular mechanisms involved could
lead to novel diagnostic and therapeutic approaches for mental illness in humans. We are using
pharmacological, histochemical, electrophysiological and behavioural genetic approaches to study
the neural circuits underlying anxiety behaviour in mice. Several ongoing projects in the lab are
addressing this question from different angles.
Early gene-by-environment risk factors: We are particularly interested in understanding how exposure to early adverse experiences can
program anxiety behaviour in adulthood. We have shown that exposure to low levels of maternal care is associated with increased anxiety and
depression-related behaviour in adulthood and that this effect is moderated by specific mutations in genes that are known to play a role in
brain development and plasticity. We are using tissue-specific and temporally controlled gene expression technology in transgenic mice to identify
the neural circuits and critical time periods for these effects. We are also examining changes in gene expression and epigenetic marks associated
with altered early environmental exposure. Finally, we are collaborating with psychiatrists to examine whether gene-by-environment
risk factors identified in the mouse are also predisposing factors for behavioural disorders in humans.
Cellular substrates of anxiety: To help identify the cellular substrates of anxiety, we are using pharmaco-genetic transgenic tools for the
rapid modulation of electrical activity in selected cell-types in the brain. We have used a pharmaco-genetic inhibition strategy to examine the
contributions of hippocampal and amygdala cell-types to anxiety and fear behaviour. We are further developing these tools and combining
them with electrophysiological recordings in awake behaving mice to identify the cell-types and circuits involved.
Future projects and goals
• identification of molecular mechanisms that mediate the long-term programming of behaviour by early environmental experiences
in mice and humans (genetic, epigenetic, hormonal, electrophysiological, morphological and signalling mechanisms);
• creation of mouse models of specific human genetic variations that have been associated with behavioural disorders;
• development and application of pharmaco-genetic transgenic technologies for the tissue and cell-type specific suppression of neural
activity in behaving mice;
• identification and manipulation of the neurophysiological correlates of anxiety in awake behaving mice;
• study of copy number variations as predisposing factors for disease in mice.
Together these approaches are aimed at discovering the long-term plastic mechanisms that underlie susceptibility to anxiety. A better understanding
of the molecular signals that trigger these plastic changes will allow us to form specific hypotheses about how human anxiety is
determined and may lead to improved diagnostic and therapeutic tools in the clinic.
Selected references
Audero, E., Coppi, E., Mlinar, B., Rossetti, T., Caprioli, A.,
Banchaabouchi, M.A., Corradetti, R. & Gross, C. (2008). Sporadic
autonomic dysregulation and death associated with excessive
serotonin autoinhibition. Science, 321, 130-133
Carola, V., Frazzetto, G., Pascucci, T., Audero, E., Puglisi-Allegra, S.,
Cabib, S., Lesch, K.P. & Gross, C. (2007). Identifying molecular
substrates in a mouse model of the serotonin transporter x
environment risk factor for anxiety and depression. Biol. Psychiatry,
63, 80-6
Tsetsenis, T., Ma, X.H., Lo Iacono, L., Beck, S.G. & Gross, C. (2007).
Suppression of conditioning to ambiguous cues by pharmacogenetic
inhibition of the dentate gyrus. Nat. Neurosci., 10, 896-902
Gross, C. & Hen, R. (200). The developmental origins of anxiety.
Nat. Rev. Neurosci., 5, 55-552
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