Gross Group

The Gross group uses pharmacological, histochemical, electrophysiological and behavioural genetic approaches to study the neural circuits underlying anxiety behaviour in mice.

Previous and current research

Anxiety disorders are debilitating mental illnesses characterised by excessive worry and rumination and exaggerated responses to threatening stimuli. Studies suggest that both genetic and environmental factors contribute to the prevalence of these disorders. For example, exposure to adverse events such as trauma during childhood is known to result in an increased risk of anxiety disorders in adulthood, 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-by-environment risk factors. A better understanding of the molecular mechanisms involved could lead to novel diagnostic and therapeutic approaches for mental illness in humans. Several ongoing projects in the lab are addressing this question from different angles.

Early gene-by-environment risk factors: We are 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 such tools to examine the contribution of hippocampal and amygdala cell-types to anxiety and fear behaviour and are further developing these tools in combination with in vivo electrophysiology in awake behaving mice to dissect the circuits involved.

Future projects and goals

• Identification of the molecular mechanisms that mediate the long-term programming of behaviour by early environmental experiences in mice and humans.
• 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 tissue and cell-type specific suppression of neural activity in behaving mice.
• Identification and validation of the neurophysiological correlates of anxiety with particular focus on hippocampus, amygdala, and medial hypothalamus.
• Study of copy number variations as predisposing factors for disease in mice.

A better understanding of the molecular signals that trigger these long-term plastic mechanisms 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.