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Hannah Clarke PhD

MRC Research Fellow
Tel: +44 (0)1223 339012, Fax: +44 (0)1223 339014, E-mail: hfc23@cam.ac.uk

Neural and Neurochemical basis of negative emotional behaviour; implications for psychiatric disorders.

Imagine walking down a dark street at night. Hearing unexpected footsteps behind you, you feel fear, your heart races, and you get ready to run – all aspects of a complex emotional response. As the example above illustrates, the ability to regulate one’s emotions appropriately in response to such stimuli is crucial for successful and appropriate interaction with our environment. However, abnormal emotional regulation causes major problems and is seen in depression and anxiety disorders. It may result from cognition being abnormally biased by emotive stimuli, and from failure to integrate the behavioural and physiological aspects of emotional responses. However, the neural bases of emotional response integration and cognitive biases are poorly understood.

In depression, there is evidence that specific brain regions are abnormal, including the amygdala (well known to influence emotional responses) but also the hippocampus and medial prefrontal cortex.  In addition, therapies for depression and other affective disorders primarily target the serotonergic system, yet how and where they are acting is poorly understood.

Our research therefore seeks to understand;

1)    How the hippocampus and amygdala communicate with the medial prefrontal cortex to regulate emotion,

2)    How these different brain areas contribute to the physiological and behavioural integration of an emotional response

3)    How these structures and their communication is modulated by neurochemicals such as serotonin.

To do this we combine neuroimaging techniques with specific neurochemical manipulations, telemetric monitoring of cardiovascular responsiveness, and neuropsychological tests that tax cognition and emotion. We combine this with genetic screening and monitoring for proteins involved in emotional responsiveness such as BDNF and cortisol. This information is critical to our understanding of the aetiology of specific symptom clusters within affective and other psychiatric disorders, and may eventually lead to developments in pharmacotherapy better targeted to dysfunctional regions of interest.

Lab members
Miss Chloe Wallis, Graduate student (PhD)
Professor Jorge Zeredo, Visiting Scholar from University of Brasilia, Brasil.

Main Collaborators
Prof Angela C Roberts (Physiology, Development and Neuroscience)
Professor Trevor W Robbins (Psychology, Cambridge)
Dr Jeff Dalley (Psychology, Cambridge)
Dr Annette Brühl (BCNI)

Main sources of funding: MRC

Selected publications
Agustín-Pavón C., Braesicke K., Shiba Y., Santangelo A.M., Mikheenko Y., Cockroft G., Asma F., Clarke H., Man M., Roberts A.C. (2012) Lesions of ventrolateral prefrontal or anterior orbitofrontal cortex in primates heighten negative emotion. Biological Psychiatry 72:266-272.

Clarke H.F., Hill G.J., Robbins T.W., Roberts A.C. (2011) Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus. Journal of Neuroscience 31:4290-4297.

Clarke H.F., Roberts A.C. (2011). Reversal learning in fronto-striatal circuits: a functional, autonomic and neurochemical analysis. In Delgado M, Phelps E, Robbins TW (eds), Attention and Performance Volume XXIII: Decision Making. Oxford University Press, Oxford, UK.

Rygula R., Walker S., Clarke H., Robbins T.W., Roberts A.C. (2010) Differential contributions of the primate ventrolateral prefrontal and orbitofrontal cortex to serial reversal learning. Journal of Neuroscience 30:14552-14559.

Man M.S., Clarke H.F., Roberts A.C. (2009) The role of the orbitofrontal cortex and medial striatum in the regulation of prepotent responses to food rewards. Cerebral Cortex 19:899-906.

Clarke H.F., Robbins T.W., Roberts A.C. (2008). Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex. Journal of Neuroscience 28: 10972–10982.

Clarke H.F., Walker S.C., Dalley J.W., Robbins T.W., Roberts A.C. (2007) Cognitive inflexibility after prefrontal serotonin depletion is behaviourally and neurochemically specific. Cerebral Cortex 17:18-27.

Clarke H.F., Dalley J.W., Crofts H.S., Robbins T.W., Roberts A.C. (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 7:878-880.

image

Above: Fallypride (D2 receptor) binding in the striatum.
[Picture courtesy of the Wolfson Brain Imaging Centre]