University of Cambridge > Talks.cam > Departmental Seminar Programme, Department of Veterinary Medicine > From the whole CNS to defined brain nuclei to neurotransmitter cell type-specific circuits: Using mouse genetics to dissect CRF-dependent mechanisms driving stress-induced emotional behaviour

From the whole CNS to defined brain nuclei to neurotransmitter cell type-specific circuits: Using mouse genetics to dissect CRF-dependent mechanisms driving stress-induced emotional behaviour

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Corticotropin-releasing factor (CRF) is a neuropeptide widely distributed throughout the CNS where it acts as a neuromodulator orchestrating adaptive responses to stress such as anxiety, locomotor activity, fear response, and neuroendocrine regulation. Impairments in the physiological CRF responses to stress are substantially involved in the causation and development of mood disorders such as depression and anxiety. Therefore, there is an urgent need to understand the brain areas involved, activated neurotransmitter circuits and molecular mechanisms underlying the effects of CRF /CRF-R1 on emotional behaviour.

As neuroregulator, CRF does not have neurotransmitter effects per se but its function rely on the modulation of true neurotransmitter systems. Which neurotransmitter circuits are involved in modulating CRF -R1-dependent behaviours is a fundamental question in the biology of stress and stress-related disorders. In order to dissect the neurotransmitter identity of neurons expressing CRF -R1, we mapped CRF -R1 expression throughout the brain using double labelling histochemical approaches and by means of a newly developed CRF -R1-EGFP reporter mouse line.

Using genetically engineered mice, we have shown that conventional CRF1 knock-out (KO) and limbic-specific CRF -R1-CamKII conditional KO mice display reduced anxiety-like behaviour. Nevertheless the cellular identity of telencephalic circuits controlling anxiety via CRF and the putative contribution of other brainstem-located neurotransmitter systems remain unclear. To address this question we used a conditional mutagenesis approach based on the Cre/loxP system to dissect the precise contribution of CRF -R1 on different neuronal populations in living animals. We crossed CRF -R1flox/flox mice with neurotransmitter-cell type specific Cre lines to specifically ablate CRF -R1 only in glutamatergic, GAB Aergic, dopaminergic and serotonergic neurons of the brain. A comprehensive series of studies were performed in every mutant mouse line including behavioural phenotyping, neuroendocrine response, expression profiling, neurotransmitter release, and electrophysiological analysis. The specific contribution of CRF -R1 in each neurotransmitter system on different aspects of the stress response and its putative role in affective disorders will be discussed.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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