Molecular genetics of behaviour – genes’ perspective of brain function
Senior Research Fellow
tel: +44 20 3108 8018
A fascinating question in biology is how genes orchestrate not only the body plan but also complex physiological responses to the environment and experience. The central nervous system represents an elaborate example in which the genome programs a network of cells to perform the computations necessary for individual behaviours. Furthermore, gene regulation serves as one of the fundamental modes by which animals’ experiences and internal states modify neural circuit operations. Our laboratory’s goal is to obtain a principal logic by which genes operate to control neural circuits by uncovering “genomic codes” that allow circuits to change upon experiences and adapt to the environment. We study social behaviours, genetically hardwired yet highly flexible and experience-dependent, as a model linking gene activities to the control of neural circuits and behaviour.
1) The social brain
Rodents rely heavily on special scents known as pheromones for social information such as species, gender, and social status. An important insight from classical ethology is that many animals use a specific set of discrete stimuli to trigger social behaviours such as aggression and mating. We are interested in uncovering which specific sensory inputs, olfactory and non-olfactory, can activate these innate circuits and how combinations of these specific stimuli are reconstituted as social information in the brain. To tackle this problem, we use a combination of molecular biology, biochemistry, genomics and physiology to understand how animals perceive their social environments. Our studies so far have uncovered specific chemosensory receptors that control specific social and defensive behaviours including pup-directed behaviours and predator defense. These findings will now allow us to identify specific population of brain cells critical for these behaviours. Importantly, the recognition of social cues are prominently affected in human disorders of social behaviours, and our studies will shed light on the circuit basis of social recognition and its regulation at the molecular level.
2) Logic of gene regulation in the brain
A remarkable property of the brain is that neuronal networks are highly plastic upon experiences. Pioneering studies in invertebrates and vertebrates showed that molecular changes that occur within synapses and cell nuclei, as well as the actions of neuromodulators, can “reprogram” existing neural circuits. In fact, while it is widely appreciated that neural activation and inhibition accompany unique transcriptional changes, it has been difficult to attain a clear logic by which these transcriptional changes are linked to the performance of the circuit as a whole. To tackle this question, we need substantially improved tools to probe and control gene expression in brain tissues. We have, for example, pioneered a system to dissect the mechanisms of transcription at the biochemical level in single cells in Drosophila. Building on these methods we will continue to develop and use advanced imaging techniques, such as single molecule, cleared tissue, and/or live microscopy, to probe mechanisms of gene regulation in heterogeneous tissues such as the brain in a quantitative fashion. With an increasing appreciation that neuronal cell types classified physiologically, anatomically, and transcriptionally determine the functions of each neuron type within a circuit, our goal is to uncover the regulatory logic of how a single genome can produce diverse neuronal cell types and tune their properties on demand.
- Group Members
Mathew Edwards, Postdoctoral Research Associate
- Selected Publications
- Isogai, Y., Richardson, D., Dulac, C., and Bergan, J.F. (2017)
Optimized protocol for imaging cleared neural issues using light
microscopy, in Synapse Development, Methods in Molecular Biology,
- Menegas, W., Bergan, J.F., Ogawa, S.K.,
Isogai, Y., Venkataraju, K.U., Osten, P., Uchida, N., and Watabe-Uchida,
M. (2015) Projection-specific inputome for dopamine neurons: dopamine
neurons projecting to the posterior striatum form a distinct subclass,
eLife, 4: e10032.
- Isogai, Y., Si, S., Tan, T., Pont-Lezica, L.,
Kapoor, V., Murthy, V., and Dulac, C. (2011) Molecular organization of
vomeronasal chemoreception, Nature 478: 241-5.
- King, N.,
Westbrook, J., Young, S., Abedin, M., Chapman, J., Fairclough, S.,
Hellsten, U., Isogai, Y. et al. (2008) The genome of the
choanoflagellate Monosiga brevicollis and the origins of metazoan
multicellularity, Nature 451:783-8.
- Isogai, Y., Keles, S., Prestel, M., Hochheimer, A., and Tjian, R. (2007) Transcription of histone gene cluster by differential core-promoter factors, Genes & Development 21:2936-49.
- Isogai, Y., Takada, S., Tjian, R., and
Keles, S. (2007) Novel TRF1/BRF target genes revealed by genome-wide
analysis of Drosophila Pol III transcription, EMBO Journal 26:79-89.
- Marr, M.T., Isogai, Y., Wright, K.J., and Tjian, R. (2006) Coactivator crosstalk specifies transcriptional output, Genes & Development 20:1458-69.
- Isogai, Y. and Tjian, R. (2003) Targeting genes and transcription factors to segregated nuclear compartments. Current Opinion in Cell Biology 15:296-303.
- Isogai, Y., Richardson, D., Dulac, C., and Bergan, J.F. (2017) Optimized protocol for imaging cleared neural issues using light microscopy, in Synapse Development, Methods in Molecular Biology, Springer, 1538:137-153.