Investigating the sexually dimorphic neural circuit in Drosophila melanogaster using behavioural genetics and structural biology

“我们的大脑是如何控制我们的行为的？”自希波克拉底时代以来一直是人类的一个好奇。试图解开这个谜团仍然是一项艰巨的任务，因为人类大脑由近1000亿个神经元组成，它们之间有100万亿个连接。我们如何理解这样一个复杂的系统是如何工作的呢？为了帮助我们更深入地了解我们的大脑是如何工作的，我们把常见的果蝇作为模型系统。苍蝇的神经系统只有大约10万个神经元，要简单得多。学习一个简单网络的基础，比如苍蝇的大脑，将为更大网络的运作提供相关的基础知识。

"How does our brain govern how we behave?" has been a curiosity of mankind since the time of Hippocrates. Attempting to solve this mystery is still a monumental task as the human brain consists of close to 100 billion neurons making 100 trillion connections. How do we make sense of how such a complicated system works? To help us gain some insight into how our brain works, we turn to the common fruit fly as a model system. With only ~100,000 neurons, the fly nervous system is much simpler. Learning the underpinnings of a simple network such as a fly's brain will provide the fundamental knowledge relevant to the operation of a larger network. Animals are born with certain instincts that ensure their survival and reproductive success. Since instincts are hard-wired, it gives us an opportunity to use genetic tools to manipulate the nervous system in order to understand how the nervous system functions to elicit a behaviour. In flies, courtship is a sex-specific complex instinctive behaviour. Males perform a series of courtship rituals (orientation, tapping, singing, licking, copulation) while females decide whether to run away or slow down and allow copulation. Requiring the use of all senses (i.e., vision, smell, and taste) and a decision process that triggers a motor output to perform the courtship rituals, male courtship behaviour is controlled by a neural network called the fruitless (fru) circuit. The fru circuit consists of ~2000 neurons in the nervous system. While the neuronal organization of this circuit is available, how each neuron functions in the context of courtship behaviour has not been fully worked out. The fru circuit is gender-specific in that some neurons are absent in females, some are present in both sexes but have different morphology, and others may have different functions in males and females. The male-form of the fru gene product (FruM) is the key protein that is responsible for the development of the fru circuit. Recently, it was discovered that FruM works with two protein factors (HDAC1 and HP1a) to fine-tune the gender property of at least two small regions of the circuit. It is not known whether the same protein factors affect other gender-specific regions of the fru circuit as well. With my unique training both in structural biology and behavioural genetics and reagents generated from my previous work that permits gene targeting to a small subsets of the fru circuit, I will be able to pursue my research program in three directions: 1) what role do these subsets of fru neurons play in courtship? 2) What factors associate with FruM to influence the development of different gender-specific regions of the circuit? 3) How does FruM interact with its binding partners in three-dimensional space to cause behavioural and morphological outcomes. In my five-year proposal, I will focus on three short-term objectives: 1) to identify fru neurons that process visual senses during courtship; 2) to evaluate the role of HDAC1 and HP1a in the gender-specific development of a small group of fru neurons isolated in our previous work; and 3) to investigate the different binding property of FruM to HDAC1 and HP1a in vitro. The significance of my research program is in the novelty of combining holistic and reductionist approaches to understand the functioning and development of the fru circuit. The unique insights developed from this combined approach will benefit the field of neurobiology of innate behaviour. The HQPs funded by this grant will become experts in a wide range of very technical experimental approaches, ensuring their competitiveness in the Canadian and international scientific workforce. The multidisciplinary research program can lead to new techniques that can be used to study animal behaviour.