Periodic Reporting for period 1 - NeuroEE (Delineation of a brain circuit regulating energy expenditure to impact body weight)
Okres sprawozdawczy: 2016-02-01 do 2018-01-31
The second stage of the NeuroEE (2016 Q2) involved the training and evaluation necessary to carry out in vivo experiments with live animals. During this time, I began attending seminars and training to gather scientific public engagement skills. I was also invited to give a presentation in the International Behavioural and Neuronal Genetics Society annual meeting in Maine, USA.
After completing the training objectives, I started the research program. First, I characterized 5-HT producing cells in the brainstem raphe pallidus (RPa-5-HT) under different energy availability states. By means of immunohistochemistry techniques, I found the 5-HT neurons in the RPa changed their activity in response to different energy states. Also during this period, I applied for a small grant to investigate a different neuronal population that may be important and complementary to this project.
The next step in the NeuroEE (2016-Q3 and Q4) was to interrogate specifically RPa-5-HT and its role in energy expenditure. I produced some very interesting results during this period. My experiments showed that RPa-5-HT neurons were required for maintaining an appropriate energy balance during a short period of refed after fasting challenge. I have found that the inhibition of 5-HT RPa neurons activity induces feeding and produces a shift in the overall energy balance increasing body weight. I have presented these results in seminars and revised the research program to update it in light of these results. Also, I attended the British Society of Neuroendocrinology 2016 annual meeting where I met experts and shared my results.
During the last months of 2016 and until the third quarter of 2017, I performed the major bulk of the research program. At the beginning (2017-Q1 and Q2) I performed the chemogenetic interrogations of 5-HT-RPa cells. Specifically, I introduced genetically modified receptors in the 5-HT-RPa cells (via infection with viral particles expressing Designer Receptors Exclusively Activated by Designer Drug) that allowed me to activate and inhibit their overall activity by means of injecting a designer drug. I then interrogated the role of 5-HT-RPa cells in the regulation if the energy balance and thermogenic program in the brown adipose tissue. I found that 5-HT-RPa cells form a key hub of neurons that modulate both energy expenditure and feeding behavior in situations of energy imbalance. I next interrogated the role of these neurons in a chronic model. To achieve this, I genetically block the expression of the gene involved in the production of 5-HT only in the RPa. The results obtained were exciting and revealed a key role of 5-HT-RPa in the regulation of the energy expenditure. Specifically, preventing 5-HT-RPa production increased energy expenditure and reduced body weight. This was directly mediated by the modulation of the thermogenic program in the brown adipose tissue. I presented these results in an invited talk at the prestigious Keystone Symposium in Copenhagen in 2017. Thus, my hypotheses proposed in NeuroEE were supported and I uncovered a new energy expenditure circuit that improves obesity.
Having achieved my primary research objectives, milestones and tasks, I am now working on the write up of these key discoveries for publication. I have also submitted a small grant to continue to build upon the results. My goal now is to obtain funding to establish my own laboratory clarifying how the brain regulates energy expenditure.