Case Western Reserve University
Grant: $37,800 - National Institutes of Health - May. 5, 2009
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Award Description: Abstract Serotonin (5-hydroxytryptamine; 5HT) has been demonstrated to play important roles in various physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation and breathing (Mooney et al., 1998). In addition, changes in 5HT levels have been related to several diseases, e.g. depression, anxiety, schizophrenia and asthma (Davidson et al., 2000; Lucki, 1998; Mann et al., 2001; Nelson and Chiavegatto, 2001). Thus, understanding how 5HT signaling modulates the brain and the periphery is very relevant for understanding the physiology and behavior of mammals. Furthermore, controlling the activity and modulation of the 5HT system in the brain with non-invasive techniques will ultimately lead to the understanding of mammalian behavior and may accelerate the development of therapeutic treatments for diseases mentioned above. The serotonergic neurotransmitter system consists of a small number of neurons that are mainly restricted to the ventral regions of the hindbrain and are clustered in nuclei. 5HT neurons project into almost every brain area to modulate downstream neuronal circuits via 5HT receptors. The activity of the serotonergic transmitter system is regulated via transmitter release from local neurons and/or afferents to the different 5HT neuron containing nuclei (hetero-regulation) and in particular via autoregulatory mechanisms arising from the serotonergic neurons themselves (autoregulation). It can be assumed that the overall activities set by the autorgulation in the 5HT nuclei determine the strength of the output of 5HT to the forebrain and periphery. The autoregulation is specifically mediated via 5HT-1 receptors, which couple to the inhibitory G protein pathway (Gi/o). Our lab, including myself, has recently developed a non-invasive technique to control the Gi/o pathway by light using vertebrate rhodopsin. I have created mice that will allow for the neuron-type specific expression of vertebrate rhodopsin in the serotonergic system of mice. I will use these mice to characterize and understand the role of the Gi/o pathway activation within the autoregulation of the 5HT transmitter system and for the control of 5HT levels in the brain. PUBLIC HEALTH RELEVANCE: Project narrative Serotonin (5HT) is an important transmitter for modulating important physiological functions such as emotions, sleep, cognition and breathing. Various diseases have been associated with altered 5HT levels such as anxiety disorders and depression. The relevance of this proposal lies in the understanding of how 5HT regulates its own transmitter release in the brain, a process called autoregulation. The autoregulation has been suggested to be altered by anti-depressants via downregulation of 5HT-1 receptors coupling to the Gi/o pathway. This pathway will now be controlled by light directly, non-invasively and exclusively in the 5HT transmitter system in the mouse brain.
Project Description: Davina's project involves the development of a mouse model to analyze the influence of the Gi/o pathway. We (including Davina) established recently the use of vertebrate rhodopsin as a tool to control the Gi/o pathway by light Li, X., D.V. Gutierrez, M.G. Hanson, J. Han, M.D. Mark, H. Chiel, P. Hegemann, L.T. Landmesser, and S. Herlitze. 2005. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc Natl Acad Sci U S A. 102:17816-21). Davina now created a mouse model, where vertebrate rhodopsin can be activated by cell-type specific expression of the light- activated protein. She demonstrated first as a proof of principle that activation of the vertebrate rhodopsin in Purkinje cells of the cerebellum can be used to control the Gi/o pathway by light in behaving mice and that light pulses lead to changes in motor coordination. She is now crossing the floxed vertebrate rhodospin mice with mice where cre recombinase is specifically expressed in the 5HT system of mice. The goal here is to control the Gi/o pathway within the serotonergic system by light to gain an understanding in particular of the autoregualtion of this system. The autoregulation of the 5HT system via Gi/o pathway has been suggested to be altered in anxiety and depression. Therefore the studies will shed light on how Gi/o pathway activation will influence the behavioral changes.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Less Than 50% Completed
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