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.
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.
|Gutierrez, Davina V; Mark, Melanie D; Masseck, Olivia et al. (2011) Optogenetic control of motor coordination by Gi/o protein-coupled vertebrate rhodopsin in cerebellar Purkinje cells. J Biol Chem 286:25848-58|
|Mark, Melanie D; Maejima, Takashi; Kuckelsberg, Denise et al. (2011) Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations. J Neurosci 31:4311-26|