Blakely Lab

The neurotransmitter dopamine (DA) is a critical modulator of neuronal function in both vertebrate and invertebrates, controlling many behavioral responses, including addiction, motor activity, reward, sleep and arousal. A major control point of DA signaling is the DA transporter (DAT), which limits the magnitude and duration of DA action and is a target of addictive and therapeutic psychostimulants. DAT dysfunction may also contribute to the etiology of DA-linked brain disorders including ADHD, Parkinson’s disease, and schizophrenia. In my project, I capitalize on the powerful forward and reverse genetic approaches available in the model system Caenorhabditis elegans and a novel DA and DAT-dependent behavioral phenotype to evaluate structural determinants of DAT that guide its trafficking to synapses and to identify and characterize regulators of DAT trafficking and function in vivo.

My primary research focus is on receptor and signaling pathways that regulate the expression and activity of the serotonin transporter (SERT). Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter involved in controlling mood. Alterations in 5-HT neurotransmission are linked to neuropsychological disorders, such as depression. Extracellular levels of 5-HT are tightly controlled by the antidepressant-sensitive SERT. Pro-inflammatory cytokines, released in response to immune challenge and activation of the stress axis, can increase SERT activity and have been shown to generate depressive-like effects on behavior. Using genetic, biochemical, and behavioral approaches, I am using rodent models to investigate the role of IL1R/p38 MAPK signaling pathways in modulating SERT across the lifespan and in relation to autism and mood disorders. Editor's Note: Nicole is also a prolific writer, winning the nonfiction category in the 2011 House Organ writing competition and was the first Guest Writer for Scientific American's The Scicurious Brain Blog.

The high-affinity choline transporter (CHT) supplies the immediate precursor for acetylcholine (ACh) synthesis in cholinergic nerve terminals. Although ACh synthesis has been known for decades to rely on high-affinity choline uptake, only recently have we appreciated the fact that CHT is primarily localized to a pool of intracellular synaptic vesicles, providing a physical basis for excitation-driven elevations in choline uptake. We are using novel transgenic models, synaptosome preparations, and transfected cells to examine the molecular mechanisms that can regulate high-affinity choline uptake either by altering membrane trafficking of CHT or by changing transporter intrinsic activity. We believe that the elucidation of CHT regulatory mechanisms is of broader significance, both for the coordination of release and reuptake of other neurotransmitters and for a deeper understanding of mechanisms impacting risk for cognitive disorders.

Presynaptic neurotransmitter transporters play important roles in terminating the transmission and recycling of neurotransmitters. Perturbing neurotransmitter transporters by manipulating genes or administering drugs significantly alters neural activity. In many psychiatric disorders, neurotransmitter transporters can be altered and may contribute to the symptom of these disorders. My research involves the use of electrophysiological methods in combination with fluorescence imaging to assess the functional roles of neurotransmitter transporters on neural activity in brain slice and neuromuscular junction preparations.

Serotonin transporter (SERT) regulates serotonin levels both in the brain and in the periphery. The expression, function and trafficking of SERT are known to be regulated by a number of SERT-associated proteins, such as PKC, PP2A, Hic-5, and integrin. By using proteomic and biochemical approaches, I am working to identify novel members of the SERT protein complex and understand the mechanism by which SERT is regulated. Through these efforts we also hope the findings can be used to identify serotonin regulatory genes that explain SERT-associated phenotypes associated with genetic variation in mouse and man as well as in mental illness.