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Novel Targeting of Adult Brain Serotonin Reveals New Roles in Behavior

Whitney, Meredith Sorenson, Deneris
http://rave.ohiolink.edu/etdc/view?acc_num=case1473440530837021

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders, including major depression, post-traumatic stress disorder, generalized anxiety disorder, obsessive compulsive disorder, and suicide. Yet, after more than six decades of study, its role in behavior remains poorly understood, in part, because of a lack of techniques to specifically target 5-HT synthesis in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the effect of deficient brain 5-HT synthesis on behavior and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Additionally, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal ~2-hour break in nocturnal activity (siesta), a period of REM and NREM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas and implicate it in the regulation of sleep-wake homeostasis. Preliminary results from other testing suggests that adult 5-HT may also be involved in regulating immune gene expression in the brain, peripheral metabolic homeostasis, CNS norepinephrine levels, and autonomic functions. In addition to demonstrating a specific role for adult 5-HT in controlling locomotor activity, daily circadian patterns, and siestas, our results highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT’s role in behavior.
Evan Deneris, Ph.D. (Advisor)
Jerry Silver, Ph.D. (Committee Chair)
Gemma Casadesus, Ph.D. (Committee Member)
Edward Gilmore, M.D.,Ph.D. (Committee Member)
Daniel Wesson, Ph.D. (Committee Member)
151 p.
Behavioral Sciences; Neurobiology; Neurosciences
circadian behavior; hyperactivity; serotonin; tryptophan hydroxylase; siesta

Recommended Citations

Citations

  • Whitney, Deneris, M. S. (2017). Novel Targeting of Adult Brain Serotonin Reveals New Roles in Behavior [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1473440530837021

    APA Style (7th edition)

  • Whitney, Deneris, Meredith. Novel Targeting of Adult Brain Serotonin Reveals New Roles in Behavior. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1473440530837021.

    MLA Style (8th edition)

  • Whitney, Deneris, Meredith. "Novel Targeting of Adult Brain Serotonin Reveals New Roles in Behavior." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1473440530837021

    Chicago Manual of Style (17th edition)

case1473440530837021
419
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.