Brain Serotonin: Studies of Neurogenesis, Neurotransmission, and Neurotoxicity
Open Access
- Author:
- Ochroch, Jason Benjamin
- Area of Honors:
- Veterinary and Biomedical Sciences
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Dr. Anne Milasincic Andrews, Ph D, Thesis Supervisor
Dr. Anne Milasincic Andrews, Ph D, Thesis Supervisor
Dr. Lester C Griel Jr., Thesis Honors Advisor - Keywords:
- Serotonin
Neurogenesis
Neurotransmission
Neurotoxicity - Abstract:
- The serotonin neurotransmitter system has been linked to both the onset and treatment of depression. Despite much research in this area, this relationship is still not well understood. Moreover, clinical treatments of depression have much room for improvement. A better understanding of this association would not only shed light on the causes and mechanisms of this debilitating disorder, but also provide models from which future treatments can be generated. Researchers have sought to answer these questions from a variety of angles. This thesis studies the role of the serotonin neurotransmitter system on depression in three ways: (1) A meta-analysis of the effectiveness of bromodeoxyuridine (BrdU) as a marker for hippocampal neurogenesis in aging mice was carried out. Although antidepressants work immediately chemically, there is a clinical ‘lag’ in actual modified behavior. One hypothesis on why antidepressants take so long to work is that they modulate adult neurogenesis, the post-developmental creation of new neurons, within the hippocampus. Hippocampal function is strongly associated with depression as well. Specifically, this project gathers all current data on BrdU (a synthetic nucleoside commonly used in the detection of proliferating cells) and compiles a meta-analysis to elucidate patterns of BrdU labeling and the effects of neurogenesis across murine age, gender, and a variety of other variables. This literature search was also used to supplement another project in this laboratory that investigated the effects of both genetic and environmental factors on neurogenesis. Hopefully, this consolidation of information will help gain further insight into the role of neurogenesis in hippocampal function in depression. Though the majority of data points collected for this meta-analysis represented younger mice, a non-linear decrease in BrdU+ labeled cells across age was identified. The data reveal that neurogenesis (both proliferation and survival rates) declines by an entire order of magnitude during aging, with rates being high in younger mice, but decreasing dramatically as mice enter adulthood. This decrease continues into senescence, but at a much slower rate. Further, this meta-analysis indicates a higher ratio of cells surviving the ‘pruning’ process following proliferation in older mice, although the chance of these cells becoming neurons (indicated in BrdU+/NeuN+ colabeling at 28 day survival) decreases with age. (2) Work was carried out to initiate studies that use zero net flux in vivo microdialysis to investigate changes in extracellular serotonin levels in the hippocampus of SERT deficient mice. On one level, antidepressants work by pharmacologically blocking extracellular reuptake of serotonin by inhibiting the serotonin transporter (SERT). However, genetically reducing the expression of this same protein will not cause these behavioral changes, but may in fact induce increases in anxiety- and depressive-related behaviors. This study seeks to understand how the extracellular environment in the hippocampus is modified by various degrees of pharmacologic and genetic alterations of the SERT protein, with a special focus on serotonin. The hippocampus is highly innervated by the serotonin neurotransmitter system and plays a key role in modulating mood. This project also attempts new analytical methods (zero net flux in vivo microdialysis with HPLC-ED detection) for better detection of serotonin and other related biomolecules. Due to the methodological difficulties of quantifying CNS signaling at detectable limits and time scales pertinent to function, most work to date has been focused on refining the experimental protocols. ‘Method validation’ studies on probe placement, microdialysis conditions, and biomolecule detection and stability are still underway, and the actual project is expected to begin later this year. (3) An analysis of data from studies on 2'-NH2-MPTP in nonhuman primates and its use as a selective serotonergic and noradrenergic neurotoxin was conducted. One way to study the role of serotonin is to eliminate it entirely. Many diseases (i.e., Alzheimer's) are characterized by serotonergic neurodegeneration. This study examines the neurotoxin, 1-methyl-4-(2’-amino-phenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP), which chemically depletes serotonin and norepinephrine axons. Previous studies by this research group have described the mechanism of action of 2'-NH2-MPTP in rodents. In addition to a literature review, here I analyze previously collected data in an attempt to understand the effectiveness of 2'-NH2-MPTP in two species of nonhuman primates. This project sought to disrupt serotonergic and noradrenergic functioning, while leaving other neurotransmitter systems (i.e., dopamine) intact. Never before studied in nonhuman primates, inducing serotonin neurotoxicity in species bearing closer resemblance to humans will help provide models from which serotonin-related pathologies can be studied. Work with African Green monkeys and baboons proved inconclusive. Analysis failed to conclusively show serotonergic- and noradrenergic-selective neurodegeneration, while leaving the dopamine neurotransmitter system untouched. A small sample size, coupled with inherent natural variability of these neurotransmitters and their metabolites within individuals, limited the scope of this study. Moreover, analysis was blind to any biases due to species resistivities of 2'-NH2-MPTP or novel routes of administration (intravenous or intracarotid) to this compound. Altogether, these studies of neurogenesis, neurotransmission, and neurotoxicity provide unique insights into the serotonin neurotransmitter system. It is hoped that a better understanding of this system will yield better insight into the processes behind depression. Ideally, this work will culminate in the development of better treatments (and eventually cures and preventative measures) for this debilitating disorder.