Modulation of Adult Neurogenesis in Opioid Addiction
2016-05
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Modulation of Adult Neurogenesis in Opioid Addiction
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2016-05
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One of the major problems in treatment of opioid addiction is the repeated reuse and long-term memory of the drug-experience even after prolonged periods of abstinence. During the past decades, there has been enormous expansion in our understanding of how opioid drugs act on the nervous system. A complex brain network including the mesolimbic dopamine system, ventral striatum, extended amygdala, prefrontal cortex and hippocampus is suggested to be associated with the addiction cycle, in particular, the adult neurogenesis taken place in the dentate gyrus (DG) of the hippocampus has a functional implication in opioid addiction. It is intriguing to study the convergence between the modulation of adult neurogenesis and opioid addiction, since the adult-born granule cells were shown to play a role in neuroplasticity of hippocampus function and in the development and retention of drug-contextual memory. In the first part of my study, I attempted to define the temporal window of morphine’s inhibitory effect on adult neurogenesis with a transgenic mouse model. Four days of conditioned place preference (CPP) training with morphine significantly reduced the number of late stage progenitors and immature neurons in the sub-granular zone (SGZ) of mouse hippocampus but did not affect the number of early progenitor cells. The results from colocalization of cell-type selective markers suggested that under the condition of CPP training, morphine affects the transition of neural progenitor/stem cells differentiate into immature neurons. When the transcription factor neural differentiation1 (NeuroD1) was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. Next, a synthetic small molecule KHS101 which was reported to increase NeuroD1 mRNA in cultured neural progenitors and induce neuronal differentiation in the DG of hippocampus, was utilized to mimic the effect of lentivirus-mediated NeuroD1 overexpression on morphine-primed CPP. The results indicated that subcutaneous injection of KHS101 before conditional training could enhance the retention of drug-related memory and prolong CPP extinction; while the same treatment after conditional training disrupted the drug-contextual associations and shortened CPP extinction. Such KHS101’s effect paralleled that observed when the over-expression of NeuroD1 was temporally controlled with an inducible tetracycline system. Furthermore, the KHS101’s effect could be abolished by the stereotaxic injected NeuroD1 shRNA lentivirus. These studies suggest that morphine decrease the total numbers of newborn neurons in the SGZ by interfering with neural progenitors’ differentiation via a mechanism involving NeuroD1. Since adult neurogenesis serves as an important form of neural plasticity, we assume that certain immature neurons contribute to the formation and consolidation of drug-contextual association memory, and NeuroD1 plays a key role during this process. Such assumption is supported by the observation that compounds such as KHS101 that could regulate NeuroD1 expression in the hippocampus possess the ability to manipulate the extinction of drug contextual memory. In conclusion, the regulation of NeuroD1 activity leads to modulation of adult neurogenesis, thus affecting the drug-association memory.
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University of Minnesota Ph.D. dissertation. 2016. Major: Pharmacology. Advisor: PINGYEE LAW. 1 computer file (PDF); 145 pages.
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