Browsing by Subject "memory"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Modulation of Adult Neurogenesis in Opioid Addiction
    (2016-05) ZHANG, YUE
    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.
  • Thumbnail Image
    Item
    The Royal Road to Semantic Cognition: Untangling Semantic Components in Temporal Lobe
    (2015-06) Hoversten, Shane
    Functional magnetic resonance imaging (fMRI) research into semantic cognition has returned highly variable results, especially in anterior temporal regions. One likely reason for this variability is that tasks used to investigate this topic are believed to engage only shallow semantic processing. Another reason is that certain classes of stimuli (particularly abstract words) are often confounded by un-modeled social or emotional content; many researchers believe that it is this social and emotional information, rather than general semantic information per se, that elicits response in ATL. Our experiments use a task designed to elicit deep semantic processing (the triads task) along with explicit investigation into the social and emotional content of semantic stimuli to try to pry these factors apart and characterize the temporal lobes in general, and the ATLs in particular, with regard to their involvement in semantic cognition. We find that, contrary to some reports, the ATL is highly involved in semantic processing even in its most anterior aspects; that counter to prominent theories this involvement is not (or is not always) due to the inclusion of social or emotional content in the stimuli; and that a semantic task that engages deep semantic processing has an activation signature that closely resembles the signature of full-sentence processing, despite the seeming un-structured nature of the processing required by the triads task. We propose a general role for ATL as semantic integrator to characterize these disparate findings.