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Study on the roles and changes of synaptic plasticity during fear memory formation and cocaine addiction

Title
Study on the roles and changes of synaptic plasticity during fear memory formation and cocaine addiction
Authors
김주현
Date Issued
2011
Publisher
포항공과대학교
Abstract
Synaptic plasticity is a key cellular mechanism for neurons to respond to an ever-changing internal environment and external stimuli, especially during learning and memory processes. To maintain basal and activity-dependent synaptic plasticity, lots of cell adhesion molecules are involved in the formation and maturation of synapses. Even after complete maturation, the synapses still continuously change their characteristics in response to the dynamically changing external stimulus. Under some persistent external stimuli, neurons show homeostatic synaptic plasticity by adjusting their intrinsic, synaptic, and structural plasticity. This process is quietly different to the input-specific synaptic plasticity and it is called homeostatic neuroadaptation. To figure out a role of synaptic plasticity in learning process and an effects of persistent stimuli on neuronal changes, I have focused on two brain subregions, the amygdala and the nucleus accumbens. The amygdala and the nucleus accumbens are known for the central regions for fear memory formation and drug addiction, respectively. By using fear conditioning paradigm and repeated cocaine treatment, I studied about the functional roles of neuroligin-1 involved in the fear memory formation which occurs in the amygdala, and the cell type-specific alterations of nucleus accumbens neurons induced by repeated cocaine treatment. Neuroligin-1 is a potent trigger for the de novo formation of synaptic connections, and it is recognized as an essential factor for the maturation of functionally competent excitatory synapses. Despite evidence for the role of neuroligin-1 in specifying excitatory synapses, the underlying molecular mechanisms and physiological consequences that neuroligin-1 may have at mature synapses of normal adult animals remain unknown. By silencing endogenous neuroligin-1 acutely in the amygdala of live behaving animals, I have found that neuroligin-1 is required for the storage of associative fear memory. Subsequent cellular physiological studies showed that suppression of neuroligin-1 reduces NMDA receptor-mediated currents and prevents the expression of long-term potentiation without affecting basal synaptic connectivity at the thalamo-amygdala pathway. These results indicate that persistent expression of neuroligin-1 is required for the maintenance of NMDAR-mediated synaptic transmission, which enables normal development of synaptic plasticity and long-term memory in the amygdala of adult animals. In the latter part, I describe repeated cocaine injection-induced cell type-specific intrinsic, synaptic, and structural changes in the nucleus accumbens neurons. The nucleus accumbens (NAc) is a key brain region critically involved in psychostimulant-induced neuroadaptations. A major fraction of NAc neurons is γ-aminobutyric acid (GABA)-ergic medium spiny neurons (MSNs), commonly divided into two major subsets based on their expression of D1 dopamine receptor (D1R-MSNs) or D2 dopamine receptor (D2R-MSNs). Although it is well known that the NAc MSNs undergo extensive alterations in their characteristics upon exposure to drugs of abuse, the functional and structural changes specific to each type of MSNs have not been fully resolved yet. I analyzed cocaine-induced alterations in D1R- and D2R-MSNs by use of transgenic mouse models. I found that D1R-MSNs exhibit decreased membrane excitability but increased frequency of miniature excitatory postsynaptic currents (mEPSCs) after repeated cocaine administration, whereas D2R-MSNs display a decrease in mEPSCs frequency with no change in the excitability. Moreover, miniature inhibitory postsynaptic currents decreased in D1R-MSNs, but unaffected in D2R-MSNs at the same condition. Finally, neuronal processes labeled by a recombinant lentivirus and rabies virus revealed an increase of spine density selectively in D1R-MSNs after chronic cocaine exposure, which was also confirmed by pathway-specific tracing with rabies viral vectors. Collectively, these studies provide experimental evidence of how neuroligin-1 contributes to fear memory formation and how D1R- and D2R-MSNs differentially contribute to the repeated cocaine-induced neuroadaptations by respectively changing their intrinsic, synaptic, and structural characteristics.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000001094469
http://oasis.postech.ac.kr/handle/2014.oak/1193
Article Type
Thesis
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