Rich, Matthew / T.
(2018)
Investigating a Novel Thalamo-Amygdala Circuit for the Regulation of a Drug-Cue-Specific Memory.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Addiction is a chronic, progressive disorder caused by repetitive drug use, which leads to long-lasting synaptic alterations in the brain. Drugs of abuse are powerful reinforcers that ‘hijack’ specific brain circuits that control reward-motivated behaviors, creating a maladaptive state that can trigger craving and relapse, even after prolonged periods of abstinence. Environmental contexts and cues that are present during drug use can later evoke drug-related memories that promote drug-seeking conditioned responses. Despite recent attempts to treat addiction with a combination of behavioral and pharmacological tools, success has been limited, mainly because the underlying mechanisms that govern drug-associated memories have not been fully elucidated. Studying the neural circuits and the synaptic and molecular underpinnings of drug-associated memories may uncover a means to reduce their salience, thereby reducing the likelihood of relapse.
The amygdala is important for integrating sensory information during cue-dependent learning and is activated by both fear- and drug-related stimuli. Preclinical models have shown that the amygdala activates behavioral responses to fear- or drug-conditioned cues. Neuroadaptations within amygdala-based circuits have been examined in models of aversive learning but have not been well studied during reward-based learning, especially in the context of drugs of abuse. The work presented in this dissertation focuses on understanding the circuit-specific synaptic and molecular changes that occur within the amygdala both during the formation of a drug-cue memory and upon subsequent re-exposure to drug-related cues. Through a combination of electrophysiological, molecular, optogenetic, and behavioral techniques we find that repeated self-administration of cocaine, paired with an audiovisual cue, involves strengthening of auditory thalamic, but not cortical, synapses in the lateral amygdala. We also find that reversing drug-cue induced plasticity in this pathway, either through extensive cue re-exposure or by optical induction of postsynaptic LTD, inhibits cue-elicited relapse-like behavior. Finally, we show that specific pharmacological manipulations of an intracellular signaling pathway involved in bidirectional regulation of synaptic activity can interfere with reconsolidation and promote extinction of a drug-cue memory. Together, these studies suggest a projection-specific mechanistic approach for the inhibition of drug-cue memory, which may be informative for future pharmacobehavioral relapse prevention strategies.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
3 August 2018 |
| Date Type: |
Publication |
| Defense Date: |
19 June 2018 |
| Approval Date: |
3 August 2018 |
| Submission Date: |
31 July 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
229 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cue extinction, amygdala, drug-associated memory, reconsolidation, cocaine, cue-induced reinstatement |
| Date Deposited: |
03 Aug 2018 15:12 |
| Last Modified: |
03 Aug 2018 15:12 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/34944 |
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