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Lin Lu

Lin Lu

 

Email: linlu(at)bjmu(dot)edu(dot)cn;

Telephone: +86-10-8280-2459 (office);

Lab Homepage: http://jichu.bjmu.edu.cn/teacher/ShowArticle.asp?ArticleID=48

 

Research Area:

 

1. Neurobiological mechanisms of drug caving and relapse prevention
High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Cue-induced drug craving in addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the past several years, we have investigated the phenomenon and underlying neurobiological mechanisms of the time-dependent increase of cue-induced drug craving (i.e., incubation of drug craving) in both rats and humans dependent on cocaine, heroin, and methamphetamine. Although much has been discovered about the neurobiology of the incubation of drug craving, many questions remain unanswered. In the future, we will continue to explore the brain regions, molecular mechanisms, synaptic plasticity, and genetic factors involved in the incubation of drug craving in animals and humans.
Additionally, relapse is often associated with stress exposure that can provoke a state of drug craving that can also be demonstrated under controlled laboratory conditions. To determine the effect of environment-gene interactions on drug craving, we will seek to identify the clinical (e.g., subjective and behavioral measures), biological (e.g., endocrine measures), and neural (e.g., brain atrophy) factors that predict relapse risk and focus on determining the biological markers of relapse risk that may be used to identify individuals who are at the highest risk of relapse. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae to significantly improve relapse outcomes.

 

2. Neurobiological mechanisms of drug-associated memories
Despite years of abstinence from drugs, relapse can occur when addicts encounter cues, including people or places, associated with prior drug use. The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or drug withdrawal-associated aversive feelings have been suggested to contribute to the high rate of relapse among addicts. Initially, drug-associated memories undergo memory consolidation after being paired with cocaine exposure. During abstinence, memory retrieval returns this memory to a labile, sensitive state, during which it can be modified, changed, or even erased. Our research focuses on the neurobiological mechanisms of drug-associated memories. Using molecular pharmacological, molecular biological, optogenetic, electrophysiological, and behavioral techniques, we attempt to answer the following scientific questions: (1) How are drug-associated memories consolidated, reconsolidated, retrieved, and maintained after learning? (2) Do differences exist between different types of drug-associated memories, such as differences between cocaine- and heroin- cue memories? (3) Why are drug-associated memories so intense and persistent? (4) Do differences exist between natural reward memories and drug-associated memories? We are also exploring a behavioral paradigm to erase drug-associated memories without affecting natural reward memories, based on the theories of memory reconsolidation and extinction, and we have obtained some important results in this field. We are also developing a novel procedure to impair the persistence of several cue-drug associations concurrently.

3. Unconditioned stimulus retrieval-extinction procedure as an effective, drug-free paradigm for the persistent erasure of fear memory
Our research in this area will focus on mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. Extinction applied during the reconsolidation phase when fear memory is destabilized updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. Previous studies have shown that exposure to the conditioned stimulus (CS) initiates the CS-specific reconsolidation of learned fear. During the reconsolidation window, the learned fear memory can be updated with extinction training. However, the procedure is specific to the reactivated memories. Various CSs may be associated with an aversive event. Therefore, we expect to introduce a technique to target all of the CSs associated with the fear memory. Important work in this area has been performed by our team. We found that presentation of a lower intensity unconditioned stimulus (US) alone rendered all CS associations with the US susceptible to disruption by extinction conducted during reconsolidation in both rats and humans. These findings suggest that the modified extinction strategy may lead to new therapeutic approaches for anxiety disorders. However, the neural mechanisms that underlie the adaptive reconsolidation of conditioned fear are less well known. Moreover, one of the CSs extinguished during reconsolidation can disrupt the fear response to all of the CSs, and the disruption of reconsolida¬tion was specific to the activated US. In future studies, we will use human functional magnetic resonance imaging (fMRI) to investigate activity in brain systems linked to conditioned fear and extinction. Resting fMRI will be used to assess functional connectivity alterations associated with US retrieval and extinction. Additionally, we will explore the molecular mechanisms that underlie this behavior paradigm based on reconsolidation updating. We will analyze synaptic membrane fractions, including membrane-bound proteins and associated proteins.

4. Hippocampal neuronal activity and depression
The complex electrical signals produced by neurons in the central nervous system mediate mood and behavioral performance. Abnormalities in structure and function, such as neuronal atrophy and morphological deficits, play a key role in the etiology and development of depression, but the neural pathways and specific types of neurons that fire in the hippocampus are obscure. Our research will focus on hippocampal neuronal activity and neuroadaptation-related signaling pathways in the development of depression to (1) investigate whether excitation or inhibition of hippocampal neuronal activity is associated with depressive-like behavior and clarify the effect of specific types of neuronal activity in the hippocampus on depression, (2) examine behavioral consequences with optogenetic drive “burst” patterns of hippocampal firing and analyze hippocampal synaptic structure and function that underlies optogenetic stimulation, (3) explore the effect of chronic stress and optogenetic stimulation on the firing patterns of hippocampal neurons to confirm the alterations in excitatory postsynaptic potential in the hippocampus in depression, and (4) clarify the contributions of receptors, downstream kinase systems, and molecular signaling pathways in the hippocampus to the development of depression. Neuronal activity is an important factor in the encoding and regulation of central nervous system function and is closely related to behavioral performance. Further investigations of specific brain functional activity will provide new targets for the treatment of depression.


 

Selected Publications:

1. Xue YX, Luo YX, Wu P, Shi HS, Xue LF, Chen C, Zhu WL, Ding ZB, Bao YP, Shi J, Epstein DH, Shaham Y, Lu L. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science. 2012 Apr 13; 336(6078):241-5.
2. Zhang XL, Shi J, Zhao LY, Sun LL, Wang J, Wang GB, Epstein DH, Lu L. .Effects of Stress on Decision-Making Deficits in Formerly Heroin-Dependent Patients After Different Durations of Abstinence. Am J Psychiatry. 2011 Jun; 168(6):610-6.
3. Li YQ, Xue YX, He YY, Li FQ, Xue LF, Xu CM, Sacktor TC, Shaham Y, Lu L. Inhibition of PKM in nucleus accumbens core abolishes long-term drug reward memory. J Neurosci, 2011,
4. Li FQ, Xue YX, Wang JS, Fang Q, Li YQ, Zhu WL, He YY, Liu JF, Xue LF, Shaham Y, Lu L. Basolateral amygdala cdk5 activity mediates consolidation and reconsolidation of memories for cocaine cues. J Neurosci, 2010, 30:10351-10359.
5. Wang X, Luo YX, He YY, Li FQ, Shi HS, Xue LF, Xue YX, Lu L. Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J Neurosci. 2010 Sep 22;30(38):12632-41
6. Li SX, Shi J, Epstein DH, Wang X, Zhang XL, Bao YP, Zhang D, Zhang XY, Kosten TR, Lu L. Circadian Alteration in Neurobiology During 30 Days of Abstinence in Heroin Users. Biol Psychiatry. 2009; 65(10):905-12
7. Wang XY, Zhao M, Ghitza UE, Li YQ, Lu L. Stress impairs reconsolidation of drug memory via glucocorticoid receptors in the basolateral amygdala. J Neurosci, 2008, 28:5602-5610.
8. Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci. 2005, 8:212-219.

 

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