NMDA receptors in addiction
The neuroadapation theory of addiction suggests that, similar to the development of most memories, experiencing drugs of abuse induces adaptive molecular and cellular changes in the brain, and some of these adaptive changes mediate addiction-related memories, or the addictive state. Compared with “regular” memories, addiction-related memories develop fast and last extremely long, suggesting that the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. We recently demonstrated that repeated exposure to cocaine generated a large portion of “silent” glutamatergic synapses within the nucleus accumbens (NAc). Silent glutamatergic synapses are synaptic connections in which only NMDAR-mediated responses are readily detected whereas AMPARs are absent or highly labile. Extensive experimental evidence suggests that silent synapses are conspicuously efficient plasticity substrates, at which long-lasting plastic changes can be more facilely induced and maintained. Thus, generation of silent synapses can be regarded as a process of metaplasticity, which primes the NAc for subsequent more robust and durable forms of plasticity for addiction-related memories. Focusing on silent synapse-based metaplasticity, we attempt to determine how the key brains regions such as the NAc utilize the metaplasticity mechanism to optimize the plasticity machineries and achieve fast and durable plastic changes following exposure to cocaine. Our hypothesis is that upon cocaine exposure, newly generated silent synapses may prime excitatory synaptic synapses within the NAc for long-term potentiation (LTP), thus setting up the direction of future plasticity for the affected synapses. Furthermore, because cocaine-generated silent synapses are enriched in NMDAR NR2B subunits, the enhanced NR2B-signaling may set up a selective recruitment of certain type of AMPARs to silent synapses. Thus, silent synapse-based metaplasticity may lead to not only quantitative but also qualitative alterations in excitatory synapses within the NAc.
Homeostatic plasticity in the nucleus accumbens
Homeostatic neuroplasticity is a powerful self-correcting mechanism through which neurons undergo plastic cellular changes to functionally compensate for the ‘undesirable’ consequences caused by internal and external interferences. Because of homeostatic plasticity and other homeostatic processes, brain function remains constant during developmental regulation, metabolic turnover, and even serious pathological conditions. Exposure to drugs of abuse causes malfunction of NAc neurons, which underlies a major pathophysiology of addiction. Despite the estimate that an enormous number of drug-induced alterations in the NAc are homeostatic responses, homeostatic neuroplasticity in the NAc remains largely unknown. Our goal is to identify the key homeostatic mechanisms that are involved in drug-induced homeostatic dysregulation of brain function and that can be potentially targeted for repairing drug-distorted neuronal function. We are particularly interested in a form of homeostatic crosstalk between excitatory synaptic inputs and intrinsic membrane excitability in NAc neurons. 3)
Regulation of emotional state by sleep
Sleep profoundly regulates the emotional and motivational state. Sleep disturbance is a key co-morbidity in several pathological emotional states such as drug addiction, depression, and schizophrenia. Indeed, sleep disturbance is not only just a symptomic consequence, but also a key causal factor for the progression/aggravation of these pathological emotions; clinical statistics also shows that people with insomnia are more prone to addiction. Poorly understood are how sleep disturbance regulates the function of key brain regions that control emotion and motivation. We aim to address this glaring knowledge gap by determining the effect of sleep deprivation on the functional output of NAc. This is a new line of research in the lab.
Depression in drug withdrawal
Severe depression often happens in drug addicts when they stop using drugs. This drug Withdrawal-Induced Depression (WID) disrupts motivation, triggers relapse of drug use, promotes suicidal impulsion, and, thus, prevents addicts from returning to normal living. Aimed at developing novel mechanism-based treatment for this urgent medical need, this proposal will analyze neural mechanisms that potentially mediates WID. Furthermore, because WID is primarily attributable to a history of drug use and thus has a relatively clear etiology, studying WID provides a potentially useful and heuristic framework for understand the complicated pathophysiology underlying ‘normal’ depression. A potential molecular pathway for WID has been identified: First, a critical role of the NAc in depression has been recently conceptualized. Second, exposure to drugs of abuse causes long-term molecular changes in the NAc, in particular, activation of the transcription factor cAMP-response element binding protein (CREB). Third, experimentally decreasing the activity of NAc CREB leads to anti-depressant effects in animal models, whereas increasing the activity of NAc CREB induces various depressive effects, such as anhedonia, dysphoria, and reduced motivation. Fourth, among the downstream targets of CREB, the dynorphin-signaling is particularly important in the depressogenic effect of NAc CREB; expression of dynorphin in NAc is temporarily and functionally correlated with CREB activation, and blocking the dynorphin-signaling abolishes the CREB-mediated aversive responses. Thus, this line of research aims to determine the physiological role of CREB in the NAc.