Silent synapse-based circuit remodeling
The neuroadaptation theory of addiction postulates that, similar to the development of most memories, experiencing drugs of abuse induces adaptive molecular and cellular changes in the brain, some of which underlie the formation of addiction-related memories contributing to addictive behaviors. Compared with "regular" memories, addiction-related memories are extremely durable and long lasting, suggesting the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. Our previous studies have demonstrated that self-administration of cocaine generates a "silent" glutamatergic synapses within the nucleus accumbens (NAc). Silent synapses are synaptic connections in with only stable NMDA receptors, while AMPA receptors are absent or high labile. Our findings suggest these silent synapses are new, immature synaptic connections, reminiscent of what occurs during early development. After their generation, these silent synapses functionally mature through the incorporation of AMPA receptors, and this maturation process critically contributes to the intensification or 'incubation' of cocaine-seeking behaviors. Based on these findings, we hypothesize exposure to cocaine generates new synaptic connections, forming new circuits of informational flow through the brain encoding critical aspects of cocaine-associated memories. Our ongoing studies are aimed at identifying the molecular and cellular substrates governing the processes of silent synapse generation and maturation, and how these processes contribute to the dynamics of cocaine-associated memories and cocaine seeking behavior. In addition, we are also seeking to understand how the formation of these new connections alters circuit function contributing to behavioral output.
Related projects
Our lab has several other ongoing projects related to silent synapse-based circuit remodeling. First, we are conducting studies to investigate silent synapse generation following exposure to opioids. Our recent studies have shown that repeated exposure to morphine also generates silent synapses in the NAc. However, in contrast to cocaine, morphine silences pre-existing synapses, which are subsequently eliminated during withdrawal. Thus, morphine exposure reshapes the NAc circuitry through the removal of pre-existing connections. Our ongoing studies are seeking to identify the mechanisms underlying this synaptic elimination and how this process contributes to morphine seeking behavior. Second, we are conducting studies to determine the role glia play in drug-induced synaptic generation and elimination. Previous studies have demonstrated an important role glia in synapse formation and elimination during brain development. We are seeking to determine if glia contribute to silent synapse generation after drug exposure.
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 previous studies have identified a novel bidirectional synapse-to-membrane and vice versa homeostatic plasticity in the NAc, which we have termed synapse-membrane homeostatic crosstalk (SMHC). This process involves signals from the synapse indicating relative synaptic strength to machinery regulating membrane excitability and vice versa, such that changes in synaptic strength triggers opposing adaptations in excitability (and vice versa) to maintain a relatively consistent neural output. Recently, we have demonstrated that cocaine self-administration leads to a dysregulation of this process, whereby cocaine-induced up regulation of GluN2B-containing NMDA receptors provides a 'false' signal of increase synaptic strength, triggering a first round of SMHC to decrease membrane excitability. This decrease in excitability triggers a second round of SMHC, leading to the up regulation of AMPARs and the incubation of cocaine seeking. Thus, cocaine exposure triggers cascades of homeostatic dysregulation that contributes to the development of addictive behaviors. Our ongoing studies seek to understand the mechanisms and evolution of these dynamic homeostatic processes and how to contribute to addictive behavior.
Inhibitory Interneurons in the nucleus accumbens
The output of neural circuits is largely governed by the balance of excitation and inhibition. One of the main sources of inhibition throughout the brain arises from local inhibitory interneurons. Despite the fundamental role of inhibitory interneurons in normal brain function, the function of interneurons in the NAc remains largely unexplored. Our previous studies have identified a novel type of fast-spiking interneurons (FSIs) in the NAc that express the CB1 receptor, that overlap with he PV expressing FSIs and provide robust feedforward inhibition to medium spiny neurons (MSN). Recent studies from our lab have shown that cocaine self-administration increases the excitatory input to these FSIs in the NAc, strengthening the feedforward inhibitory circuitry in the NAc. Furthermore, this enhancement of the feedforward circuitry facilitates the acquisition of cocaine seeking behaviors. Ongoing studies in the lab are seeking to delineate the mechanisms driving this enhancement of the feedforward circuitry and how such enhancement contributes to addictive behaviors.
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 work is conducted in close collaboration with the Huang lab.
The neuroadaptation theory of addiction postulates that, similar to the development of most memories, experiencing drugs of abuse induces adaptive molecular and cellular changes in the brain, some of which underlie the formation of addiction-related memories contributing to addictive behaviors. Compared with "regular" memories, addiction-related memories are extremely durable and long lasting, suggesting the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. Our previous studies have demonstrated that self-administration of cocaine generates a "silent" glutamatergic synapses within the nucleus accumbens (NAc). Silent synapses are synaptic connections in with only stable NMDA receptors, while AMPA receptors are absent or high labile. Our findings suggest these silent synapses are new, immature synaptic connections, reminiscent of what occurs during early development. After their generation, these silent synapses functionally mature through the incorporation of AMPA receptors, and this maturation process critically contributes to the intensification or 'incubation' of cocaine-seeking behaviors. Based on these findings, we hypothesize exposure to cocaine generates new synaptic connections, forming new circuits of informational flow through the brain encoding critical aspects of cocaine-associated memories. Our ongoing studies are aimed at identifying the molecular and cellular substrates governing the processes of silent synapse generation and maturation, and how these processes contribute to the dynamics of cocaine-associated memories and cocaine seeking behavior. In addition, we are also seeking to understand how the formation of these new connections alters circuit function contributing to behavioral output.
Related projects
Our lab has several other ongoing projects related to silent synapse-based circuit remodeling. First, we are conducting studies to investigate silent synapse generation following exposure to opioids. Our recent studies have shown that repeated exposure to morphine also generates silent synapses in the NAc. However, in contrast to cocaine, morphine silences pre-existing synapses, which are subsequently eliminated during withdrawal. Thus, morphine exposure reshapes the NAc circuitry through the removal of pre-existing connections. Our ongoing studies are seeking to identify the mechanisms underlying this synaptic elimination and how this process contributes to morphine seeking behavior. Second, we are conducting studies to determine the role glia play in drug-induced synaptic generation and elimination. Previous studies have demonstrated an important role glia in synapse formation and elimination during brain development. We are seeking to determine if glia contribute to silent synapse generation after drug exposure.
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 previous studies have identified a novel bidirectional synapse-to-membrane and vice versa homeostatic plasticity in the NAc, which we have termed synapse-membrane homeostatic crosstalk (SMHC). This process involves signals from the synapse indicating relative synaptic strength to machinery regulating membrane excitability and vice versa, such that changes in synaptic strength triggers opposing adaptations in excitability (and vice versa) to maintain a relatively consistent neural output. Recently, we have demonstrated that cocaine self-administration leads to a dysregulation of this process, whereby cocaine-induced up regulation of GluN2B-containing NMDA receptors provides a 'false' signal of increase synaptic strength, triggering a first round of SMHC to decrease membrane excitability. This decrease in excitability triggers a second round of SMHC, leading to the up regulation of AMPARs and the incubation of cocaine seeking. Thus, cocaine exposure triggers cascades of homeostatic dysregulation that contributes to the development of addictive behaviors. Our ongoing studies seek to understand the mechanisms and evolution of these dynamic homeostatic processes and how to contribute to addictive behavior.
Inhibitory Interneurons in the nucleus accumbens
The output of neural circuits is largely governed by the balance of excitation and inhibition. One of the main sources of inhibition throughout the brain arises from local inhibitory interneurons. Despite the fundamental role of inhibitory interneurons in normal brain function, the function of interneurons in the NAc remains largely unexplored. Our previous studies have identified a novel type of fast-spiking interneurons (FSIs) in the NAc that express the CB1 receptor, that overlap with he PV expressing FSIs and provide robust feedforward inhibition to medium spiny neurons (MSN). Recent studies from our lab have shown that cocaine self-administration increases the excitatory input to these FSIs in the NAc, strengthening the feedforward inhibitory circuitry in the NAc. Furthermore, this enhancement of the feedforward circuitry facilitates the acquisition of cocaine seeking behaviors. Ongoing studies in the lab are seeking to delineate the mechanisms driving this enhancement of the feedforward circuitry and how such enhancement contributes to addictive behaviors.
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 work is conducted in close collaboration with the Huang lab.