Dong Laboratory Research
Currently, there are four lines of ongoing research:
NMDA receptors in cocaine addiction
Cocaine
addiction is a devastating brain disease that results, at least
in part, from a large number of cocaine-induced maladaptive
changes in the nucleus accumbens (NAc). In theory, correcting
the cocaine-induced NAc adaptations may treat addiction. In
reality, however, no therapeutic design can manipulate such an
overwhelmingly large number2 of substrates simultaneously. One
strategy to circumvent this difficulty is to identify the key
molecules that govern drug-induced adaptations in the NAc;
manipulation of these key molecules may collectively correct
their secondary pathophysiological cellular adaptations. In
attempt to identify such key molecules in NAc, we have focused
on N-methyl-D-aspartate receptors (NMDARs). NMDARs govern
multiple forms of neural adaptive changes and are essential for
a variety of addictive behaviors. Shifting the subunit
composition of NMDARs steers NMDAR-subordinated adaptive neural
changes toward specific directions. However, the exact role of
NMDARs in cocaine addiction remains largely unclear. Our
objective of this project is to understand the role of NAc
NMDARs in cocaine addiction such that an NMDAR-based therapeutic
strategy can be designed to treat addiction. The central
hypothesis is that the cocaine-induced NAc NMDAR adaptation is
gradually and selectively expressed in addiction-associated
synaptic afferents, is mediated by surface expression of new
NMDAR subunits, and triggers secondary cellular changes related
to addiction.
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.
