Addiction is a brain disorder where a combination of genetics and environmental influences converge to regulate molecular and cellular networks in the brain to produce maladaptive behaviors like drug use and compulsion. Our center is using cutting edge experimental approaches to understand these biological processes and inform novel therapeutics.
Ongoing Studies
REELIN SIGNALING AND FUNCTION IN COCAINE RESPONSE
(PI: Dr. Jeremy Day; R01DA053743)
Drugs of abuse activate specific cell populations within brain reward circuits, but it is not clear what molecular mechanisms regulate this process or how drug experience can result in long-lasting changes within these cells. This proposal will examine the role of Reelin, a large extracellular protein, in regulation of the molecular and genetic mechanisms that contribute to cellular and behavioral responses to cocaine. This research will contribute fundamental knowledge to our understanding of how brain circuits drive motivated behaviors in the context of substance abuse disorders, and has the potential to identify novel cellular targets for addiction therapeutics.
ENHANCER RNA REGULATION OF EXPERIENCE-DEPENDENT NEUROEPIGENETIC PROCESSES
(PI: Dr. Jeremy Day; R01MH114990)
Enhancer elements in the genome are essential for brain function, and dysregulation of enhancer elements is highly implicated in cognitive disease states such as addictions. This proposal will investigate the role of enhancers activity-regulated neuronal processes and memory formation using cutting-edge tools. This project will deliver new insights into how genomic enhancers regulate individual genes in neuronal systems, which is critical for unraveling transcriptional contributions to brain health and disease as well as the development of more effective therapeutics for cognitive disease states.
A Nociceptin Central Amygdala to Hindbrain Circuit for the Control of Palatable Food Consumption
(PI: Dr. Andrew Hardaway; K01DK115902)
The repeated consumption of energy-dense, palatable food is a major contributor to risk for binge eating disorder, obesity, and obesity-related conditions like type II diabetes, hypertension, and heart failure. In this proposal, we are combining neural circuit, electrophysiological, and behavioral methodologies in laboratory mice to understand how neuropeptidergic neuronal ensembles in the central amygdala, the primary output nucleus of the brain’s emotional center, control the consumption of palatable food. These studies hope to inform novel brain substrate-specific therapies for individuals with obesity and binge eating disorder.
Link to abstract in NIH ReporterLearn more about Andrew Hardaway
The Role of the Dopamine Transporter in Psychostimulant Abuse
(PIs: Dr. Aurelio Galli; Dr. Heinrich Matthies; R01DA038058)
The abuse potential and psychomotor stimulant properties of amphetamines (AMPH) have been associated with their ability to cause mobilization of cytoplasmic dopamine (DA), leading to an increase in extracellular DA levels. This increase is mediated, at least in part, by the reversal of the DA transporter (DAT) function, which causes non-vesicular DA release, here defined as DA efflux. This efflux is thought to be important for the psychomotor stimulant and addictive properties of AMPHs, a notion supported by evidence demonstrating that specific inhibition of DA efflux impairs the ability of AMPH to cause locomotor behaviors. To date, no pharmacotherapies for the treatment of AMPH abuse are available. Therefore, it is essential to understand:
- the molecular mechanisms targeted by AMPH to promote DA efflux;
- whether DA efflux disrupts DA functions in brain, and whether these disruptions support AMPH-induced behaviors (i.e. preference); and
- how we can target these mechanisms to impair DA efflux to regulate AMPH behaviors.
The goal of this research is to offer new molecular targets for the treatment of AMPH use disorder and associated behaviors.
Link to abstract in NIH ReporterLearn more about Aurelio Galli Learn more about Heinrich Matthies
TARGETING TIAM1-MEDIATED SYNAPTIC PLASTICITY FOR THE RELIEF OF OPIOID TOLERANCE
(PI: Dr. Lingyong Li; R01DA056673)
The major objective of this proposal is to identify Tiam1-mediated synaptic plasticity as the molecular mechanism underlying opioid tolerance and validate Tiam1 as a promising therapeutic target in the relief of tolerance. Opioid pain medications remain the gold standard for the treatment of moderate to severe perioperative and chronic pain. However, over time, opioid use can result in tolerance, which is a primary driver for opioid misuse and overdose that directly contribute to increased morbidity and mortality. Opioid action at µ opioid receptors (MORs) expressed by nociceptors not only acutely depresses nociceptive transmission, but can induce glutamate release and brain-derived neurotrophic factor (BDNF) release in the spinal dorsal horn, which initiate downstream events that trigger the molecular, synaptic, and network-level adaptations that drive tolerance. Among these, synaptic plasticity is assumed to be the key determinant in opioid tolerance. However, the molecular mechanisms that trigger synaptic plasticity remain unclear. The contribution of this proposed research is significant because it will uncover a previously unknown mechanism that underlies opioid tolerance and will provide a promising therapeutic target for the long-lasting relief of opioid tolerance.
Link to abstract in NIH ReporterLearn more about Lingyong Li