Drenan, Ryan, PhD

Current Research

Current Research

Dopamine System nAChRs
Tobacco addiction is a serious threat to public health, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in the mesolimbic dopamine (DA) pathway are crucial for the rewarding and reinforcing properties of nicotine in rodent models, suggesting that they may be key mediators of nicotine’s action in humans. We use a variety of approaches to study the specific nAChR subunits and subtypes that mediate cholinergic modulation of DA circuits. A key aspect that we are engaged in is elucidating the identity and function of nAChRs in the various cell types within the midbrain reward system. For example, we use Cre/lox methods to identify dopamine-, glutamate-, and GABA-producing neurons in the ventral tegmental area, allowing us to make targeted electrophysiological recordings, image cellular events, and conduct gene expression analyses. We also employ DREADD technology, optogenetics, 2-photon laser scanning microscopy, uncaging techniques, and behavioral methods. Identifying the nAChRs in this pathway will strengthen our understanding of cholinergic control of reward system transmission, and could lead to novel therapeutic approaches for smoking cessation.

Nicotine Withdrawal Mechanisms
There is a significant unmet need for more effective strategies to treat nicotine dependence. Nicotine exposure produces physical dependence, and the physical and/or emotional nicotine withdrawal symptoms – as compared to the rewarding effects of nicotine – are often the most important contributors to relapse. Unfortunately, a critical gap in knowledge exists regarding our understanding of how chronic nicotine exposure establishes physical dependence and therefore makes smokers highly susceptible to relapse. In this project, we use mouse models to study the medial habenula (MHB), a small brain area in the epithalamic region that has recently been implicated in nicotine withdrawal, and which expresses extraordinarily high levels of several types of nicotinic acetylcholine receptors (nAChRs). We are identifying the relevant nAChRs and MHB circuits involved in nicotine dependence and withdrawal. This study will help us solve the problem of understanding how cessation of nicotine intake causes the brain to generate aversive physical and emotional withdrawal responses that inevitably lead to relapse.

Opto-Pharmacology Approaches to Cholinergic Neurobiology
Pharmacology is a powerful discipline the seeks to understand how drugs and biologics interact withbiological systems such as receptors, cells, networks, and behaving animals. Optical techniques are useful in pharmacology, as light can often be harnessed and delivered to experimental system in ways that overcome certain challenges and allow new insights to be made.
In the Drenan lab, we are employing several advanced optical approaches in our studies of nicotinic acetylcholine receptor neurobiology. We use 2-photon laser scanning microscopy (2PLSM) to image important types of neurons that contribute to nicotine reward and withdrawal. Typically, this is done during simultaneous electrophysiological (patch clamp) recordings.
We also combine 2PLSM with “uncaging” approaches that allow us to precisely interrogate nicotinic receptor function in neurons, with subcellular resolution. We are uncovering new details pertaining to cholinergic biology and nicotine addiction with these new tools and approaches. In collaboration with Dr. Luke Lavis (JaneliaFarms HHMI), we are characterizing photoactivatable nicotine molecules during imaging/recording. These probes can be "uncaged" with 405 nm light from epi-illumination sources, or lasers.

Information

Name

Drenan, Ryan, PhD

Title

Associate Professor

Email

drenan@northwestern.edu

Department

Pharmacology

Office

Searle 5-562

Website

http://labs.feinberg.northwestern.edu/drenan/

Areas of Research

Cell Biology, Circuits and Behavior, Electrophysiology, Imaging & Microscopy, Learning & Memory, Mechanisms of Drug Action, Molecular Neuroscience

Training Grants

Neurobiology of Information Storage Training Program (NISTP)