The Neurobiology of Addiction and Addiction-related Behaviors

Our laboratory is interested in elucidating the brain areas, circuits, and molecular mechanisms underlying addiction and addiction-related behaviors.  Toward this goal, we use a multidisciplinary approach that includes optogenetic, biophysical, molecular, and behavioral tools that, to date, have helped uncover novel molecular mechanisms underlying the rewarding properties of nicotine and alcohol, identified brain areas, circuits, and molecular components critical for nicotine withdrawal symptoms, and elucidated circuit-based mechanisms that determine novelty preference, a behavioral trait often associated with addiction. We anticipate that our continuing work will lead to new therapeutic strategies to alleviate addiction.

The Habenulo-Interpeduncular axis in nicotine dependence.

Much of our recent work has focused on two understudied and interconnected brain areas, the medial habenula (MHb) and the interpeduncular nucleus (IPN).  The MHb is an epithalamic brain region consisting of substance P expressing neurons on the dorsal side and a dense cluster of cholinergic neurons that can also co-release glutamate on the ventral side.  Bundles of MHb neuron axons, together forming the fasciculus retroflexus (FR), project almost exclusively to the IPN which sits deep within the midbrain ventral and medial to the ventral tegmental area (VTA), the hub of the brain’s “reward” circuitry.  Our lab has discovered that, during nicotine withdrawal, discreet sub-regions of the IPN become activated triggering not only physical symptoms but also increased anxiety during withdrawal, in part, through increased excitatory input from the MHb.  In addition, we have determined that a sub-set of neurons within the VTA project to and innervate the IPN indicating cross-talk between reward- and withdrawal-associated brain areas. Currently, we are characterizing how the VTA and IPN interact and how other IPN-connected brain regions may also control nicotine withdrawal symptoms.

The Interpeduncular Nucleus in addiction-related behaviors.

There has been great interest in identifying behavioral/personality traits that may predispose one to addiction. A common trait associated with addiction by epidemiological studies is an increased response to or preference for novel stimuli (i.e. sensation seeking).  In rodent models, rodents with a high novelty preference (NP), defined as more time spent interacting with novel compared to familiar stimuli when given a choice, will work harder to obtain a drug compared to rodents with low NP. We have recently discovered that the IPN is a major node for controlling NP.  We found that IPN inhibitory GABAergic neurons become increasingly activated when we expose mice to the same stimuli multiple times; that is, activation of GABAergic neurons increase as novel stimuli became familiar.  Using optogenetics, we found that we could control an animals’ exploratory activity or interest towards novel or familiar stimuli by activating or silencing GABAergic IPN neurons, which either decreased exploration of novel stimuli or increase exploration of familiar stimuli, respectively.  Thus, activation of IPN GABAergic neurons acts as a brake that reduces exploratory activity towards novel stimuli with repeated exposures.  We went on to map two inputs to the IPN that determine, in part, NP:  MHb excitatory IPN afferents were necessary and sufficient to activate IPN GABAergic neurons during familiarity encounters, while activation of IPN afferents from VTA DAergic neurons could inhibit overall GABAergic activity of the IPN and increase interaction with familiar stimuli during NP.  We are continuing to map the circuitry implicated in controlling the preference for novelty which should yield insights into novel mechanisms that may predict vulnerability to addiction.