Research projectsShow/Hide content

Neuronal and molecular mechanisms of compulsive drug use 

The purpose of the current neuroscience research is to understand the molecular mechanisms that promote transition to drug addiction, with a main focus on alcohol use disorders.

Photo credit Anna NilsenIn humans, only a subset of alcohol users (~15%) will develop alcohol-related problems. We use animal models to study the individual variabilities and identify the subpopulation of animals that show features of alcohol addiction including excessive drinking and drinking despite negative consequences. Using chemogenetics, in situ hybridization and gene expression analysis, we have found PKC-delta GABA-ergic neurons of the Central Nucleus of Amygdala (CeA) promote compulsive alcohol use in a vulnerable subset group of rats. Using a PKC-delta rat Cre rat line we now investigate the neurocircuitry and downstream signaling triggered by the manipulation of these neurons. Understanding the neuronal features that contribute in individual differences in alcohol use despite adverse consequences will facilitate the development of effective treatments in alcohol use disorders.

Neural circuits underlying decision-making in alcohol addiction

Using a model of compulsive alcohol self-administration model in rats, we have found that a subpopulation of animals continues to self-administer despite an aversive consequence.

Photo credit Anna NilsenNeurons of the orbitofrontal cortex (OFC) and central amygdala are highly activated during this behavior. The OFC projects to multiple regions involved in motivation and emotion, including several nuclei of the amygdala and the striatum, as well as the periaqueductal gray. Through its interactions with these structures, the OFC is believed to be crucial in outcome valuation and goal-directed decision-making. We use transgenetic rats combined, with immunohistochemical analysis and chemogenetics to manipulate specific projections of the OFC. We have found that the main neuronal population in the OFC activated in compulsive drinking was in CaMKII positive neurons which are necessary for Ca2+homeostasis. We are now beginning to use in vivo calcium imaging recordings to functionally validate the potential neural circuit. We aim to elucidate the potential neuronal type specific circuits that contribute to goal-oriented behavior and provide a deep understanding of the neural mechanisms driving excessive responses in alcohol use disorder.

Epigenetic reprogramming as a mechanism in anxiety and alcohol use disorder (AUD).

This project aims to identify long-term neuroadaptations involved in alcohol addiction and anxiety disorders.

Photo credit Anna NilsenWe particularly focus on epigenetic mechanisms as these have emerged as important mechanisms for the translation of environmental stimuli, including drug and stress exposure, into specific changes in gene expression. Enzymes that control these epigenetic modifications are increasingly recognized to mediate behaviors associated with alcohol addiction and anxiety disorders. Using RNA sequencing and Nanostring technology, we have found that a history of alcohol dependence induces persistent changes in genes that encode epigenetic enzymes such as the histone methyltransferase PRDM2. Knockdown of Prdm2 using a viral approach was able to mimic behavioral features of alcohol addiction, suggesting a functional role of PRDM2 in these behaviors. Recently, we found that PRDM2 is also involved in anxiety-like behaviors. Prdm2 KD in the prelimbic cortex enhances expression of fear memory, a hallmark of anxiety disorders. Together, these results suggest that changes in Prdm2 expression may be a common mechanism in alcohol use and anxiety disorders. A better understanding of the shared molecular underpinnings of these conditions may therefore help identify novel therapeutic targets for stress-related psychiatric diseases.