CCB Seed Grant

2024 – Current

Project Title:
From behavior to epigenomics – a translational approach to characterize compulsive behavior and neurodegeneration in AUD across species

Abstract:
Alcohol use disorder (AUD) is a chronic, relapsing disorder characterized by compulsive alcohol use. While treatments for AUD exist, their effectiveness are limited by the heterogeneity of the AUD phenotype. Additionally, forward translation of promising treatments for AUD in animal models have yielded limited success in human populations. To address this problem, the Addictions Neuroclinical Assessment (ANA) was developed as a clinical framework that aims to understand the etiology and heterogeneity of AUD through three neurofunctional domains based on the three stages of addiction: incentive salience, negative emotionality, and executive function. Reverse-translating this framework to animal models provide an opportunity to apply in vivo approaches to study the neurobiology of AUD and identify novel treatment targets.

To further bridge the translational gap between species, we aim to identify and compare markers of DNA methylation associated with alcohol use in rats and humans. Chronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations leading to neurodegeneration aggravating the harm from addiction. Recent data show that alcohol has effects on the epigenome via DNA methylation such as methylation of cytosine nucleotides in the context of phosphate guanine (CpG) dinucleotides can show a dynamic pattern that correlates with alcohol use. In human and in rats, alcohol intoxication can lead to inflammation, oxidative stress, and apoptosis in various tissues. By identifying common biological systems that are dysregulated through DNA methylation across species, we seek to identify potential novel targets for the treatment of AUD.

Using a comprehensive deep phenotyping assessment battery, we have collected data pertaining to the three ANA domains in a sample of 454 individuals across the alcohol use spectrum (69.7% with AUD). Preliminary analyses have validated these neurofunctional domains using factor analyses, and they show sensitivity to AUD status and various risk factors of AUD. We aim to apply this framework to a rat model of alcohol dependence, using established behavioral tasks to elucidate behavioral correlates of DNA methylation induced by chronic alcohol consumption.

2022 – Current

Project Title:
Transcriptional and functional characterization of interneuron subpopulations within macaque hippocampus and prefrontal cortex

Abstract:
Compulsive behaviors, including drug-seeking, can be broadly viewed as disorders of cognitive flexibility. Multiple brain regions are involved in compulsive drug-seeking, including the prefrontal cortex (PFC) and hippocampus (HPC). Notably, frontal cortex is particularly enlarged in the primate neocortex relative to other mammalian species2,3, suggesting to fully understand this behavior, it is necessary to expand beyond rodent models. Within the PFC, the ventromedial PFC (vmPFC, Brodmann Areas 25, 32) is ancestrally related to HPC4, while the granular dorsolateral PFC (dlPFC, Brodmann Area 46) has no rodent homologue5, representing a primate-specific innovation. This proposal will combine novel transcriptomic and viral tools in non-human primates (rhesus macaques) to characterize electrophysiologic and transcriptomic differences in distinct neuronal subpopulations within the anterior HPC, vmPFC, and dlPFC. Inhibitory interneurons coordinate rhythmic activity within and across brain regions. This proposal focuses on two populations, together comprising ~70% of neocortical interneurons: parvalbumin-(PV) and somatostatin-expressing (SST) cells6. In addition to critically regulating excitatory: inhibitory (E:I) balance in cortical microcircuits7,8, PV/SST cells within the PFC have robust control over reversal learning9-11, and within the HPC are suppressed by opioids12-14. The McBain lab has identified regional differences in the opioid-mediated suppression of PV/SST inhibition between HPC and cortical regions in rodents, macaques, and humans. There are also differences in opioid receptor expression in these cell populations across cortical regions in mice15-17. This proposal will build on these findings by exploring the vmPFC/dlPFC relative to anterior HPC and augment the electrophysiological experiments of the McBain Lab with novel transcriptomic tools available through the expertise of the Hope lab. Our overarching hypothesis is that PV and SST neurons have region-specific transcriptional and functional programs in the primate that give rise to differential microcircuit motifs and inhibitory control.

2022 – Current

Project Title:
A neural circuit selective for fast drug reward

Abstract:
The faster an addictive drug enters the brain, the greater its rewarding effects1. Yet we lack basic knowledge about which circuits are sensitive to the speed at which a drug enters the brain. The current project proposes to expand on previously collected data from a human clinical trial addressing this question. In a recent study, we used simultaneous PET-fMRI imaging to triangulate dynamic changes in brain dopamine signaling, functional brain activity/connectivity, and the self-reported experience of ‘high’ in 20 healthy adults receiving methylphenidate (MP) at different speeds: slow (oral 60mg) and fast (IV 0.25mg/kg) doses in a double-blind, counterbalanced, placebocontrolled study. We identified one circuit comprising the dorsal anterior cingulate cortex and its connections with the dorsal striatum, which was activated and responded only to fast (IV) MP. Activity in this circuit also activity significantly correlated with striatal dopamine dynamics (estimated with PET) and individual differences in ‘high’ ratings. While compelling, these imaging findings are limited in scope and correlational. We aim to build on this study via two components: Aim 1: Examine the contribution of adrenaline and noradrenaline to slow and fast drug reward. We will analyze blood data collected during the human study to see if this circuit’s activity/connectivity correlates with plasma levels of adrenaline and noradrenaline. MP also increases brain concentrations of these two signaling molecules2,3 and it is important to test whether noradrenaline contributes to this circuit’s involvement in fast drug reward. Aim 2: Test causality of the circuit for fast dopamine dynamics. We will perform a series of experiments in rats. We will use chemogenetic techniques to test if inhibiting this circuit during fast MP delivery can block conditioned place preference to IV MP. This study will provide causal evidence for a circuit selective for fast drug reward.

2021 – 2022

Project Title:
Establishing a mouse of alcohol drinking during conflict

Abstract:
Impaired decision-making is often reported in Alcohol Used Disorder (AUD) and obesity-related disorders, with many patients reporting difficulty managing the intention to limit their drinking/eating despite facing negative health consequences (e.g., driving under the influence arrests and social repercussions). However, the mechanisms by which alcohol impacts decision-making during conflict remains unclear. Furthermore, highly palliative foods and alcohol have intersecting neurobiological mechanisms and behavioral effects, including shared neurological reward pathways and compulsive reward-seeking behavior, respectively. Thus, developing and establishing an animal model to study conflict resolution in the context of alcohol-drinking following dietary exposure to high-fat diets (HFD) would allow us to characterize how alcohol affects behavioral strategies for resolving approach-avoidance conflict and how HFDs interact with alcohol to impact decision-making processes. Establishing this model will be an important first step towards identifying novel mechanisms by which alcohol and a HFD affects decision-making.

Previous models to examine the effects of alcohol on approach-avoidance behavior limit rodents to a dichotomy between approaching both a reward and an aversive stimulus or avoiding a reward and an aversive stimulus. To this end, we propose assessing conflict resolution in approach-avoidance conflict in a task that allows rodents to both, seek rewards, and avoid aversive outcomes within a given trial. Thus, we have worked together to establish a platform-mediated avoidance (PMA) to assess approach avoidance conflict resolution. Our results reveal that mice can adapt their behavior to changes in reward and punishment contingencies to maximize rewards while minimizing punishments. Our data support the utility of the PMA task in assessing short-and long-term strategies in the resolution of motivational conflict in mice. Thus, this task more comprehensively captures the complexities of decision-making, beyond dichotomous choice models, allowing animals to uniquely strategize their decision making during conflict. These complexities more closely capture some elements of human decision-making. Therefore, our main goal is to use this procedure to characterize how alcohol seeking behavior in the presence of threats affects approach-avoidance strategies in mice and examine how a history of HFD feeding affects alcohol drinking behaviors during conflict.