Research
The Green Lab studies complex psychiatric conditions — addiction, depression, and anxiety — that arise from interactions between genes and the environment. Using preclinical rodent models, we investigate the molecular mechanisms underlying protective and susceptible phenotypes with the goal of identifying novel therapeutic targets.
Research Pillar 1
Frustration in Neuropsychiatric Conditions
A fourth factor in substance use disorders
People with substance use disorders show heightened susceptibility to frustration — the emotional response when expected rewards are not received. We pioneered a method to measure frustration state in real time during operant responding for drug or non-drug reinforcers in rats, allowing assessment of individual differences in sensitivity to frustration and identification of the neurobiological pathways underlying addiction-, depression-, and anxiety-related behavior.
Key publication: Vasquez et al. (2021) Psychopharmacology — Lever-press duration as a measure of frustration
Key Findings
- Real-time frustration measurement via lever-press duration
- Frustration proposed as a fourth factor alongside craving, impulsivity, and habit
- A minority of rats (about 10-15% across cohorts) shows escalated fentanyl responding under frustration-sensitive paradigms
- Individual differences in frustration sensitivity predict drug-taking behavior
Research Pillar 2
Environmental Enrichment & Protective Phenotypes
Inoculation stress hypothesis
Positive environmental stimuli — novelty, social contact, and exercise — produce a protective phenotype that renders some individuals resistant to addiction or depression, even after exposure to drugs of abuse or stress. Rats housed in enriched conditions do not self-administer cocaine or amphetamine as readily as isolated rats. We propose an inoculation stress hypothesis: environmental enrichment produces mild daily stressors that build resilience against subsequent major stressors.
Key publication: Green et al. (2014) Frontiers in Behavioral Neuroscience — Environmental enrichment alters protein expression
Key Findings
- Enriched condition (EC) vs. isolated condition (IC) housing paradigms
- EC rats show reduced cocaine and amphetamine self-administration
- Inoculation stress hypothesis reframes enrichment as resilience-building
- Protective phenotypes for both addiction and depression-related behaviors
Research Pillar 3
Retinoic Acid Signaling in Addiction
Novel therapeutic strategies
Transcriptomic and proteomic analysis of nucleus accumbens tissue revealed that retinoic acid signaling is altered in environmentally enriched animals that display protective phenotypes. Specific components of the retinoic acid signaling pathway in the nucleus accumbens shell control susceptibility and resilience to cocaine self-administration, opening the door to novel therapeutic strategies for addiction.
Key publication: Green et al. (2016) Frontiers in Molecular Neuroscience — Transcriptomics of environmental enrichment reveals a role for retinoic acid signaling
Key Findings
- Aldh1a1 knockdown in NAc shell produces a protective phenotype in emotional reactivity and drug-taking models
- RAR versus PPARβ/δ signaling pathway dissection
- Transcriptomic and proteomic analyses implicate retinoic acid signaling in enrichment-linked resilience
- Recent work extends these findings to fentanyl self-administration paradigms