Welcome to the Natividad Lab!

Addiction is a chronic, relapsing disorder in which preventing relapse after abstinence from long-term drug or alcohol use remains a central clinical challenge. Reinforcement-based models have been essential for defining the motivational, affective, and environmental drivers of relapse, and have contributed significantly to our understanding of neural systems regulating stress, reward, and motivation. Yet relapse remains difficult to prevent, in part because vulnerability does not emerge from a fixed set of triggers. The conditions that precipitate renewed drug or alcohol use can vary across individuals and shift over the course of abstinence, as some risks diminish and others become more salient. Abstinence may therefore reflect an extended period of rebalancing between systems that promote relapse and regulatory mechanisms that constrain their influence.

Given this complexity, targeting any one relapse trigger is unlikely to be therapeutically effective for all individuals in treatment. A critical point of vulnerability may instead lie in the capacity of cortical systems to regulate behavior when relapse risk is elevated. Factors such as craving, withdrawal, negative affect, stress, and drug-associated cues may fluctuate throughout abstinence, while the neural systems supporting behavioral control may recover on a different timescale. Available pharmacotherapies for addiction act through different nodes of neurotransmission, including receptor activation or blockade, transmitter release, and uptake. Although these approaches can be effective, they are not primarily designed to address cortical dysregulation that may persist into longer periods of abstinence.

To this end, the NativiLab seeks to define signaling mechanisms within cortical networks that influence relapse vulnerability during abstinence. A central hypothesis of the laboratory is that chronic drug or alcohol exposure produces a signaling state in which relapse-relevant inputs are more readily translated into behavior. Thus, even after intoxication and withdrawal resolve, cortical regulation may remain weakened, reducing its ability to temper the influence of relapse triggers. The NativiLab investigates this possibility by integrating behavioral models of cognitive control with mass spectrometry-based discovery approaches to identify neurochemical, protein, and phosphoprotein features of cortical dysregulation during abstinence. The long-term goal of this work is to uncover signaling mechanisms that could ultimately be leveraged to restore cognitive control and reduce vulnerability to relapse. Current research programs develop this framework in the context of alcohol use disorder.

Cortical signaling and cognitive control during abstinence: This program examines how chronic alcohol exposure alters signaling within cortical systems that regulate behavioral flexibility, decision-making, and adaptive control during abstinence. The goal is to define molecular features of cortical dysregulation that may allow relapse-relevant inputs to exert greater influence over behavior.

Neurochemical and peptide mechanisms of alcohol-induced behavioral dysfunction: This program focuses on how chronic alcohol exposure alters neurochemical and peptide signaling systems that regulate cortical function. Emphasis is placed on identifying endogenous signaling molecules and receptor-linked adaptations that may contribute to impaired behavioral control during abstinence.

Mass spectrometry-based discovery of relapse-relevant signaling states: This program uses discovery-based analytical approaches to identify protein, phosphoprotein, and neurochemical signatures associated with alcohol-induced changes in cortical regulation. The goal is to move from broad molecular discovery toward mechanistic targets that may help explain long-term vulnerability during abstinence.

Research in the NativiLab has been supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) through the following mechanisms: K99/R00AA025393, R21AA030862, and R01AA031452. Additional institutional support has been provided through a Rising STARS Award.