BDNF in ventrolateral orbitofrontal cortex to dorsolateral striatum circuit moderates alcohol consumption, seeking and relapse – Nature

Report on Neurobiological Mechanisms of Alcohol Use Disorder and Alignment with Sustainable Development Goals

Introduction: Addressing SDG 3 through AUD Research

Alcohol Use Disorder (AUD) represents a significant global health challenge, directly addressed by the United Nations Sustainable Development Goal 3 (Good Health and Well-being), particularly Target 3.5, which aims to strengthen the prevention and treatment of substance abuse, including the harmful use of alcohol. This report details research into the neurobiological underpinnings of AUD, focusing on the role of Brain-Derived Neurotrophic Factor (BDNF) within specific corticostriatal circuits. Understanding these mechanisms is critical for developing novel therapeutic strategies that can help achieve global health targets by mitigating the negative health and societal impacts of excessive alcohol consumption.

Key Findings on BDNF’s Role in Alcohol Consumption

Impact of Chronic Alcohol Use on BDNF Expression

The study identified a critical link between long-term, heavy alcohol consumption and the regulation of BDNF, a protein essential for neuronal health and function. This finding has implications for understanding vulnerability to AUD and aligns with SDG 3 by identifying a potential biomarker for alcohol-induced neurological changes.

• Chronic binge alcohol drinking was found to significantly reduce BDNF gene expression in the ventrolateral orbitofrontal cortex (vlOFC), a brain region implicated in decision-making and addiction.
• This reduction was not observed in other cortical regions, such as the medial orbitofrontal cortex (mOFC) or the M2 motor cortex, indicating a highly localized effect of chronic alcohol exposure.
• Notably, this effect was sex-specific, occurring in male but not female mice. This highlights the importance of considering sex as a biological variable in health research, a principle that supports the broader aims of SDG 5 (Gender Equality) by ensuring health interventions are effective for all populations.

The Protective Function of the vlOFC-to-DLS BDNF Circuit

The research demonstrates that BDNF signaling within the neural circuit projecting from the vlOFC to the dorsolateral striatum (DLS) serves as an endogenous protective mechanism against excessive alcohol intake. Restoring BDNF levels in this pathway presents a viable strategy for treatment, contributing directly to SDG Target 3.5.

1. Overexpression of BDNF specifically in the vlOFC-to-DLS circuit successfully reduced voluntary alcohol intake and preference in mice subjected to long-term binge drinking.
2. This effect was specific to alcohol, as BDNF overexpression did not alter the consumption of or preference for a sucrose solution, suggesting the mechanism is not a general dampening of reward but is targeted to alcohol-related behaviors.
3. The anatomical specificity of this protective function was confirmed, as overexpressing BDNF in related circuits (vlOFC-to-dorsomedial striatum or M2-to-DLS) did not alter alcohol consumption.

Influence on Compulsive and Relapse Behaviors

A core challenge in treating AUD is addressing the compulsive seeking and high rates of relapse that characterize the disorder. The study found that BDNF in the vlOFC-to-DLS circuit is a key regulator of these behaviors, offering a pathway to develop interventions that promote long-term recovery and well-being (SDG 3).

• Restoring BDNF levels in this circuit significantly reduced operant alcohol self-administration, indicating a moderation of the motivation to work for alcohol rewards.
• The intervention also decreased alcohol-seeking behavior after the reward was removed (extinction) and attenuated the reinstatement of alcohol seeking (relapse) following a period of abstinence.

Therapeutic Implications and Contribution to SDG Target 3.5

Potential of TrkB Agonists for Treatment

The findings were translated into a potential pharmacological intervention by testing a systemic drug that mimics the action of BDNF. This demonstrates a clear path from basic science to clinical application, essential for achieving the goals of SDG 3.

• Systemic administration of LM22A-4, an agonist for the BDNF receptor TrkB, successfully reversed habitual alcohol-seeking behavior.
• Treated mice shifted from compulsive, habitual lever-pressing to more flexible, goal-directed behavior, where actions were sensitive to the outcome.
• This result suggests that pharmacological agents targeting the BDNF/TrkB signaling pathway could be effective in treating the compulsive aspects of AUD, providing a novel therapeutic strategy to support the objectives of SDG Target 3.5.

Conclusion: Advancing Global Health Goals

This research identifies the BDNF signaling pathway in the vlOFC-to-DLS circuit as a critical moderator of alcohol consumption, seeking, and relapse. The breakdown of this endogenous protective mechanism contributes to the development of AUD-like phenotypes. The successful reversal of these behaviors through genetic and pharmacological restoration of BDNF signaling provides a strong scientific foundation for developing new treatments. By elucidating these neurobiological targets, this work directly supports the United Nations Sustainable Development Goal 3, contributing valuable knowledge toward the global effort to strengthen the prevention and treatment of harmful alcohol use.

SDGs Addressed in the Article

1. SDG 3: Good Health and Well-being

   • The article directly addresses issues of health and well-being by focusing on Alcohol Use Disorder (AUD), a significant global health concern. The research investigates the neurobiological mechanisms underlying excessive alcohol consumption and addiction, stating that “Dysregulation of BDNF signaling has been implicated in psychiatric disorders, such as… addiction.” By seeking to understand and find potential treatments for AUD, the study contributes to the overarching goal of ensuring healthy lives and promoting well-being.

Specific SDG Targets Identified

1. Target 3.5: Strengthen the prevention and treatment of substance abuse, including narcotic drug abuse and harmful use of alcohol.

   • This target is central to the article’s research. The study is entirely focused on the “harmful use of alcohol,” examining the factors that lead to “escalation of alcohol drinking and compulsive alcohol intake.” The investigation into the role of the BDNF protein and the testing of a TrkB agonist, LM22A-4, represent a clear effort to find novel therapeutic pathways. The conclusion that “systemic administration of a TrkB agonist biases habitual alcohol seeking to goal-directed behavior” points directly toward strengthening the “treatment of substance abuse.”

2. Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.

   • Alcohol Use Disorder is a mental health condition that contributes significantly to the burden of non-communicable diseases. The article’s aim to “provide evidence for a potentially new drug target to combat AUD phenotypes” is a direct contribution to the promotion of “mental health and well-being.” By exploring foundational science that could lead to more effective treatments, the research supports the long-term goal of reducing the negative health outcomes and premature mortality associated with chronic harmful alcohol use.

Indicators for Measuring Progress

1. Indicators for Target 3.5

   • While the article does not use official national or global indicators like population-level alcohol consumption (Indicator 3.5.2), it employs several specific, quantifiable preclinical indicators in its animal models. These experimental measures serve as proxies to assess the “harmful use of alcohol” and the effectiveness of potential treatments, thereby measuring progress toward the target in a research context.
   • Implied Preclinical Indicators from the Article:
     • Alcohol intake (g/kg of body weight): This was a primary measure used to quantify consumption levels in mice. The article notes, “overexpression of BDNF in vlOFC to DLS projecting neurons significantly reduces alcohol drinking.”
     • Alcohol preference ratio: This indicator measures the motivation to consume alcohol over water. It was “calculated by dividing the volume of alcohol consumed to the total volume of fluid intake.”
     • Operant alcohol self-administration: This models alcohol-seeking behavior and was measured by “the number of active lever presses and reward port entries, as well as the number of reward deliveries.”
     • Habitual alcohol seeking: The article used a “contingency degradation” procedure to assess compulsive, habit-driven behavior, a key feature of addiction. The study found that a TrkB agonist could “reverse habitual alcohol seeking.”
     • Relapse: Progress in preventing relapse was measured through “extinction and reacquisition procedures,” where a reduction in reacquired lever presses indicated a positive outcome. The study found that BDNF overexpression “reduced total active lever presses… following a period of extinction.”

Summary Table: SDGs, Targets, and Indicators

Source: nature.com