Alcohol intoxication mediated through medial septal circuitry
In this research, researchers will use a novel mouse line to test the involvement of a specific neural circuit in brain in controlling alcohol intoxication. Selected cells in this circuit will be manipulated in an attempt to enhance or diminish the magnitude of intoxication. If the role of the circuit and cells can be shown, future work would expand the analysis of the neural connections to this circuit with the goal of inspiring novel avenues for therapeutic intervention in alcohol used disorders.
Darin Knapp, Ph.D.
Need/Problem: A complete understanding of the brain mechanisms of alcohol intoxication has remained elusive. Research devoted to defining the neurocircuits of intoxication with state of the art neurobiological tools offers an opportunity to make advances in our understanding.
Grant Summary: This grant offers a novel approach to a long-standing mystery involving the circuits of the brain that control alcohol intoxication. The grant will employ a novel mouse line that will permit examinations of a hypothalamic/medial septal circuit in the actions of alcohol.
Goals & Projected Outcomes: We predict that excitation of neurons originating in the hypothalamus will mimic the effects of analeptic (anti-intoxicating) peptides, while inhibition of these neurons or blockade of the peptide receptors will mimic the effects of alcohol. Through this effort, we will define an important brain circuit in this neurobehavioral effect of alcohol.
Grant Details: Alcohol abuse disorders (AUDs) are exceedingly common, devastating, and the source of $200 billion per year in costs in the U.S. alone. While progress is being made on many fronts with regard to our understanding of possible behavioral and neurobiological dynamics that impact on select aspects of these disorders such as relapse risk, little progress has been made in understand the fundamental neurobehavioral effects of alcohol intoxication itself. Clinical researchers have known for a long time that the single most predictive factor in the risk of developing of an AUD is the magnitude of intoxication following an acute dose of alcohol in sons of alcoholics regardless of prior history of consumption. In animal models, the underlying neural circuitry supporting intoxication has remained elusive. Research conducted in our laboratory points to the potential importance of the thyroid hormone thyrotropin releasing hormone (TRH) in mediating the intoxicating effect of alcohol. We also understand that the action of TRH in a region of the brain known as the medial septum is somehow involved in that TRH blocks aspect of intoxication through this brain region.
More recently, the peptide orexin (hyopcretin) has been implicated in some consciousness-related states such as sleep and narcolepsy and neurons of the hypothalamus likely play a role. In our work supported by the Foundation of Hope, we intend to define the neurocircuitry of the orexin and TRH effects on intoxication with the prediction that hypothalamic/medial septal pathways are critical. Through the use of contemporary tools in chemogenetics and custom viral delivery tools, we will for the first time gain experimental control over either medial septal neurons and/or hypothalamic orexin neurons and their capacity to regulate the intoxicating effects of alcohol and other sedatives. The Foundation of Hope funding will also allow us prove that a novel line of mice are a valid and useful model for testing our hypothesis that a hypothalamic/medial septal pathway is critically involved in mediating the intoxication effects. Such work will advance our understanding of a fundamental yet fairly mysterious action of alcohol and possibly provide a new framework for approaching therapeutically impactful interventions.