Role of dopaminergic signaling on anesthesia-induced retrograde amnesia

Summary Forgetting is a familiar phenomenon, but the neurobiological underpinnings of this process remain unclear. Many memory disorders, including retrograde amnesia, involve the inability to recall certain memories. Retrograde memory loss affects memories formed before the onset of an event. This event can be acute and include anesthesia, alcohol intoxication, head trauma, seizures, or chronic, like senescence and neurodegenerative diseases. Drosophila has served as an excellent animal model when studying memory and memory loss, as they can form strong olfactory memories through classical conditioning. Retrograde amnesia induced by an acute event can be modeled in Drosophila. Fruit flies experience retrograde amnesia of a conditioned response when anesthetized with a cold shock (a rapid temperature change). The mushroom body is a critical brain structure involved in forming, storing, and retrieving these olfactory memories. The axon terminals of dopaminergic neurons projecting to specific compartments within the mushroom body convey the aversive unconditioned stimulus during learning. Surprisingly, these same dopaminergic neurons also regulate forgetting. The bidirectional regulation of memory by dopaminergic neurons is mediated by two distinct receptors, dDA1 for learning and DAMB for forgetting. Despite understanding a potential signaling pathway involving dopaminergic neurons that regulates normal forgetting, it remains unknown if anesthesia-induced amnesia is an active process dependent on dopamine signaling. To address this question, this proposal will 1) use in vivo imaging to characterize individual dopaminergic neurons’ dynamics of responses during anesthesia. 2) Characterize the cellular and circuit basis of dopaminergic activity during anesthesia. 3) Evaluate whether dopaminergic signaling is required for anesthesia-mediated amnesia. The long-term goal of this proposal is to gain knowledge on the neurobiological basis of insult-induced memory loss. This study may uncover novel mechanisms of anesthesia-induced amnesia. In addition, this study will provide a deeper insight into the biological mechanisms and cognitive consequences of the use of anesthetics. This proposal is highly significant because there is a big gap in our knowledge of the neurobiological basis of insult-induced amnesia. Despite an increasing interest in understanding the neurobiological mechanisms of active forgetting, we need to determine if insults like anesthesia induce amnesia through an active process. In addition to the scientific component, this proposal includes a comprehensive plan for professional and personal development. Aligned with the long-term objective of becoming an effective investigator and mentor capable of sustaining a robust research program and nurturing future generations, the proposal outlines strategies to enhance communication skills, both in scientific writing and oral presentation, as well as to cultivate effective mentoring abilities. Recognizing these as indispensable qualities, the proposal aims to refine and strengthen these skills over the duration of the award period.