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Towards a circuit-based understanding of neuropsychiatric disorders: circuit-specific contributions to major depressive disorder and addiction

  • Author(s): Knowland, Daniel Adam
  • Advisor(s): Lim, Byungkook
  • et al.
Abstract

Motivation directs and guides an organisms interaction with their environment and is profoundly influenced by internal brain states in conjunction with external environmental stimuli. Motivated behaviors can range from survival-based actions such as foraging for food or avoiding potentially deadly conflict to pursuit of pleasure or sex. Proper maintenance of every day motivation is essential for guiding behavior to preserve homeostatic balance and stable functioning.

However, states of pathological motivation result when proper motivational control is lost. Instances of hyper-motivation misdirected towards harmful or negative stimuli can manifest as addiction, and conversely loss of motivation and extreme apathy is a hallmark of major depressive disorder (MDD). How then, does the brain regulate motivation and what kind of adaptations lead to conditions such as addiction and depression?

Components of the reward circuitry in the brain such as the nucleus accumbens (NAc) has been heavily studied in the context of addiction and MDD. As a central node in the reward circuitry, the NAc receives dopaminergic input from the ventral tegmental area (VTA) in the midbrain and sends its primary output to the ventral pallidum (VP) and back to the VTA. While structural and electrophysiological changes in neurons within the NAc have been well described in addiction and MDD, much less is known how the NAc interacts with the reward circuitry as a whole. In particular, how do the various interconnections within the reward circuit relate to the complex behaviors characteristic of neuropsychiatric conditions such as MDD and addiction? This dissertation aims to shed light on how discrete aspects of circuits involving the NAc and VP contribute to discrete behavioral aspects of addiction and MDD. Chapter I illustrates that discrete components of the ventral pallidal circuit mediates separate depressive-like behaviors in a mouse model of depression. In chapter II, we outline discrete structural changes in separate input structures of the NAc at different stages of addiction. In all, this dissertation hopes to illuminate the circuit-specific changes governing neuropsychiatric disorders that may provide a platform for more specific treatments.

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