Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease

Abstract

Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions.

Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

“…In DA-Rictor KO mice, we found a moderate reduction in peak evoked DA release specifically in the ventral half of the striatum and NAc (sites 4–7), while DA release in the dorsal-most regions (sites 1–3) was unchanged ( Figure 7a–c and Figure 7—figure supplement 1 ). On average, we observed an approximately 25% reduction in peak evoked DA release both with single pulse ( Figure 7b and c ) and high frequency burst ( Figure 7—figure supplement 1 ) stimulation at sampling sites 4–7, which receive proportionately denser innervation from the VTA compared to the SNc ( Chen et al, 2021 ). The observation that release impairments in DA-Rictor KO mice were selectively present in ventral regions is consistent with the more pronounced electrophysiological changes we found in VTA neurons compared to SNc neurons with Rictor deletion (see Figure 5 ).…”

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

“…An increasing number of preclinical studies are revealing that anxiety is linked to mitochondrial functions including bioenergetics, oxidative stress, neurosteroid production, biogenesis, and apoptosis [ 310 ]. Mitochondrial dysfunction is located in the nucleus accumbens (NAc) which interfaces motivation and action, playing a key role in motivation, aversion, reward, and reinforcement learning.…”

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System

“…An increasing number of preclinical studies are revealing that anxiety is linked to mitochondrial functions including bioenergetics, oxidative stress, neurosteroid production, biogenesis, and apoptosis [278]. The mitochondrial dysfunction is located in the nucleus accumbens (NAc) which interfaces motivation and action, playing a key role in motivation, aversion, reward, and reinforcement learning.…”

“…The mitochondrial dysfunction is located in the nucleus accumbens (NAc) which interfaces motivation and action, playing a key role in motivation, aversion, reward, and reinforcement learning. The shell of NAc is considered to be part of the extended amygdala [278]. The outbred Wiser rats which exhibit anxiety-like behavior showed the reduced expression of the mitochondrial GTPase mitofusin-2 (MFN2) in the NAc, altered mitochondrial morphology and functions, and the morphology of medium spiny neurons (MSNs) projecting from the NAc.…”