Abstract
Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change with drug exposure remains poorly understood. We leverage cell type-specific labeling with large volume serial electron microscopy to detail DA connections in the nucleus accumbens (NAc) of the mouse (Mus musculus) before and after exposure to cocaine. We find that individual DA axons contain different varicosity types based on their vesicle contents. Spatially ordering along individual axons further suggests that varicosity types are non-randomly organized. DA axon varicosities rarely make specific synapses (<2%, 6/410), but instead are more likely to form spinule-like structures (15%, 61/410) with neighboring neurons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls, formed blind-ended 'bulbs' filled with mitochondria, and were surrounded by elaborated glia. Finally, mitochondrial lengths increased by ~2.2 times relative to control only in DA axons and NAc spiny dendrites after cocaine exposure. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large-scale axonal re-arrangements with correlated changes in mitochondria.
Highlights
The dopaminergic (DA) system, like many neuromodulatory systems of the brain, profoundly influences behaviors including learning risks and rewards, social cooperation, goal-directed behavior, and Wildenberg et al eLife 2021;10:e71981
By performing large-scale serial electron microscopy combined with genetic labelling methods, this study reveals that dopaminergic axonal varicosities lack features of classical synapses and that following exposure to cocaine dopaminergic axons undergo extensive remodeling
We focused our analysis on DA axons projecting to the medial shell of the nucleus accumbens (NAc) because: (1) It receives the majority of ventral tegmental area (VTA) projecting DA axons (Beckstead et al, 1979)
Summary
The dopaminergic (DA) system, like many neuromodulatory systems of the brain, profoundly influences behaviors including learning risks and rewards, social cooperation, goal-directed behavior, and Wildenberg et al eLife 2021;10:e71981. Alterations in DA circuitry in animal models and humans are a hallmark of addictive behaviors and are likely the result of changes in how DA neurons communicate with targets (Berke and Hyman, 2000). While much is known about the molecular composition and functional roles of DA neurons in normal behavior and addiction (Alcaro et al, 2007; Beeler et al, 2009; Berke and Hyman, 2000; Liu and Kaeser, 2019; Liu et al, 2018), much less is known about how DA neurons physically communicate with targets and how that communication changes with exposure to drugs of abuse. We conclude that connectomic tools can give new insights into DA axon biology and how brief exposure to cocaine impacts mesoaccumbens dopamine circuitry
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