January 17, 2021

Cocaine causes rapid remodeling of dopaminergic axons, synapses, and mitochondria

Detailing the ways drugs of abuse physically change dopaminergic circuits would provide new mechanisms for explaining addictive behaviors, future targets for therapeutic intervention, and insights into the nature of synaptic plasticity. We combine recent advances in genetic labeling with large volume serial electron microscopy to detail how normal dopaminergic (DA) axons interact with putative targets and how those interactions change in mice briefly exposed to cocaine. We find that while most DA boutons are devoid of obvious signs of synapses (i.e. synaptic vesicles or synaptic densities) many DA boutons physically interdigitate with both dendrites and excitatory and inhibitory axons. After a brief exposure to cocaine, we find evidence of large-scale structural remodeling: extensive axonal branching and frequent occurrences of axonal blind-ended bulbs, filled with mitochondria, reminiscent of axonal retraction in the developing and damaged brain. The number of physical interdigitations and vesicle filled boutons between DA axons and targets scales linearly with the length of axon whether in controls or cocaine exposed animals and the size or the type of interaction (i.e. axo-axonic or axo-dendritic) does not change. Finally, we find significant cell-type and sub-cellular specific increases in mitochondrial length in response to cocaine. Specifically, mitochondria in dopamine axons and local Nucleus Accumbens (NAc) dendrites are ~3.5 times and 2 times longer, respectively, in cocaine treated mice than controls. These results show for the first time the effects of cocaine on remodeling of dopamine circuitry and reveal new details on how dopamine neurons physical associate with downstream targets.

 bioRxiv Subject Collection: Neuroscience

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