Project Details
Description
Abstract
Substance use and addiction pose significant and increasing challenges to public health. The distribution of
dopamine efferents from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and to the medial
prefrontal cortex (mPFC) has been hypothesized to influence the predisposition to drug abuse. In addition, the
continued maturation of mesocortical projection into early adulthood renders it more susceptible to risk factors
such as exposure to drugs of abuse during adolescence. Netrin1/DCC-mediated signaling has emerged as a
key regulator of VTA dopamine circuit formation and maturation. However, while reducing DCC activity in mice
is shown to increase mesocortial projection, humans carrying monoallelic DCC mutations are found to have
reduced mesocortial connectivity. This notable discrepancy reflects a significant gap in knowledge as to how
DCC signaling directs VTA dopamine axon targeting and in turn influences addiction-related behaviors.
Our recent study has identified novel genetic means to dampen and elevate DCC function by overexpressing
distinct receptor variants. Combining the new genetic approach, advanced whole brain imaging, and real-time in
vivo dopamine recording, we will test the central hypothesis that axon targeting in the mesocorticolimbic
pathway influences the functional responses to drugs of abuse. Specifically in this pilot study, we will investigate
how bidirectional changes in DCC signaling alters mesocortical connection, particularly during the circuit
maturation through adolescence. We will determine both anatomical and functional changes and also correlate
these changes with addition-related behaviors in mice.
Aim 1: Determine how changes in DCC activity affects mesocortical axon connection.
Using the Cre-loxP system, we will dampen or elevate DCC signaling by overexpressing distinct DCC isoforms
specifically in VTA dopamine neurons and during adolescent development. We will follow the resulting VTA axon
projection with a tdTomato reporter in the intact brain, using high-speed high-resolution ribbon scanning confocal
microscopy after tissue clearing. Completion of this aim will allow us to compare how bidirectional changes in
DCC signaling impact mesocortical circuit maturation. It will also help distinguish different possibilities that could
contribute to the discrepancy between mice and humans regarding mesocortical connectivity.
Aim 2. Determine how changes in DCC activity affects dopamine release in the mPFC during behavioral
responses to drugs of abuse.
Using the same genetic approach to induce bidirectional changes in DCC signaling as in Aim 1, we will also
determine the corresponding alterations in dopamine release in the mPFC and the effects on animal behaviors.
Using dLight1.3b fluorescent indicator and fiber photometry, we will follow real-time dopamine dynamics in the
mPFC during conditioned place preference testing. This will help determine the functional outcomes of altered
mesocortical circuit maturation and delineate the anatomical-structural relationship in the dopamine circuit.
Status | Finished |
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Effective start/end date | 4/1/23 → 3/31/24 |
Funding
- National Institute on Drug Abuse: $232,500.00
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