Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

Flores, Cecilia

doi:10.1503/jpn.100171

Cited by 52 publications

(64 citation statements)

References 133 publications

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“…We have previously shown, that in contrast to early adolescence (Yetnikoff et al, 2011), exposure to the exact same regimen of amphetamine upregulates DCC expression in the VTA when given to adult mice and rats (Yetnikoff et al, 2007(Yetnikoff et al, , 2010. This age-dependent effect is consistent with the idea that DCC signaling within dopamine neurons mediates different events at different developmental times (Flores, 2011).…”

Section: Amph In Adolescence But Not In Adulthood Alters Dopamine Isupporting

confidence: 82%

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

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Section: Amph In Adolescence But Not In Adulthood Alters Dopamine Isupporting

confidence: 82%

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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“…Recent evidence indicates that DCC and UNC5H also contribute to the organization of synaptic circuitry by defining the localization of pre-and post-synaptic components (Colon-Ramos et al 2007;Poon et al 2008;Manitt et al 2009). Importantly, we and others have shown that DCC and UNC5H are highly expressed in DA cell body and terminal regions (Flores 2010;Osborne et al 2005). While DCC is expressed by DA neurons across the lifespan, UNC5H expression by DA cells emerges only at puberty (Manitt et al 2010(Manitt et al , 2011.…”

Section: Introductionmentioning

confidence: 53%

“…Neurite attraction is mediated mainly by deleted in colorectal cancer (DCC) receptors, while repulsion is mediated by UNC5 homologue (UNC5H) receptors (Manitt and Kennedy 2002;Moore et al 2007;Flores 2010). Recent evidence indicates that DCC and UNC5H also contribute to the organization of synaptic circuitry by defining the localization of pre-and post-synaptic components (Colon-Ramos et al 2007;Poon et al 2008;Manitt et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period

et al. 2011

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“…The cellular and molecular processes mediating these effects are essentially unknown. Our past work identified a role for the netrin-1 receptor DCC (deleted in colorectal cancer) in the functional organization of mesocorticolimbic DA systems (Flores et al, 2005Grant et al, 2007Grant et al, , 2009Yetnikoff et al, 2007Yetnikoff et al, , 2010, leading us to propose that DCC-mediated netrin-1 signaling is a mechanism whereby risk factors exert their enduring effects on DA function (Flores, 2011). Here, we report that DCC contributes to the organization of mesocorticolimbic DA systems by influencing medial prefrontal cortex (mPFC) DA synaptic connectivity.…”

Section: Introductionmentioning

confidence: 73%

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

Manitt¹,

Mimee²,

Eng³

et al. 2011

Journal of Neuroscience

115

182

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Netrins are guidance cues involved in neural connectivity. We have shown that the netrin-1 receptor DCC (deleted in colorectal cancer) is involved in the functional organization of the mesocorticolimbic dopamine (DA) system. Adult mice with a heterozygous loss-of-function mutation in dcc exhibit changes in indexes of DA function, including DA-related behaviors. These phenotypes are only observed after puberty, a critical period in the maturation of the mesocortical DA projection. Here, we examined whether dcc heterozygous mice exhibit structural changes in medial prefrontal cortex (mPFC) DA synaptic connectivity, before and after puberty. Stereological counts of tyrosine-hydroxylase (TH)-positive varicosities were increased in the cingulate 1 and prelimbic regions of the pregenual mPFC. dcc heterozygous mice also exhibited alterations in the size, complexity, and dendritic spine density of mPFC layer V pyramidal neuron basilar dendritic arbors. Remarkably, these presynaptic and postsynaptic partner phenotypes were not observed in juvenile mice, suggesting that DCC selectively influences the extensive branching and synaptic differentiation that occurs in the maturing mPFC DA circuit at puberty. Immunolabeling experiments in wild-type mice demonstrated that DCC is segregated to TH-positive fibers innervating the nucleus accumbens, with only scarce DCC labeling in mPFC TH-positive fibers. Netrin had an inverted target expression pattern. Thus, DCC-mediated netrin-1 signaling may influence the formation/maintenance of mesocorticolimbic DA topography. In support of this, we report that dcc heterozygous mice exhibit a twofold increase in the density of mPFC DCC/TH-positive varicosities. Our results implicate DCC-mediated netrin-1 signaling in the establishment of mPFC DA circuitry during puberty.

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Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

Cited by 52 publications

References 133 publications

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

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