Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice

Bahí, Amine; Dreyer, Jean-Luc

doi:10.1016/j.bbr.2018.10.028

Cited by 50 publications

(30 citation statements)

References 91 publications

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“…Moreover, increased DA signaling and reduced glutamatergic firing within the NAcc is associated with increased anxiety [2]. A link between reduced NAcc DAT expression and anxiolytic behavior was recently reported [41], also consistent with our findings. Given that we used an AAV9 viral serotype, Rit2-KD likely occurred across multiple DAergic circuits, including VTA PFC, VTA NAc, and SNc DS.…”

Section: Rit2 Expression Increases Throughout Postnatal Development Asupporting

confidence: 92%

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Sweeney

Kearney

Fagan

et al. 2019

Neuropsychopharmacol.

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Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here, we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3 IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.

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Section: Rit2 Expression Increases Throughout Postnatal Development Asupporting

confidence: 92%

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Sweeney

Kearney

Fagan

et al. 2019

Neuropsychopharmacol.

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“…Using a foot-shock avoidance task, Wenzel et al (82) found that activation of VTA DA neurons enhanced active avoidance in rats, and this was blocked by D1 antagonist injection into the NAc core. In addition, knocking down the DA transporter in the NAc core, which decreases DA reuptake and increases synaptic DA levels, reduces anxiety-and depression-like behaviors (83). As depression is marked by reduced avoidance of aversive stimuli (helplessness), these data imply that dysregulation of NAc D1 receptor activation could increase vulnerability to stress-induced helplessness.…”

Section: Discussionmentioning

confidence: 95%

Vulnerability to helpless behavior is regulated by the circadian clock component CRYPTOCHROME in the mouse nucleus accumbens

Porcu

Vaughan

Nilsson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN–specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.

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“…Similarly, the MIX‐by‐MAT group was generally more inactive than all the other ones at 9:00 PM. As a whole, sleep and reward disturbances (that cause major changes in circadian rhythms) can indeed result from a dysfunctional dopaminergic system (Germain & Kupfer, 2008; Nezlek et al, 1994; see Bahi & Dreyer, 2019).…”

Section: Discussionmentioning

confidence: 99%

Truncated dopamine transporter's epigenetics: Heterozigosity of the grandmother rat temperates the vulnerable phenotype in second‐generation offspring

Pepe

Calcaprina

Vaquer

et al. 2022

Intl J of Devlp Neuroscience

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Behavioral phenotype differs among epigenotypes of dopamine‐transporter heterozygous (DAT‐HET) rats. Epigenetic regulations act through transgenerational effects, referring to phenotypic variations emerging at second or third generation. To investigate transgenerational influences exerted by maternal grandmothers, we developed breeding schemes where only the genotype of maternal grandmothers varied. HET females, to serve as MAT vs. MIX mothers, were generated, respectively, from WT × KO = MAT and MAT × KO = MIX breeding, with KO males acting as grandfather. The HET experimental groups, generated from either MAT or MIX mothers, were called MIX‐by‐MAT and MIX2 (male‐fathers KO; asset‐M: wild/healthy‐allele from dam) or SOT and SIX (male‐fathers WT; asset‐P: mutated‐allele from dam). Thus, sequelae of first encounter between wild/healthy and mutated DAT alleles (in maternal‐lineage) were compared at first‐ (MAT‐dam, WT‐grandmother) vs. at second‐ (MIX‐dam, HET‐grandmother) generation. We characterized, within these epigenotypes, (1) circadian home‐cage activity and (2) preference for social stimuli. Marked alterations of circadian activity appeared in MIX‐by‐MAT HETs, offspring of MAT‐dams, compared with MIX2 HET (offspring of MIX‐dams); The latter, in turn, were undistinguishable from WT‐controls. A clear‐cut social preference by WT rats was expressed towards SIX compared with SOT stimulus rats, confirming that the latter elicited reduced social motivations. In conclusion, significant epigenetic modulations took place in DAT‐HET rats, as a function of maternal grandmother's genotype.

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Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice

Cited by 50 publications

References 91 publications

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

Vulnerability to helpless behavior is regulated by the circadian clock component CRYPTOCHROME in the mouse nucleus accumbens

Truncated dopamine transporter's epigenetics: Heterozigosity of the grandmother rat temperates the vulnerable phenotype in second‐generation offspring

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