Cocaine induces input and cell-type-specific synaptic plasticity in ventral pallidum-projecting nucleus accumbens medium spiny neurons

Inbar, Kineret; Levi, Liran A.; Kupchik, Yonatan M.

doi:10.1038/s41386-022-01285-6

Cited by 10 publications

(8 citation statements)

References 108 publications

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“…While NAcore shNPAS4 D1-Cre in NAc had no effect on the D1-MSN:D2-MSN FOS+ ratio (Figure 4C, right), NAcore shNPAS4 D2-Cre produced a significant shift in the D1-MSN:D2-MSN FOS+ ratio, with D2-MSNs representing the majority (39% shScram vs. 61% shNPAS4; Figure 4D, right), and a significant decrease in presumed D1-MSN FOS+ neurons (Figure 4D, right). Consistent with this observation, we also observed a significant reduction in FOS+ neurons in the dorsolateral ventral pallidum (dlVP) (Figure 4E-F), a key projection target of NAc D2-MSNs that is required for cued drug seeking 19,21,24,26,[62][63][64] .…”

Section: Npas4 Regulates the Preponderant Activation Of Nac D1-msns F...supporting

confidence: 83%

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

Hughes

Tsvetkov

Siemsen

et al. 2022

Preprint

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Use of addictive substances creates powerful drug-cue associations that often trigger relapse. Drug seeking is gated in the nucleus accumbens (NAc) by competing activation of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs) that promote, and D2 dopamine receptor-expressing neurons (D2-MSNs) that oppose, drug seeking. We show here that the ensemble of neurons in the NAc that induce the neuronal activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is required for cocaine-context associations. In addition, NPAS4 functions within NAc D2-MSNs to govern the activation balance of NAc D1-MSNs and D2-MSNs necessary for drug-context memories and cue-induced cocaine, but not sucrose, seeking. NPAS4 regulates drug-cue associations and preponderant D1-MSN activation by influencing a program of gene expression that blocks cocaine-induced potentiation of prefrontal cortical excitatory drive onto D2-MSNs. Together our findings reveal that NPAS4 is a key player governing NAc MSN cell-type activation balance and promoting drug-cue associations and relapse vulnerability.

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Section: Npas4 Regulates the Preponderant Activation Of Nac D1-msns F...supporting

confidence: 83%

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

Hughes

Tsvetkov

Siemsen

et al. 2022

Preprint

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“…Thus, based on these putative roles, our findings seemingly contradict with the notion that hyperactivity of vSUB promotes drug seeking and drug reinstatement. However, our results add to a growing literature that NAc D2R MSNs play more complex roles in drug-induced plasticity and motivated behavior than previously appreciated and, in many cases, promote reward seeking behavior (Terrier et al, 2016; Inbar et al, 2022; Sjulson et al, 2018; Soares-Cunha et al, 2016; Gong et al, 2021; Cole et al, 2018). While NAc D2R MSNs mostly project to inhibitory neurons in VP to encode aversive behavior, D2R MSNs in dorsal NAcMS promote reward via specific projections to excitatory neurons in VP (Yao et al, 2021).…”

Section: Discussionsupporting

confidence: 68%

Ventral subiculum inputs to nucleus accumbens medial shell preferentially innervate D2R medium spiny neurons and contain calcium permeable AMPARs

Boxer

Kim

Dunn

et al. 2022

Preprint

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Ventral subiculum (vSUB) is the major output region of ventral hippocampus (vHIPP) and sends major projections to nucleus accumbens medial shell (NAcMS). Hyperactivity of the vSUB-NAcMS circuit is associated with substance use disorders (SUDs) and the modulation of vSUB activity alters drug seeking and drug reinstatement behavior in rodents. However, to the best of our knowledge, the cell-type specific connectivity and synaptic transmission properties of the vSUB-NAcMS circuit have never been directly examined. Instead, previous functional studies have focused on total ventral hippocampal (vHIPP) output to NAcMS without distinguishing vSUB from other subregions of vHIPP, including ventral CA1 (vCA1). Usingex vivoelectrophysiology, we systematically characterized the vSUB-NAcMS circuit with cell-type and synapse specific resolution in male and female mice and found that vSUB output to dopamine receptor type-1 (D1R) and type-2 (D2R) expressing medium spiny neurons (MSNs) displays a functional connectivity bias for D2R MSNs. Furthermore, we found that vSUB-D1R and -D2R MSN synapses contain calcium-permeable AMPA receptors in drug-naïve mice. Finally, we find that, distinct from other glutamatergic inputs, cocaine exposure selectively induces plasticity at vSUB-D2R synapses. Importantly, we directly compared vSUB and vCA1 output to NAcMS and found that vSUB synapses are functionally distinct and that vCA1 output recapitulated the synaptic properties previously ascribed to vHIPP. Our work highlights the need to consider the contributions of individual subregions of vHIPP to SUDs and represents an important first step toward understanding how the vSUB-NAcMS circuit contributes to the etiologies that underlie SUDs.

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“…Future studies using input-and output-specific electrophysiological recordings following Nr4a1 manipulation will increase our understanding of how different VP networks drive acquisition and relapse to cocaine seeking. This will be especially important since several brain regions in key circuits (VPàMDTàmPFC/orbitofrontal cortex (OFC)àNAcàVP or VPàBLAàNAcàVP) exhibit divergent structural changes after cocaine, including spine density increases in mPFC, NAc, and BLA, but spine density decreases in OFC 1,[71][72][73][74] . Moreover, while Nr4a1 closely relates to glutamatergic function, an important role for dopamine receptors in Nr4a1 induction has been reported, especially in striatal GABAergic neurons (see 39 for review).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward

et al. 2022

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Psychostimulant exposure alters the activity of ventral pallidum (VP) projection-neurons.However, the molecular underpinnings of these circuit dysfunctions are unclear. We used RNAsequencing to reveal alterations in the transcriptional landscape of the VP that are induced by cocaine self-administration in mice. We then probed gene expression in select VP neuronal subpopulations to isolate a circuit associated with cocaine intake. Finally, we used both overexpression and CRISPR-mediated knockdown to test the role of a gene target on cocainemediated behaviors as well as dendritic spine density. Our results showed that a large proportion (55%) of genes associated with structural plasticity were changed 24 hours following cocaine intake. Among them, the transcription factor Nr4a1 (Nuclear receptor subfamily 4, group A, member 1, or Nur77) showed high expression levels. We found that the VP to mediodorsal thalamus (VPàMDT) projection neurons specifically were recapitulating this increase in Nr4a1 expression. Overexpressing Nr4a1 in VPàMDT neurons enhanced drug-seeking and druginduced reinstatement, while Nr4a1 knock down prevented self-administration acquisition and subsequent cocaine-mediated behaviors. Moreover, we showed that Nr4a1 negatively regulated spine dynamics in this specific cell subpopulation. Together, our study identifies for the first time the transcriptional mechanisms occurring in VP in drug exposure. Our study provides further understanding on the role of Nr4a1 in cocaine-related behaviors and identifies the crucial role of the VPàMDT circuit in drug intake and relapse-like behaviors.. CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made

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Cocaine induces input and cell-type-specific synaptic plasticity in ventral pallidum-projecting nucleus accumbens medium spiny neurons

Cited by 10 publications

References 108 publications

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

NPAS4 supports drug-cue associations and relapse-like behavior through regulation of the cell type-specific activation balance in the nucleus accumbens

Ventral subiculum inputs to nucleus accumbens medial shell preferentially innervate D2R medium spiny neurons and contain calcium permeable AMPARs

Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward

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