Activity in projection neurons from prelimbic cortex to the PVT is necessary for retrieval of morphine withdrawal memory

Yu, Lan-Fang; Chu, Chenshan; Yu, Yuan; Guo, Xinli; Lei, Chao; Sheng, Huan; Yang, Li; Cui, Dongyang; Lai, Bin; Zheng, Ping

doi:10.1016/j.celrep.2021.108958

Cited by 8 publications

(5 citation statements)

References 28 publications

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“…The mouse homolog of KCNN1 is differentially expressed in the nucleus accumbens following chronic morphine exposure 52 . The gene is also downregulated in the rodent prelimbic cortex after exposure to cues associated with morphine withdrawal 53 , suggesting a connection to learning and memory. NCAM1 also appears to be involved in the response to morphine exposure.…”

Section: Discussionmentioning

confidence: 99%

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Kember

Vickers-Smith²,

Xu³

et al. 2022

Nat Neurosci

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Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide signi cant (GWS) loci, with replicated ndings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classi cation of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription lls. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10 −10 ), and a recently reported exonic variant in FURIN, we identi ed intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-speci c analyses identi ed an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identi ed a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identi ed 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Signi cant genetic correlations (r g 's) were identi ed for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most signi cantly enriched cell type group was the central nervous system with gene-expression enrichment identi ed in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identi ed 14 loci for OUD, including 12 novel loci, some of which were ancestry speci c. These ndings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic. Revision (ICD-10) diagnosis of OUD and control subjects were opioid exposed. Further details on phenotyping are described below. This GWAS was used for all subsequent downstream analyses.In a supplementary analysis, we performed within-ancestry meta-analyses for AAs and EAs from the MVP, Yale-Penn

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Section: Discussionmentioning

confidence: 99%

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Kember

Vickers-Smith²,

Xu³

et al. 2022

Nat Neurosci

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“…The active circuits of PL projections, such as those of the PL–NAc circuit, cause a change in social preferences [ 16 ], while PL–VTA or PL–PVT circuit activation is necessary for the retrieval of morphine withdrawal memory [ 45 ] and the locomotion velocity in the 3-Chamber Assay [ 16 ], respectively. Here, our study sheds light on a previously unrecognized role of activation of distinct PL–dSTR/BLA pathways differentially drives autism- and anxiety-like behaviors.…”

Section: Discussionmentioning

confidence: 99%

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors

Luo

Song

et al. 2023

Mol Psychiatry

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The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs–dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs–BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL–dSTR or PL–BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL–dSTR and PL–BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

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“…Based on our findings and those of others, it is tempting to simplify the role of the PVT in reward processing by stating that when activated, the PVT evokes aversive behaviors and when inhibited, the PVT generates behaviors associated with positive reinforcement. However, reward processing encompasses a multitude of complex neural and behavioral functions that are regulated by the PVT, including arousal/wakefulness ( Gent et al, 2018 ; Ren et al, 2018 ; Wang et al, 2021 ; Eacret et al, 2023 ), stress ( Penzo et al, 2015 ; Öz et al, 2017 ; Bengoetxea et al, 2020 ; Dong et al, 2020 ; Yu et al, 2021 ; Corbett et al, 2022a , b ), learning and memory ( Hamlin et al, 2009 ; Li et al, 2011 ; Browning et al, 2014 ; Haight et al, 2015 ; Otis et al, 2017 , 2019 ; Keyes et al, 2020 ), prediction ( Munkhzaya et al, 2020 ), and reinforcement ( Marchant et al, 2010 ; Matzeu et al, 2015 ; Labouèbe et al, 2016 ; Zhang and van den Pol, 2017 ; Cheng et al, 2018 ; Giannotti et al, 2018 , 2021 ; Kuhn et al, 2018 ; Campus et al, 2019 ; Lafferty et al, 2020 ; Matzeu and Martin-Fardon, 2020 ; Chisholm et al, 2021 ; Kessler et al, 2021 ; Vollmer et al, 2022 ; Brown and Chaudhri, 2023 ). Therefore, it is more likely that the role of the PVT in reward processing is nuanced and multifaceted, depending upon the specific stage of reward learning, the type of reward (natural or drug-related), the PVT region (e.g., anterior, middle, posterior), the PVT cell type ( Gao et al, 2023 ), and the brain regions that the PVT interacts with.…”

Section: Discussionmentioning

confidence: 99%

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations

McDevitt,

Wade,

McKendrick

et al. 2024

eNeuro

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The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse) are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, whole-cell brain slice electrophysiology recordings on PVT neurons that project to the NAcSh showed that bath perfusion of morphine (10 μM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath perfused morphine (10 μM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1-receptor and D2-receptor expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP. Together, these results provide valuable insights into the intricate interplay between the PVT and reward-related behaviors.Significance StatementThis study investigates the direct impact of paraventricular thalamic nucleus (PVT) inhibition on reward-related behaviors, employing manipulations related to drugs of abuse, specifically morphine, as well as employing chemogenetic approaches that replicate the inhibitory effects induced by morphine. Our findings reveal that morphine exerts an inhibitory effect on PVT neurons projecting to the nucleus accumbens shell (NAcSh). Furthermore, local administration of morphine within the PVT elicits reward-related behaviors, a response mimicked by the inhibition of PVT neurons projecting to the NAcSh. These results firmly establish the PVT as an integral component of a complex neurocircuit involved in the acquisition of associations with opioid-related contexts. Additionally, these results provide compelling evidence linking the inhibition of PVT neurons to reward processes.

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Activity in projection neurons from prelimbic cortex to the PVT is necessary for retrieval of morphine withdrawal memory

Abstract: Highlights d Conditioned context activates PrL-PVT projection neurons in morphine-withdrawn mice d Silencing of PrL-PVT projection neurons inhibits withdrawal memory retrieval d Context induces an increase in neural plasticity in PrL-PVT projection neurons

Cited by 8 publications

References 28 publications

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations

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