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  • 1.
    Barchiesi, Riccardo
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Overlapping Neural Substrates of Alcohol- and Anxiety-Related Behavior in the Rat2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alcohol use is a leading cause of death and disease worldwide. A large part of this disease burden is associated with alcohol use disorder (AUD), a diagnostic category characterized by excessive use in spite of negative consequences ("compulsive use"), a loss of control over intake, and choice of alcohol over natural rewards. These behavioral symptoms are believed to reflect the emergence of persistent neuroadaptations in key brain regions that exert control over motivated behavior. A major challenge to addressing the treatment needs of patients with AUD is the high prevalence of co-occurring psychiatric disorders, of which anxiety disorders are the most common. Both AUD and anxiety disorders are characterized by broad changes in gene expression within brain regions that include the prelimbic cortex (PL) and the amygdala complex. Although the risk for AUD has a substantial genetic component, heavy alcohol use and stress also contribute to disease risk. 

    Our lab previously identified DNA hypermethylation as a mechanism behind alcohol-induced downregulation of prelimbic Syt1 and Prdm2. In a subsequent study, our lab demonstrated a functional role of Prdm2 in alcohol-associated behaviors. In the work that constitutes this thesis, we have further investigated the behavioral consequences of Syt1 and Prdm2 downregulation. We found that Syt1 knock-down in the PL of non-dependent rats is sufficient to promote several behaviors that model critical aspects of AUD. We further identified the PL-basolateral amygdala (BLA) projection as a key brain circuit within which Syt1 knock-down promotes compulsive-like alcohol intake. In another study, we showed that Prdm2 knock-down in the PL increases the expression of fear memory, a central feature of anxiety disorders. Knock-down after memory formation (consolidation) did not increase the fear expression, indicating that Prdm2 regulates fear memory consolidation. We further showed that knock-down of Prdm2 in the PL-BLA projection was sufficient to promote the increased fear expression. Transcriptome analysis specifically in neurons projecting from the PL to the BLA showed a marked up-regulation of genes involved in synaptogenesis, suggesting that Prdm2 downregulation leads to excessive fear by strengthening fear memory consolidation in the PL-BLA circuit. 

    In a third study, we used a model of social defeat- and witness stress to investigate mechanisms of co-occurring escalated alcohol intake and increased anxiety-like behavior ("comorbidity"). We recapitulated the broad range of individual stress responses observed in human populations. With gene expression analysis, we identified a marked upregulation of Avp in the amygdala of rats with "co-morbid" characteristics, and this upregulation correlated with the magnitude of the comorbidity. 

    Together, our findings highlight the contribution of epigenetic mechanisms in regulating the behavioral consequences of alcohol-dependence, and identify specific downstream target genes whose expression is influenced by alcohol-induced epigenetic reprogramming to mediate long-term behavioral consequences. Our work also identifies amygdala Avp as a possible neurobiological substrate of individual susceptibility for stress-induced alcohol- and anxiety-related behaviors.

    List of papers
    1. Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats
    Open this publication in new window or tab >>Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats
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    2021 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 89, no 4, p. 398-406Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. METHODS: We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). RESULTS: Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences ("compulsivity"). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL-basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS: Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL-basolateral amygdala brain circuit.

    Place, publisher, year, edition, pages
    Elsevier Science INC, 2021
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-173626 (URN)10.1016/j.biopsych.2020.08.027 (DOI)000610845900015 ()33160605 (PubMedID)
    Note

    Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [201307434, 2018-028149]; Region Ostergotland; Stiftelsen Psykiatriska Forskningsfonden; Wallenberg FoundationEuropean Commission

    Available from: 2021-02-26 Created: 2021-02-26 Last updated: 2021-12-29
    2. Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats
    Open this publication in new window or tab >>Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats
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    2021 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 26, no 5, article id e13009Article in journal (Refereed) Published
    Abstract [en]

    Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.

    Place, publisher, year, edition, pages
    Wiley, 2021
    Keywords
    alcohol use disorder; anxiety disorders; comorbidity; social defeat stress; vasopressin; witness stress
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-173908 (URN)10.1111/adb.13009 (DOI)000616404100001 ()33565224 (PubMedID)
    Note

    Funding Agencies|Wallenberg FoundationEuropean Commission [KAW 2018.0322]; Region Ostergotland; Stiftelsen psykiatriska forskningsfonden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-07434]

    Available from: 2021-03-09 Created: 2021-03-09 Last updated: 2022-03-18
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  • 2.
    Barchiesi, Riccardo
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Chanthongdee, Kanat
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Mahidol Univ, Thailand.
    Petrella, Michele
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Xu, Li
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Esi
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Coppola, Andrea
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wiskerke, Joost
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Szczot, Ilona
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Augier, Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    An epigenetic mechanism for over-consolidation of fear memories2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 12, p. 4893-4904Article in journal (Refereed)
    Abstract [en]

    Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

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  • 3.
    Domi, Esi
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. School of Pharmacy, Pharmacology Unit, Center for Neuroscience, University of Camerino, Camerino, Italy.
    Barchiesi, Riccardo
    Department of Neuroscience, Waggoner Center for Alcohol and Alcohol Addiction Research, University of Texas at Austin, Austin, TX, USA.
    Barbier, Estelle
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience.
    Epigenetic Dysregulation in Alcohol-Associated Behaviors: Preclinical and Clinical Evidence.2023Chapter in book (Refereed)
    Abstract [en]

    Alcohol use disorder (AUD) is characterized by loss of control over intake and drinking despite harmful consequences. At a molecular level, AUD is associated with long-term neuroadaptations in key brain regions that are involved in reward processing and decision-making. Over the last decades, a great effort has been made to understand the neurobiological basis underlying AUD. Epigenetic mechanisms have emerged as an important mechanism in the regulation of long-term alcohol-induced gene expression changes. Here, we review the literature supporting a role for epigenetic processes in AUD. We particularly focused on the three most studied epigenetic mechanisms: DNA methylation, Histone modification and non-coding RNAs. Clinical studies indicate an association between AUD and DNA methylation both at the gene and global levels. Using behavioral paradigms that mimic some of the characteristics of AUD, preclinical studies demonstrate that changes in epigenetic mechanisms can functionally impact alcohol-associated behaviors. While many studies support a therapeutic potential for targeting epigenetic enzymes, more research is needed to fully understand their role in AUD. Identification of brain circuits underlying alcohol-associated behaviors has made major advances in recent years. However, there are very few studies that investigate how epigenetic mechanisms can affect these circuits or impact the neuronal ensembles that promote alcohol-associated behaviors. Studies that focus on the role of circuit-specific and cell-specific epigenetic changes for clinically relevant alcohol behaviors may provide new insights on the functional role of epigenetic processes in AUD.

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