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      Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

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          Abstract

          Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2 −/− mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2 −/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2 −/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

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          Most cited references72

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          Diagnostic and Statistical Manual of Mental Disorders

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            Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

            Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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              Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

              Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
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                Author and article information

                Contributors
                glerup@biomed.au.dk
                an@biomed.au.dk
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                25 January 2021
                25 January 2021
                2021
                : 11
                : 74
                Affiliations
                [1 ]GRID grid.7048.b, ISNI 0000 0001 1956 2722, Department of Biomedicine, , Aarhus University, ; Hoegh-Guldbergsgade 10, DK-8000 Aarhus C, Denmark
                [2 ]GRID grid.424580.f, ISNI 0000 0004 0476 7612, Neurodegeneration and Biologics, H. Lundbeck A/S, ; Ottiliavej 9, DK-2500 Valby, Denmark
                [3 ]GRID grid.7048.b, ISNI 0000 0001 1956 2722, Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, , Aarhus University, ; Hoegh-Guldbergsgade 10, DK-8000 Aarhus C, Denmark
                [4 ]GRID grid.7048.b, ISNI 0000 0001 1956 2722, The Danish National Research Foundation Center PROMEMO, , Aarhus University, ; Hoegh-Guldbergsgade 10, DK-8000 Aarhus C, Denmark
                [5 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Neurosurgery, , Skejby University Hospital, ; Palle Juul-Jensens Blvd. 99, DK-8200 Aarhus N, Denmark
                [6 ]GRID grid.7048.b, ISNI 0000 0001 1956 2722, Present Address: Department of Biomedicine, , Aarhus University, ; Hoegh-Guldbergsgade 10, DK-8000 Aarhus C, Denmark
                Author information
                http://orcid.org/0000-0002-4200-9543
                http://orcid.org/0000-0002-9686-8124
                http://orcid.org/0000-0001-6422-6736
                Article
                1199
                10.1038/s41398-021-01199-9
                7835366
                33495438
                00b57718-dbf8-4f0d-b6e2-d96fc40721f4
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 July 2018
                : 12 December 2020
                : 5 January 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003554, Lundbeckfonden (Lundbeck Foundation);
                Award ID: R151-2013-14202
                Award ID: R198-2015-168
                Award Recipient :
                Funded by: Danish Ministry of Higher Education and Science
                Funded by: FundRef https://doi.org/10.13039/501100009708, Novo Nordisk Fonden (Novo Nordisk Foundation);
                Funded by: FundRef https://doi.org/10.13039/501100002808, Carlsbergfondet (Carlsberg Foundation);
                Funded by: The Danish Council for Independent Research Sapere Aude starting grant (Grant No. DFF 4183-00604)
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Clinical Psychology & Psychiatry
                adhd,molecular neuroscience
                Clinical Psychology & Psychiatry
                adhd, molecular neuroscience

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