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Cortico-Basal Ganglia Interactions

Objective

The research lab of Associate Professor Mattias Rickhag has established strong expertise in cellular neuroscience and viral modulation platforms for studying cortico-basal ganglia circuits in health and disease.

We implement state-of-the-art genetic and viral-based tool allowing cell-type specific manipulations of cortical neuronal subsets to causally dissect these neural circuits and its relation to behavior using animal models. By use of engineered receptors (chemogenetics) and light-activated ion channels (optogenetics) in transgenic mouse models, we are able to target specific neuronal subsets and perturb their activity and correlate with behavioral outcomes.

In parallel, we use pharmacological and toxin-based models of Parkinson’s disease (PD) in mice to mimic key motor symptomatology and whether targeted circuit modulation can reduce PD motor symptoms.  It is the ambition that our research will fill major knowledge gaps regarding the involvement of cortico-basal ganglia systems for the genesis of parkinsonian motor symptoms and how to target them. Thus, we provide a strong link between preclinical and clinical research at DRCMR framing an interdisciplinary environment research that will yield mechanistic insights for how the motor cortex communicates with the basal ganglia to govern motor behavior.

Key Projects

  • Role of Cortico-striatal projection systems in dopaminergic dyskinesias - supported by the Michael J. Fox Foundation, US
  • ADAptive and Precise brain-circuit Targeting in Parkinson's disease (ADAPT-PD) - supported by the Lundbeck Foundation

Selected Publications

Atudorei M, del Agua Villa C, Gether U, Cenci MA, Siebner HR and Rickhag M (2025) Bilateral chemogenetic activation of Intratelencephalic Neurons in Motor Cortex Reduces Spontaneous Locomotor Activity in Mice. Neurobiology of Disease. 2024 Nov 26:106755. doi: 10.1016/j.nbd.2024.106755)

Del Agua Villa C, Atudorei M, Siebner HR and Rickhag M (2024) Pharmacological Targeting of Dopamine D1 or D2 Receptors Evokes a Rapid-Onset, Distinct Parkinsonian Motor Phenotype in Mice. European Journal of Neuroscience. 2024 Dec 3. doi: 10.1111/ejn.16622)

Apuschkin M, Støier JF, Skov L, Ejdrup A, Chan Andersen R, Dmytriyeva O,  Sørensen AT, Egerod K, Holst B,  Rickhag M,  Schwartz T and Gether U (2024) An atlas of GPCRs in dopamine neurons: identification of the free fatty acid receptor-4 (FFAR4) as a regulator of food and water intake. (2024 Jul 23;43(7):114509. doi: 10.1016 - Cell Reports)

Herborg F, Konrad L, Pugh C, Delignat-Lavaud B, Friis Rather C, , Awadallah N, Pino Reyes J, Berlin F, Rickhag M, Torres G, Holst B, Trudeau LE and Gether U (2023) Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and psychiatric disease. bioRxiv, 2023.08. 17.553695

Sørensen G, Rickhag M, Leo D, Lycas MD, Ridderstrøm PH, Weikop P, Lilja JH, Rifes P, Herborg F, Woldbye D, Wörtwein G, Gainetdinov RR, Fink-Jensen A, Gether U, Disruption of the PDZ-domain binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis and reward motivation, Journal of Biological Chemistry (2021), doi: https:// doi.org/10.1016/j.jbc.2021.101361.

Herborg F, Jensen K, Tolstoy S, Arends N, Posselt L, Shekar A, Aguilar J, Lund V, Erreger K, Rickhag M, Lycas M, Lonsdale M, Rahbek-Clemmensen T, Sørensen A, Newman A, Løkkegaard A, Kjærulff O, Hansen T, Møller L, Matthies H, Galli A, Hjermind L, Gether U (2021) Dominant-negative actions of a dopamine transporter variant identified in patients with parkinsonism and neuropsychiatric disease. Journal of Clinical Investigation Insight 2021 Aug 10:151496

Christensen M, Nørr SE, Gether U and Rickhag M (2021). Direct-Pathway Spiny Projection Neuron Inhibition Evokes Transient Circuit Imbalance Manifested as Rotational Behavior.  Neuroscience. 2021 Jan 15;453:32-42

Ciriachi C, Svane-Petersen D and Rickhag M (2019). Genetic Tools to Study Complexity of Striatal Function. Journal of Neuroscience Research. 2019 Oct;97(10):1181-1193

DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, Hashemi P, Herborg F, Rickhag M, Chen H, Gether U, Wallace MT, Galli A (2019). Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. Journal of Clinical Investigation. 2019 May 16;129(8):3407-3419.

Bay Kønig A, Ciriachi C, Gether U and Rickhag M (2019). Chemogenetic Targeting of Dorsomedial Direct-Pathway Striatal Projection Neurons Selectively Elicits Rotational Behavior in Mice. Neuroscience. 2019 Mar 1; 401:106-116

Runegaard A, Sørensen AT, Fitzpatrick C, Jørgensen S, Petersen A, Hansen N, Weikop P, Andreasen J, Mikkelsen J, Perrier JF, Woldbye D, Rickhag M, Wörtwein G and Gether U (2018). Locomotor- and reward-enhancing effects of cocaine are differentially regulated by chemogenetic stimulation of Gi-signaling in dopaminergic neurons. eNeuro: 0345-17.2018 

Jensen K, Sørensen G, Dencker D, Owens W, Rahbek-Clemmensen T, Brett Lever M, Runegaard A, Riis Christensen N, Weikop P, Wörtwein G, Fink-Jensen A, Madsen K, Daws L, Gether U and Rickhag M (2018). PICK1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis. eNeuro:0422-17.2018

Jensen KL, Runegaard AH, Weikop P, Gether U and Rickhag M (2017). Assessment of Dopaminergic Homeostasis in Mice by Use of High-Performance Liquid Chromatography Analysis and Synaptosomal Dopamine Uptake. Journal of Visualized Experiments, 127, e56093, doi:10.3791/56093

Runegaard AH, Jensen KL, Fitzpatrick CM, Dencker D, Weikop P, Gether U and Rickhag M (2017). Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice. European Journal of Neuroscience, 45(1):121-128

Apuschkin M, Stilling S, Rahbek-Clemmensen T, Sørensen G, Fortin G, Herborg Hansen F, Eriksen J, Trudeau LE, Egerod K, Gether U and Rickhag M (2015). A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity. European Journal of Neuroscience 42: 2438-2454

Steinkellner T, Montgomery TR, Hofmaier T, Kudlacek O, Yang JW, Rickhag M, Jung G, Lubec G, Gether U, Freissmuth M, Sitte HH (2015). Amphetamine action at the cocaine- and antidepressant sensitive serotonin transporter is modulated by αCaMKII. Journal of Neuroscience 27;35(21):8258-71

Steinkellner T, Mus L, Eisenrauch B, Constantinescu A, Leo D, Konrad L, Rickhag M, Sørensen G, Efimova EV, Kong E, Willeit M, Sotnikova TD, Kudlacek O, Gether U, Freissmuth M, Pollak DD, Gainetdinov RR, Sitte HH (2014). In vivo amphetamine action is contingent on alpha-CaMKII. Neuropsychopharmacology 39(11): 2681-93

Rickhag M, Owens WA, Winkler MT, Strandfelt KN, Rathje M, Andresen B, Sørensen G, Madsen KL, Jørgensen TN, Wörtwein G, Woldbye DP, Sitte H, Daws LC and Gether U (2013).  Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release. Journal of Biological Chemistry 20;288(38): 27534-44

Rickhag M, Hansen FH, Sørensen G, Strandfelt KN, Andresen B, Gotfryd K, Madsen KL, Vestergaard-Klewe I, Ammendrup-Johnsen I, Eriksen J, Newman AH, Füchtbauer EM, Gomeza J, Woldbye DP, Wörtwein G and Gether U (2013). A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter. Nature Communications 4:1580

Holst B, Madsen KL, Jansen AM, Jin C, Rickhag M, Lund VK, Jensen M, Bhatia V, Sørensen G, Madsen AN, Xue Z, Møller SK, Woldbye DP, Qvortrup K, Huganir R, Stamou D, Kjærulff O and Gether U. (2013). PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance. PLoS Biology 11(4):e1001542

Ruscher K, Shamloo M, Rickhag M, Ladunga I, Soriano L, Gisselsson L, Toresson H, Ruslim-Litrus L, Oksenberg D, Urfer R, Johansson BB, Nikolich K and Wieloch T  (2011). The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain 134(3): 732-46

Ruscher K, Johannesson E, Brugiere E, Erickson A, Rickhag M and Wieloch T (2009). Enriched enviroment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke. Journal of Cerebral Blood Flow and Metabolism 29(11): 1796-805

Ruscher K, Johannesson E, Rickhag M and Wieloch T (2009). Spatio-temporal changes of apolipoprotein E (ApoE) in the rat brain after experimental stroke. Enriched housing condition attenuates ApoE expression. Journal of Cerebral Blood Flow and Metabolism 29, S267-S267

Rickhag M, Deierborg T, Patel S, Ruscher K and Wieloch T (2008). Apolipoprotein D is elevated in oligodendrocytes in the peri-infarct region after experimental stroke – Influence of enriched environment. Journal of Cerebral Blood Flow and Metabolism 28(3): 551-62;

Rickhag M, Teilum M and Wieloch T (2007). Rapid and long-term induction of effector immediate-early genes (BDNF, Neuritin and Arc) in peri-infarct cortex and dentate gyrus after ischemic injury in rat brain. Brain Research. 1151: 203-210

Shamloo M, Soriano L, von Schack D, Rickhag M, Chin DJ, Gonzalez-Zulueta M, Gido G, Urfer R, Wieloch T and Nikolich K (2006). Npas4, a novel helix-loop-helix PAS domain protein, is regulated in response to cerebral ischemia. European Journal of Neuroscience. 24(10): 2705-2720

Takao K, Rickhag M, Hegardt C, Oredsson S and Persson L (2006). Induction of apoptotic cell death by putrescine. Int J Biochem Cell Biol. 38(4): 621-8

Rickhag M, Wieloch T, Gidö G, Elmer E, Krogh M, Murray J, Lohr S, Bitter H, Chin DJ, von Schack D, Shamloo M and Nikolich K (2006). Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. Journal of Neurochemistry. 96(1): 14-29 

Urfer R, Rickhag M, Oksenberg D, Shamloo M, Lohr S, Murray J, Krogh M, Johansson B, Nikolich K, Wieloch T (2005). A new approach to enhancement of functional recovery after stroke by genomics analysis of the enriched environment model. Stroke. 36(2): 427-428

Group Members

Mattias Rickhag

Group Leader

Hartwig R. Siebner

Mihai Atudorei

Show all group members (5)

External Collaborators

Professor Angela Cenci Nilsson
Lund University, Sweden


Professor Ulrik Gether
University of Copenhagen, Denmark


Professor Gilad Silberberg
Karolinska Institutet, Sweden