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Article ; Online: Within-Mice Comparison of Microdialysis and Fiber Photometry-Recorded Dopamine Biosensor during Amphetamine Response.

Ejdrup, Aske L / Wellbourne-Wood, Joel / Dreyer, Jakob K / Guldhammer, Nina / Lycas, Matthew D / Gether, Ulrik / Hall, Benjamin J / Sørensen, Gunnar

ACS chemical neuroscience

2023 Volume 14, Issue 9, Page(s) 1622–1630

Abstract: A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and -peptides. For the past decades, the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). ...

Abstract	A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and -peptides. For the past decades, the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). The emergence of genetically encoded fluorescence-based biosensors, as well as
MeSH term(s)	Mice ; Animals ; Amphetamine/pharmacology ; Dopamine ; Microdialysis/methods ; Corpus Striatum ; Synaptic Transmission
Chemical Substances	Amphetamine (CK833KGX7E) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00817
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Article ; Online: A density-based enrichment measure for assessing colocalization in single-molecule localization microscopy data.

Ejdrup, Aske L / Lycas, Matthew D / Lorenzen, Niels / Konomi, Ainoa / Herborg, Freja / Madsen, Kenneth L / Gether, Ulrik

Nature communications

2022 Volume 13, Issue 1, Page(s) 4388

Abstract: Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by ... ...

Abstract	Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by current analysis tools that often reduce colocalization to a single value. Here, we describe a tool specifically designed for determination of co-localization in both 2D and 3D from SMLM data. The approach uses a function that describes the relative enrichment of one molecular species on the density distribution of a reference species. The function reframes the question of colocalization by providing a density-context relevant to multiple biological questions. Moreover, the function visualize enrichment (i.e. colocalization) directly in the images for easy interpretation. We demonstrate the approach's functionality on both simulated data and cultured neurons, and compare it to current alternative measures. The method is available in a Python function for easy and parameter-free implementation.
MeSH term(s)	Microscopy ; Single Molecule Imaging/methods
Language	English
Publishing date	2022-07-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32064-y
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Article: Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.

Christiansen, Line I / Ventura, Gemma C / Holmqvist, Bo / Aasmul-Olsen, Karoline / Lindholm, Sandy E H / Lycas, Matthew D / Mori, Yuki / Secher, Jan Bojsen-Møller / Burrin, Douglas G / Thymann, Thomas / Sangild, Per T / Pankratova, Stanislava

Frontiers in neuroscience

2023 Volume 17, Page(s) 1205819

Abstract: Introduction: Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation ...

Abstract	Introduction: Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants. Methods: Preterm pigs delivered by cesarean section received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage and open field activities, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements. Results: The IGF-1 treatment increased cerebellar protein synthesis rates (both Conclusion: Supplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.
Language	English
Publishing date	2023-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1205819
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Article ; Online: Behavioral encoding across timescales by region-specific dopamine dynamics.

Jørgensen, Søren H / Ejdrup, Aske L / Lycas, Matthew D / Posselt, Leonie P / Madsen, Kenneth L / Tian, Lin / Dreyer, Jakob K / Herborg, Freja / Sørensen, Andreas T / Gether, Ulrik

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 7, Page(s) e2215230120

Abstract: The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled ... ...

Abstract	The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multiregion fiber photometry and machine learning-based analysis to decode dopamine dynamics across the striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running, and grooming on a subsecond-to-minute time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.
MeSH term(s)	Mice ; Animals ; Dopamine ; Ventral Striatum ; Cocaine ; Reward
Chemical Substances	Dopamine (VTD58H1Z2X) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2215230120
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Article ; Online: Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity.

Lycas, Matthew D / Ejdrup, Aske L / Sørensen, Andreas T / Haahr, Nicolai O / Jørgensen, Søren H / Guthrie, Daryl A / Støier, Jonatan F / Werner, Christian / Newman, Amy Hauck / Sauer, Markus / Herborg, Freja / Gether, Ulrik

Cell reports

2022 Volume 40, Issue 13, Page(s) 111431

Abstract: The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application of several super- ... ...

Abstract	The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the DA transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and DA D2 autoreceptor activation in a manner dependent on Ca
MeSH term(s)	Animals ; Autoreceptors/metabolism ; Clathrin/metabolism ; Dopamine/metabolism ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Dopaminergic Neurons/metabolism ; Mice ; Phosphatidylinositols/metabolism ; Qa-SNARE Proteins/metabolism
Chemical Substances	Autoreceptors ; Clathrin ; Dopamine Plasma Membrane Transport Proteins ; Phosphatidylinositols ; Qa-SNARE Proteins ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2022-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111431
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Article ; Online: Modeling the early stages of Alzheimer's disease by administering intracerebroventricular injections of human native Aβ oligomers to rats.

Baerends, Eva / Soud, Katia / Folke, Jonas / Pedersen, Anna-Kathrine / Henmar, Simon / Konrad, Lisa / Lycas, Matthew D / Mori, Yuki / Pakkenberg, Bente / Woldbye, David P D / Dmytriyeva, Oksana / Pankratova, Stanislava

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 113

Abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease characterized by the accumulation of aggregated amyloid beta (Aβ) and hyperphosphorylated tau along with a slow decline in cognitive functions. Unlike advanced AD, the ... ...

Abstract	Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease characterized by the accumulation of aggregated amyloid beta (Aβ) and hyperphosphorylated tau along with a slow decline in cognitive functions. Unlike advanced AD, the initial steps of AD pathophysiology have been poorly investigated, partially due to limited availability of animal models focused on the early, plaque-free stages of the disease. The aim of this study was to evaluate the early behavioral, anatomical and molecular alterations in wild-type rats following intracerebroventricular injections of human Aβ oligomers (AβOs). Bioactive human AD and nondemented control brain tissue extracts were characterized using ELISA and proteomics approaches. Following a bilateral infusion, rats underwent behavioral testing, including the elevated plus maze, social recognition test, Morris water maze and Y-maze within 6 weeks postinjection. An analysis of brain structure was performed with manganese-enhanced MRI. Collected brain tissues were analyzed using stereology, immunohistochemistry, ELISA and qPCR. No sensorimotor deficits affecting motor performance on different maze tasks were observed, nor was spatial memory disturbed in AD rats. In contrast, a significant impairment of social memory became evident at 21 days postinjection. This deficit was associated with a significantly decreased volume of the lateral entorhinal cortex and a tendency toward a decrease in the total brain volume. Significant increase of cleaved caspase-3-positive cells, microglial activation and proinflammatory responses accompanied by altered expression of synaptic markers were observed in the hippocampus of AD rats with immunohistochemical and qPCR approaches at 6 weeks postinjection. Our data suggest that the social memory impairment observed in AβO-injected rats might be determined by neuroinflammatory responses and synaptopathy. An infusion of native oligomeric Aβ in the rat brain represents a feasible tool to model early plaque-free events associated with AD.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Disease Models, Animal ; Hippocampus/metabolism ; Humans ; Maze Learning/physiology ; Neurodegenerative Diseases/metabolism ; Plaque, Amyloid/metabolism ; Rats
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2022-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01417-5
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Article ; Online: Disruption of the PDZ domain-binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis, and reward motivation.

Sørensen, Gunnar / Rickhag, Mattias / Leo, Damiana / Lycas, Matthew D / Ridderstrøm, Pernille Herrstedt / Weikop, Pia / Lilja, Jamila H / Rifes, Pedro / Herborg, Freja / Woldbye, David / Wörtwein, Gitta / Gainetdinov, Raul R / Fink-Jensen, Anders / Gether, Ulrik

The Journal of biological chemistry

2021 Volume 297, Issue 6, Page(s) 101361

Abstract: The dopamine (DA) transporter (DAT) is part of a presynaptic multiprotein network involving interactions with scaffold proteins via its C-terminal PDZ domain-binding sequence. Using a mouse model expressing DAT with mutated PDZ-binding sequence (DAT-AAA), ...

Abstract	The dopamine (DA) transporter (DAT) is part of a presynaptic multiprotein network involving interactions with scaffold proteins via its C-terminal PDZ domain-binding sequence. Using a mouse model expressing DAT with mutated PDZ-binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here, we show by application of direct stochastic reconstruction microscopy not only that the striatal level of transporter is reduced in DAT-AAA mice but also that the nanoscale distribution of this transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal DA adaptations and changes in DA-related behaviors distinct from those seen in other genetic DAT mouse models. DA levels in the striatum are reduced to ∼45% of that of WT, accompanied by elevated DA turnover. Nonetheless, fast-scan cyclic voltammetry recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared with WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels, whereas immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed ratio of one and progressive ratio schedule of reinforcement but a reduction compared with WT when using cocaine as reinforcer. In summary, our data demonstrate how disruption of PDZ domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics and related behaviors.
MeSH term(s)	Animals ; Binding Sites ; Cocaine/administration & dosage ; Conditioning, Operant ; Dopamine/metabolism ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Homeostasis ; Male ; Mice ; Motivation ; PDZ Domains ; Protein Binding ; Reward ; Self Administration
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101361
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Article ; Online: Wheel running exercise attenuates vulnerability to self-administer nicotine in rats.

Sanchez, Victoria / Lycas, Matthew D / Lynch, Wendy J / Brunzell, Darlene H

Drug and alcohol dependence

2015 Volume 156, Page(s) 193–198

Abstract: Background: Preventing or postponing tobacco use initiation could greatly reduce the number of tobacco-related deaths. While evidence suggests that exercise is a promising treatment for tobacco addiction, it is not clear whether exercise could prevent ... ...

Abstract	Background: Preventing or postponing tobacco use initiation could greatly reduce the number of tobacco-related deaths. While evidence suggests that exercise is a promising treatment for tobacco addiction, it is not clear whether exercise could prevent initial vulnerability to tobacco use. Thus, using an animal model, we examined whether exercise attenuates vulnerability to the use and reinforcing effects of nicotine, the primary addictive chemical in tobacco. Methods: Initial vulnerability was assessed using an acquisition procedure wherein exercising (unlocked running wheel, n=10) and sedentary (locked or no wheel, n=12) male adolescent rats had access to nicotine infusions (0.01-mg/kg) during daily 21.5-h sessions beginning on postnatal day 30. Exercise/sedentary sessions (2-h/day) were conducted prior to each of the acquisition sessions. The effects of exercise on nicotine's reinforcing effects were further assessed in separate groups of exercising (unlocked wheel, n=7) and sedentary (no wheel, n=5) rats responding for nicotine under a progressive-ratio schedule with exercise/sedentary sessions (2-h/day) conducted before the daily progressive-ratio sessions. Results: While high rates of acquisition of nicotine self-administration were observed among both groups of sedentary controls, acquisition was robustly attenuated in the exercise group with only 20% of exercising rats meeting the acquisition criterion within the 16-day testing period as compared to 67% of the sedentary controls. Exercise also decreased progressive-ratio responding for nicotine as compared to baseline and to sedentary controls. Conclusions: Exercise may effectively prevent the initiation of nicotine use in adolescents by reducing the reinforcing effects of nicotine.
MeSH term(s)	Aging/psychology ; Animals ; Conditioning, Operant ; Dose-Response Relationship, Drug ; Infusions, Intravenous ; Male ; Physical Conditioning, Animal/psychology ; Physical Exertion ; Rats ; Rats, Sprague-Dawley ; Reinforcement (Psychology) ; Reinforcement Schedule ; Running/psychology ; Sedentary Lifestyle ; Self Administration ; Tobacco Use Disorder/psychology
Language	English
Publishing date	2015-11-01
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2015.09.022
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Article ; Online: Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.

The Journal of clinical investigation

2022 Volume 132, Issue 5

Abstract: Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been ... ...

Abstract	Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been demonstrated to coordinate the budding and formation of immature secretory granules (ISGs) at the trans-Golgi network. Here, we identify 4 coding variants in the PICK1 gene from a whole-exome screening of Danish patients with diabetes that each involve a change in positively charged residues in the PICK1 BAR domain. All 4 coding variants failed to rescue insulin content in INS-1E cells upon knock down of endogenous PICK1. Moreover, 2 variants showed dominant-negative properties. In vitro assays addressing BAR domain function suggested that the coding variants compromised BAR domain function but increased the capacity to cause fission of liposomes. Live confocal microscopy and super-resolution microscopy further revealed that PICK1 resides transiently on ISGs before egress via vesicular budding events. Interestingly, this egress of PICK1 was accelerated in the coding variants. We propose that PICK1 assists in or complements the removal of excess membrane and generic membrane trafficking proteins, and possibly also insulin, from ISGs during the maturation process; and that the coding variants may cause premature budding, possibly explaining their dominant-negative function.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Carrier Proteins/genetics ; Cell Membrane/metabolism ; Diabetes Mellitus/genetics ; Diabetes Mellitus/metabolism ; Humans ; Insulin/genetics ; Insulin/metabolism ; Nerve Tissue Proteins ; Nuclear Proteins/metabolism ; Protein Binding
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Insulin ; Nerve Tissue Proteins ; Nuclear Proteins ; PICk1 protein, human ; amphiphysin (147954-52-7)
Language	English
Publishing date	2022-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI144904
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Article ; Online: Acute and chronic administration of a low-dose combination of topiramate and ondansetron reduces ethanol's reinforcing effects in male alcohol preferring (P) rats.

Moore, Catherine F / Lycas, Matthew D / Bond, Colin W / Johnson, Bankole A / Lynch, Wendy J

Experimental and clinical psychopharmacology

2014 Volume 22, Issue 1, Page(s) 35–42

Abstract: Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of ... ...

Abstract	Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol's reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N = 22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared with the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. Although both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (Days 1-5), after repeated administration (Days 6-10), only the combination produced a sustained reduction in ethanol-maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol's reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs.
MeSH term(s)	Alcohol-Related Disorders/drug therapy ; Animals ; Behavior, Animal/drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Therapy, Combination ; Ethanol/administration & dosage ; Ethanol/pharmacology ; Fructose/administration & dosage ; Fructose/analogs & derivatives ; Fructose/pharmacology ; GABA Modulators/administration & dosage ; GABA Modulators/pharmacology ; Male ; Ondansetron/administration & dosage ; Ondansetron/pharmacology ; Rats ; Reinforcement Schedule ; Serotonin Antagonists/administration & dosage ; Serotonin Antagonists/pharmacology ; Time Factors ; Topiramate
Chemical Substances	GABA Modulators ; Serotonin Antagonists ; Topiramate (0H73WJJ391) ; Fructose (30237-26-4) ; Ethanol (3K9958V90M) ; Ondansetron (4AF302ESOS)
Language	English
Publishing date	2014-02-03
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1209960-0
ISSN	1936-2293 ; 1064-1297
ISSN (online)	1936-2293
ISSN	1064-1297
DOI	10.1037/a0035215
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