Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders

Hadar, Ravit; Edemann-Callesen, Henriette; Reinel, Claudia; Wieske, Franziska; Voget, Mareike; Popova, Elena; Sohr, Reinhard; Avchalumov, Yosef; Priller, Josef; Riesen, Christoph van; Puls, Imke; Bäder, Michael; Winter, Christine

doi:10.1038/srep39145

Cited by 13 publications

(18 citation statements)

References 48 publications

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“…As identified by Hadar et al, 28 DAT-tg rats display a time-locked induction of repetitive behavior following the injection of amphetamine. In this experiment, animals were injected with amphetamine (2.0 mg/kg, i.p., dissolved in 0.9% saline at a volume of 1.0 ml/kg, Sigma Aldrich, Germany) and thereafter immediately subjected to stimulation (either tDCS or DBS).…”

Section: Methodsmentioning

confidence: 77%

“…Experiments were performed in accordance to the European Communities Council Directive of 22 September 2010 (2010/63/EU) after approval by the local ethics committees (Senate of Berlin, Regierungspräsidium Dresden). Experiments were conducted on male Wistar DAT-tg rats ( n = 38) and their respective littermate controls ( wild types (wt ) ( n = 37) with a Sprague Dawley background once they reached postnatal day (PND) >90 28 . Following surgery, animals were single housed in a 12 h light/dark cycle (light on at 06:00 am) with food and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…Animals in the control group only received sham stimulation (see S I , Table S1 for overview of group specifics and number of animals). The repetitive behavioral paradigm described by Hadar et al 28 was employed to study the effect of tDCS and DBS on behavior. Stimulation was applied in the beginning of the paradigm and subsequent behavior was assessed during the stereotypy phase.…”

Section: Methodsmentioning

confidence: 99%

“…administration of the α2 adrenergic and imidazoline receptor agonist clonidine. The occurrence of repetitive behavior in the DAT-tg rat is time locked, which allows for evaluation of therapeutic interventions when behavioral manifestation is proven to be most prominent 28 .…”

Section: Introductionmentioning

confidence: 99%

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Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

et al. 2018

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Involuntary movements as seen in repetitive disorders such as Tourette Syndrome (TS) results from cortical hyperexcitability that arise due to striato-thalamo-cortical circuit (STC) imbalance. Transcranial direct current stimulation (tDCS) is a stimulation procedure that changes cortical excitability, yet its relevance in repetitive disorders such as TS remains largely unexplored. Here, we employed the dopamine transporter-overexpressing (DAT-tg) rat model to investigate behavioral and neurobiological effects of frontal tDCS. The outcome of tDCS was pathology dependent, as anodal tDCS decreased repetitive behavior in the DAT-tg rats yet increased it in wild-type (wt) rats. Extensive deep brain stimulation (DBS) application and computational modeling assigned the response in DAT-tg rats to the sensorimotor pathway. Neurobiological assessment revealed cortical activity changes and increase in striatal inhibitory properties in the DAT-tg rats. Our findings show that tDCS reduces repetitive behavior in the DAT-tg rat through modulation of the sensorimotor STC circuit. This sets the stage for further investigating the usage of tDCS in repetitive disorders such as TS.

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Section: Methodsmentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

et al. 2018

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“…The method of random transgene integration employed in this study may be viewed as a limitation when compared with the locus specific genome editing afforded by clustered regularly interspaced short palindromic repeats (CRISPR) technology [32]. However, this method for gene overexpression is still regularly used to generate genetically engineered rodent models, requires short development time and importantly is a method that we have previous success with in rats [33][34][35][36][37]. The generation of more than one transgenic line, using the same transgene and promoter, is critical to confirm that the phenotypic differences are the result of the transgene itself and not due to positional effects caused at the random insertion site.…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of glutathione S-transferase μ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat

Olson

Pravenec

Landa

et al. 2019

Journal of Hypertension

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Background: Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase m-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke-prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. Method: Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF-1a promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1 WKY and SHRSP-Tg(Gstm1)2 WKY ]. Results: Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2 AE 3.7 mmHg vs. SHRSP-Tg(Gstm1)1 WKY 175.5 AE 1.6 mmHg and SHRSP-Tg(Gstm1)2 WKY 172 AE 3.2 mmHg, P < 0.001; pulse pressure: SHRSP 58.4 AE 0.73 mmHg vs. SHRSP-Tg(Gstm1)1 WKY 52.7 AE 0.19 mmHg and SHRSP-Tg(Gstm1)2 WKY 40.7 AE 0.53 mmHg, P < 0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification (RQ): SHRSP-Tg(Gstm1)1 WKY 1.95 vs. SHRSP 1.0, P < 0.01; aorta RQ: SHRSP-Tg(Gstm1)1 WKY 2.8 vs. SHRSP 1.0, P < 0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidized : reduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04 AE 0.009 mmol/l vs. SHRSP-Tg(Gstm1)1 WKY 0.024 AE 0.002 mmol/l and SHRSP-Tg(Gstm1)2 WKY 0.021 AE 0.002 mmol/l; (oxidized : reduced glutathione ratio): SHRSP 5.19 AE 2.26 mmol/l vs. SHRSP-Tg(Gstm1)1 WKY 0.17 AE 0.11 mmol/l and SHRSP-Tg(Gstm1)2 WKY 0.47 AE 0.22 mmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. Conclusion: These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.

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Direct reprogramming into interneurons: potential for brain repair

Pereira

Birtele

Ottosson

2019

Cell. Mol. Life Sci.

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The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient’s own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.

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Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders

Cited by 13 publications

References 48 publications

Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

Transgenic overexpression of glutathione S-transferase μ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat

Direct reprogramming into interneurons: potential for brain repair

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