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A new model to study delay discounting in group housed mice

100%

Szumiec L., Rodriguez Parkitna J.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

BACKGROUND AND AIMS: The immediacy or delay of a reward affect its perceived value. Here we present a new model of assessing delay discounting in group housed mice. METHODS: A group of animals was implanted subcutaneously with radiofrequency identification chips and placed in a cage equipped with sensors for automatic tracking (IntelliCage Plus). Each of the cage’s corners had 2 drinking bottles accessed through a small compartment that allows only one mouse inside. The effect of the delay was assessed by first allowing mice with free access to water or 0.1% saccharin and then progressively increasing the delay till gate blocking the saccharin bottle raised. RESULTS: In line with expectations, while mice initially showed a 95.4% preference for saccharine it decreased to 50% at 17 s delay and finally to 12% at 55 s delay. In the delay discounting model with 3 types of rewards (saccharin 0.01% or 0.1% and water), initial preference of 0.1% saccharine was 92.4%, an increase in delay to 55 s of access decreased preference to 7.8% and caused an increase of preference of the 0.01% saccharine solution from 3.2% to 64.7%. We tested the effects of tranylcypromine, a monoamine oxygenase inhibitor (3 mg/kg, 3 injections in 48 h intervals), cloccinamox, an opioid receptor antagonist (10 mg/kg, single injection) and ketamine, an NMDA receptor partial antagonist (20 mg/kg, single injection) on delay discounting. Treatment with tranylcypromine led to increase in discounting of the delay, at 17 s the saccharin preference was 51% in the control group but only 4% in drug-treated mice. A similar trend towards increased discounting was observed in case of ketamine, while clocinnamox had no effect. CONCLUSIONS: The main advantages of the new model are the ability to test behaviour in the home cage, during natural activity cycles, no interaction with the experimenter and without food deprivation. Further development of the model may permit testing of social effects on discounting.

2

Carbachol-induced NMDA-independent complex bursting of midbrain dopaminergic neurons – in vivo electrophysiological and pharmacological studies on NR1DATCreERTt2 mice

81%

Walczak M., Szumiec L., Rodriguez Parkitna J., Blasiak T.

Acta Neurobiologiae Experimentalis

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2018

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tom 78

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nr Suppl.1

Dopamine plays a key role in the control of behaviour and motor functions. The amount of neurotransmitterreleased into a synapse depends on the firing pattern of dopaminergic neurons, which occurs as a continuum be‑ tween regular and bursting modes of activity. The latter mode results in a phasic increase of dopamine release, whereas a basal level of neurotransmitter is maintained by non-bursting (tonic or irregular) firing of dopaminergic neurons. While functional NMDA receptors are considered crucial for evoking dopaminergic neurons’ bursts of ac‑ tion potentials, it remains an open question whether other neurotransmitters also evoke this type of activity. There‑ fore, the aim of our research was to determine the effect of cholinergic receptor stimulation on the activity of dopa‑ mine neurons lacking functional NMDA receptor. We used a genetically modified strain of mice (NR1DATCreERT2), which allowed us to induce a deletion of the NR1 NMDA receptor subunit selectively on dopaminergic neurons of adult animals. Experiments were performed on urethane anaesthetised animals. We used multi-barrel glass micro‑ pipettes (five barrels), allowing us to combine single unit extracellular recordings of midbrain dopaminergic neu‑ rons’ activity and iontophoresis, local application of drugs (a nonspecific agonist of cholinergic receptors – carbachol; muscarinic and nicotinic receptor antagonists – scopol‑ amine and mecamylamine, respectively; and NMDA). Loss of NMDA receptors on dopaminergic neurons decreased their basal firing rate, attenuated bursting, and abolished responsivity to NMDA compared to wild-type animals. Af‑ ter application of carbachol, the vast majority of dopami‑ nergic neurons increased their firing rate. Interestingly, some of the recorded cells, both in control and NR1DAT‑ CreERT2 mice, developed slow oscillatory changes in firing rate, which transformed into robust complex bursts of ac‑ tion potentials. These results show that agonists of cholin‑ ergic receptors can modulate rate as well as pattern of fir‑ ing of the midbrain dopaminergic neurons. Furthermore, our observations suggest that activation of cholinergic re‑ ceptors alone, i.e. without the involvement of NMDA recep‑ tors, can switch a subpopulation of dopaminergic neurons to a burst firing mode. Funding: NCN, Poland, PRELUDIUM 2015/19/N/NZ4/00960.

3

A test for assessing prosocial behavior in mice

71%

Misiolek K., Harda Z., Baran B., Krzyzowski M., Rodriguez Parkitna J.

Acta Neurobiologiae Experimentalis

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2019

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tom 79

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nr Suppl.1

INTRODUCTION: Prosocial behaviors may be broadly defined as actions that benefit others. While these behaviors are intuitively simple, the underlying mechanism driving prosocial actions are only partly understood, and the methods to observe them under laboratory conditions remain limited. AIM(S): Here, we describe a novel task that assesses prosocial choices in mice and tests the frequency of prosocial behaviors in male and female C57BL/6 animals. METHOD(S): The test measures prosocial behavior towards a familiar conspecific. The tested mouse (actor) is placed in the starting compartment of the cage, from which it may enter two feeding compartments. The stimulus mouse (partner) is placed in the compartment adjacent to both actor’s feeding compartments. The wall between actor’s and partner’s compartments is transparent and perforated. Entering the compartment that was designated as “prosocial” by the actor results in the reward delivery to both actor and partner. Entering the “asocial” compartment results in a reward only for the actor. Pilot experiments were also carried out on an automated version of the test using a Skinner box‑based setup. RESULTS: We found that, on average, male mice had no significant preference for the prosocial choice (n=10, 47.5% ± 9.2% without a partner vs. 47.8±4.9% with a partner). In the case of females, we initially observed a trend towards increased preference of the prosocial decision, but the result did not reach significance when all experiments were pooled (n=14, 46.9±8.0% without a partner vs. 50.8±8.0% with a partner). CONCLUSIONS: Further experiments are required to conclude whether C57BL/6 mice show prosocial behavior towards conspecific cagemates. The results so far suggest that prosocial behavior may possibly be exhibited by females, which is consistent with observations in wild mice.

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Drug-induced gene transcription and the development of addiction

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Rodriguez Parkitna J., Engblom D., Lemberger T., Bilbao Leis A., Spanagel R., Schutz G.

Acta Neurobiologiae Experimentalis

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2007

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tom 67

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nr 3

5

The role of NMDA receptor-dependent neuronal plasticity in the dopamine system in reward-driven learning

61%

Rodriguez Parkitna J., Lopata K., Cieslak P., Szumiec L., Zygmunt M., Sikora M.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

BACKGROUND AND AIMS: Reinforcement-based learning drives behavior towards actions with highest perceived outcome value. It’s essential features are the ability to associate actions or stimuli with rewards, discounting of the delay or probability of the rewards and balance between exploitation of known rewarded actions against exploration of new possibilities. Here we investigate how disrupting NMDA receptor-dependent signaling in the brain’s dopamine systems affects reinforcement learning. METHODS: Genetically modified mice with selective inactivation of NMDA receptors on dopaminergic or dopaminoceptive neurons were generated using the CreERT2/loxP system. Behavior of control and mutant mice was assessed in tasks involving instrumental or Pavlovian learning as well as discounting of reward probability and delay. RESULTS: Inactivation of NMDA receptors on dopaminergic neurons impaired the acquisition of conditioned reinforcement, even though it had no general effect on associative learning. Conversely, in mice with inactivation of NMDA receptors in dopaminoceptive neurons, an opposite phenotype was observed: deficits in associative learning but normal conditioned reinforcement. Interestingly, the effects of the mutations on performance in probabilistic reversal or discounting was limited. CONCLUSIONS: These results show discrete functions of dopamine signaling in control of reinforcement learning. Mutations in either dopaminergic or dopaminoceptive neurons selectively affected conditioned reinforcement or associative learning, respectively.

6

Comparison of gene expression profiles in neuropathic and inflammatory pain

61%

Rodriguez Parkitna J., Korostynski M., Kaminska-Chowaniec D., Obara I., Mika J., Przewlocka B., Przewlocki R.

Journal of Physiology and Pharmacology

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2006

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tom 57

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nr 3

Molecular mechanisms underlying the differences between chronic neuropathic and inflammatory pain are still poorly understood. Identifying those differences should provide insight into the molecular mechanism underlying features unique for neuropathic pain, such as allodynia. We have performed screening for differentially expressed genes in the spinal cord in the rat models of neuropathic and inflammatory pain. Using BD Atlas Rat 4K arrays we found several differences in expression of secretion-related genes between inflammatory and neuropathic pain. Development of the latter was characterized by up-regulated expression of genes associated with immune response and microglia activation and also, to a lesser extent, with cytoskeleton rearrangement. The relative increase in abundance of four genes, intercellular adhesion molecule 1 (ICAM-1), calcitonin gene related peptide (CGRP), tissue inhibitor of metalloproteinase 1 (TIMP-1), chemokine-like receptor 1 was confirmed by reverse transcription Real-Time PCR (qPCR) validation in the spinal cord in neuropathic pain. Levels of transcripts corresponding to ICAM-1 and TIMP-1 were also increased in the dorsal root ganglia (DRG) of neuropathic rats. Our data point at the importance of immune response- and microglia activation-related genes in the development of chronic neuropathic pain, and suggest that expression of CGRP gene in the dorsal horn of the spinal cord could be involved in persistence of its symptoms.

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Application of DNA array technology in brain research

51%

Rodriguez Parkitna J., Bilecki W., Mierzejewski P., Stefanski R., Ligeza A., Bargiela A., Ziolkowska B., Kostowski W., Przewlocki R.

Acta Biochimica Polonica

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2003

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tom 50

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nr Supplement 1

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Generation of transgenic mice with selective ablation of NMDA receptors in noradrenergic neurons

51%

Rodriguez Parkitna J., Tokarski K., Golembiowska K., Kubik J., Solecki W., Novak M., Schutz D., Przewlocki R.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 3

The brain’s noradrenergic system system provides essential modulation to neuronal activity, with well established roles in control of arousal and selective attention, as well as memory, learning and response to stress. We have generated a transgenic mouse, NR1DbhCre, with ablation of the essential NMDA receptor subunit NR1 (Grin1) in noradrenergic cells. Since no functional NMDA receptors may be formed in the absence of NR1, and their expression is restricted to the central nervous system, the NR1DbhCre mice have impaired glutamate-dependent plasticity in the central noradrenergic neurons, without observable alterations in the sympathetic system or the hypothalamus-pituitary-adrenal axis. Transgenic animals were born at expected ratios and developed normally, displaying no obvious impairments. The general anatomy of the noradrenergic system in the mutant mice was normal, no loss of cells was observed and noradrenaline content in the prefrontal cortex was not altered. Interestingly, preliminary electrophysiological analysis indicates that loss of functional NMDA receptors attenuates the spontaneous activity in current-clamped locus coeruleus noradrenergic neurons manually held at −50 mV potential. In summary the NR1DbhCre transgenic mice are a novel model for the study of the roles of the noradrenergic system in the central nervous system.

Ograniczanie wyników

A new model to study delay discounting in group housed mice

Carbachol-induced NMDA-independent complex bursting of midbrain dopaminergic neurons – in vivo electrophysiological and pharmacological studies on NR1DATCreERTt2 mice

A test for assessing prosocial behavior in mice

Drug-induced gene transcription and the development of addiction

The role of NMDA receptor-dependent neuronal plasticity in the dopamine system in reward-driven learning

Comparison of gene expression profiles in neuropathic and inflammatory pain

Application of DNA array technology in brain research

Generation of transgenic mice with selective ablation of NMDA receptors in noradrenergic neurons