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

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

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nr Suppl.1

EN

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.

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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.

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nr 3

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Comparison of gene expression profiles in neuropathic and inflammatory pain

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

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nr 3

EN

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

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

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nr Supplement 1