Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum

Aldrin-Kirk, PatrickLund University,Lunds universitet,Human neural utvecklingsbiologi,Forskargrupper vid Lunds universitet,Human Neural Developmental Biology,Lund University Research Groups (författare)

The intricate balance between dopaminergic and cholinergic neurotransmission in the striatum has been thoroughly difficult to characterize. It was initially described as a seesaw with a competing function of dopamine versus acetylcholine. Recent technical advances however, have brought this view into question suggesting that the two systems work rather in concert with the cholinergic interneurons (ChIs) driving dopamine release. In this study, we have utilized two transgenic Cre-driver rat lines, a choline acetyl transferase ChAT-Cre transgenic rat and a novel double-transgenic tyrosine hydroxylase TH-Cre/ChAT-Cre rat to further elucidate the role of striatal ChIs in normal motor function and in Parkinson's disease. Here we show that selective and reversible activation of ChIs using chemogenetic (DREADD) receptors increases locomotor function in intact rats and potentiate the therapeutic effect of L-DOPA in the rats with lesions of the nigral dopamine system. However, the potentiation of the L-DOPA effect is accompanied by an aggravation of L-DOPA induced dyskinesias (LIDs). These LIDs appear to be driven primarily through the indirect striato-pallidal pathway since the same effect can be induced by the D2 agonist Quinpirole. Taken together, the results highlight the intricate regulation of balance between the two output pathways from the striatum orchestrated by the ChIs.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
AAV
Animal models
Chemogenetics
Cholinergic interneurons
Direct pathway
DREADD
Indirect pathway
L-DOPA induced dyskinesias
Parkinson's disease
Transgenic rats

Heuer, AndreasLund University,Lunds universitet,Beteendevetenskapligt laboratorium,Forskargrupper vid Lunds universitet,Behavioural Neuroscience Laboratory,Lund University Research Groups(Swepub:lu)med-ah4 (författare)
Ottosson, DaniellaLund University,Lunds universitet,Regenerativ neurofysiologi,Forskargrupper vid Lunds universitet,Regenerative Neurophysiology,Lund University Research Groups(Swepub:lu)med-drr (författare)
Davidsson, MarcusLund University,Lunds universitet,Molekylär neuromodulering,Forskargrupper vid Lunds universitet,Molecular Neuromodulation,Lund University Research Groups(Swepub:lu)med-mud (författare)
Mattsson, BengtLund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups(Swepub:lu)neur-bma (författare)
Björklund, TomasLund University,Lunds universitet,Molekylär neuromodulering,Forskargrupper vid Lunds universitet,Molecular Neuromodulation,Lund University Research Groups(Swepub:lu)mphy-tbj (författare)
Human neural utvecklingsbiologiForskargrupper vid Lunds universitet (creator_code:org_t)

Av författaren/redakt...: Aldrin-Kirk, Pat ...; Heuer, Andreas; Ottosson, Daniel ...; Davidsson, Marcu ...; Mattsson, Bengt; Björklund, Tomas

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

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