Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2

被引：23

作者：

Lindroos, Robert ^{[1
]}

Dorst, Matthijs C. ^{[1
]}

Du, Kai ^{[1
]}

Filipovic, Marko ^{[2
]}

Keller, Daniel ^{[3
]}

Ketzef, Maya ^{[1
]}

Kozlov, Alexander K. ^{[4
]}

Kumar, Arvind ^{[2
,5
]}

Lindahl, Mikael ^{[4
]}

Nair, Anu G. ^{[4
]}

Perez-Fernandez, Juan ^{[1
]}

Grillner, Sten ^{[1
]}

Silberberg, Gilad ^{[1
]}

Kotaleski, Jeanette Hellgren ^{[1
,4
]}

机构：

[1] Nobel Inst Neurophysiol, Dept Neurosci, Stockholm, Sweden

[2] Univ Freiburg, Bernstein Ctr Freiburg, Freiburg Im Breisgau, Germany

[3] Ecole Polytech Fed Lausanne, Blue Brain Project, Geneva, Switzerland

[4] KTH Royal Inst Technol, Sch Elect Engn & Comp Sci, Sci Life Lab, Solna, Sweden

[5] KTH Royal Inst Technol, Sch Elect Engn & Comp Sci, Dept Computat Sci & Technol, Stockholm, Sweden

来源：

FRONTIERS IN NEURAL CIRCUITS | 2018年 / 12卷

基金：

瑞典研究理事会;

关键词：

striatum; mediumspiny projection neurons; dopamine; simulations; Kv4.2; subcellular signaling; kinetic modeling; MEDIUM SPINY NEURONS; STRIATAL CHOLINERGIC INTERNEURONS; DEPENDENT PROTEIN-KINASE; TONICALLY ACTIVE NEURONS; EXTERNAL GLOBUS-PALLIDUS; NEGATIVE REWARD SIGNALS; LONG-TERM POTENTIATION; GATED SODIUM CURRENT; GLUR1 AMPA RECEPTOR; FIRING PATTERNS;

D O I：

10.3389/fncir.2018.00003

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The basal ganglia are involved in the motivational and habitual control of motor and cognitive behaviors. Striatum, the largest basal ganglia input stage, integrates cortical and thalamic inputs in functionally segregated cortico-basal ganglia-thalamic loops, and in addition the basal ganglia output nuclei control targets in the brainstem. Striatal function depends on the balance between the direct pathway medium spiny neurons (D1-MSNs) that express D1 dopamine receptors and the indirect pathway MSNs that express D2 dopamine receptors. The striatal microstructure is also divided into striosomes and matrix compartments, based on the differential expression of several proteins. Dopaminergic afferents from the midbrain and local cholinergic interneurons play crucial roles for basal ganglia function, and striatal signaling via the striosomes in turn regulates the midbrain dopaminergic system directly and via the lateral habenula. Consequently, abnormal functions of the basal ganglia neuromodulatory system underlie many neurological and psychiatric disorders. Neuromodulation acts on multiple structural levels, ranging from the subcellular level to behavior, both in health and disease. For example, neuromodulation affects membrane excitability and controls synaptic plasticity and thus learning in the basal ganglia. However, it is not clear on what time scales these different effects are implemented. Phosphorylation of ion channels and the resulting membrane effects are typically studied over minutes while it has been shown that neuromodulation can affect behavior within a few hundred milliseconds. So how do these seemingly contradictory effects fit together? Here we first briefly review neuromodulation of the basal ganglia, with a focus on dopamine. We furthermore use biophysically detailed multi-compartmental models to integrate experimental data regarding dopaminergic effects on individual membrane conductances with the aim to explain the resulting cellular level dopaminergic effects. In particular we predict dopaminergic effects on Kv4.2 in D1-MSNs. Finally, we also explore dynamical aspects of the onset of neuromodulation effects in multi-scale computational models combining biochemical signaling cascades and multi-compartmental neuron models.

引用

页数：23