Abstract
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.
Highlights
To survive and thrive it is crucial for all species to recognize and evaluate environmental cues, select actions and learn from previous behavioral outcomes (Redgrave et al, 1999)
The review of literature revealed that the Naf, Kas, and CaN/P channels are down-regulated by DA; the KIR and the GABA channels have been reported to be both up- and down-regulated; the Kaf channel is reported not to be modulated in striatum, there is some indirect evidence in support of modulation, see Discussion; and the CaL, AMPA, and NMDA channels are all up regulated
In an attempt to investigate how DA brings about major changes in the sub-nuclei of the basal ganglia (BG), we here focused on the DAergic effect on D1-medium spiny neuron (MSN)
Summary
To survive and thrive it is crucial for all species to recognize and evaluate environmental cues, select actions and learn from previous behavioral outcomes (Redgrave et al, 1999). The same brain structures (e.g., frontal cortex) that provide input to the BG receive direct (via thalamus and brainstem structures) or indirect feedback from the BG output nuclei (Chevalier and Deniau, 1990). This architecture is often viewed as a series of partially segregated parallel projecting re-entrant loops involving both cortical and sub-cortical structures, controlling associated behaviors (Alexander et al, 1986; McHaffie et al, 2005). Learning/plasticity requires intact DA and acetylcholine (ACh) signaling (Knowlton et al, 1996; Matsumoto et al, 1999; Kitabatake et al, 2003)
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