Computational studies of the role of serotonin in the basal ganglia

Abstract

It has been well established that serotonin (5-HT) plays an important role in the striatum. For example, during levodopa therapy for Parkinson's disease (PD), the serotonergic projections from the dorsal raphe nucleus (DRN) release dopamine as a false transmitter, and there are strong indications that this pulsatile release is connected to dyskinesias that reduce the effectiveness of the therapy. Here we present hypotheses about the functional role of 5-HT in the normal striatum and present computational studies showing the feasibility of these hypotheses. Dopaminergic projections to the striatum inhibit the medium spiny neurons (MSN) in the striatopalladal (indirect) pathway and excite MSNs in the striatonigral (direct) pathway. It has long been hypothesized that the effect of dopamine (DA) depletion caused by the loss of SNc cells in PD is to change the “balance” between the pathways to favor the indirect pathway. Originally, “balance” was understood to mean equal firing rates, but now it is understood that the level of DA affects the patterns of firing in the two pathways too. There are dense 5-HT projections to the striatum from the dorsal raphe nucleus and it is known that increased 5-HT in the striatum facilitates DA release from DA terminals. The direct pathway excites various cortical nuclei and some of these nuclei send inhibitory projections to the DRN. Our hypothesis is that this feedback circuit from the striatum to the cortex to the DRN to the striatum serves to stabilize the balance between the direct and indirect pathways, and this is confirmed by our model calculations. Our calculations also show that this circuit contributes to the stability of the dopamine concentration in the striatum as SNc cells die during Parkinson's disease progression (until late phase). There may be situations in which there are physiological reasons to “unbalance” the direct and indirect pathways, and we show that projections to the DRN from the cortex or other brain regions could accomplish this task.

A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei

“…Our findings have however not yet resolved the functional significance of these hyperdirect pathways, particularly in light of postsynaptic integration with the parallel disynaptic pathways, which remains to be determined. Future computational models describing the role of serotonin for basal ganglia function (Reed et al, 2013) will benefit from identification of these parallel pathways to generate new hypotheses on network function during specific behaviors.…”

L-Dopa and Brain Serotonin System Dysfunction

“…Deficits in 5-HT caused by acute and chronic l -dopa administration may dysregulate crucial brain areas such as the striatum and the frontal cortex that control motor function and cognitive stability. Both brain regions depend on cross-talk between 5-HT and dopamine to regulate behavior [ 82 , 83 , 84 , 85 ]. For example, many negative symptoms that appear during “ON” periods of l -dopa, such as dyskinesia and hallucinations, are thought to result from the imbalance of dopamine and 5-HT within the striatum and frontal cortex, respectively [ 86 , 87 , 88 ].…”

An updated review on pathophysiology and management of burning mouth syndrome with endocrinological, psychological and neuropathic perspectives

“…Some researchers have hypothesised that there is an overlap in the diagnoses of BMS and RLS . In healthy persons, the motor cortex sends impulses to the striatum and receives feedback from the thalamus . In RLS, the motor cortex is hyperexcitable, as it is in BMS patients .…”