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.

Keywords: basal ganglia; direct pathway; mathematical model; serotonin.

Figure 1

The influence of the DRN on the direct and indirect pathways. Dopaminergic neurons of the SNc inhibit the indirect pathway and stimulate the direct pathway from the cortex to the thalamus. Serotonin from the DRN projections to the striatum increase DA release and projections from the cortex inhibit DRN firing. The details of basal ganglia BG circuitry in the direct and indirect pathways is omitted. References for the influences are given in the text. There are many descending projections to the DRN; nucleus X represents one of these that may excite or inhibit the DRN.

Figure 2

Phasic cortical input to the direct pathway. The cortical input to the direct pathway, a₂, was doubled between t = 1 s and t = 2 s. The red and blue curves show the firing rates as a function of time in the direct and indirect pathways, respectively.