Signal enhancement in the output stage of the basal ganglia by synaptic short-term plasticity in the direct, indirect and hyper direct pathways

Many of the synapses in the basal ganglia display short-term plasticity. Still, computational models have not yet been used to investigate how this affects signaling. Here we use a model of the basal ganglia network, constrained by available data, to quantitatively investigate how synaptic short-term plasticity affects the substantia nigra reticulata (SNr), the basal ganglia output nucleus. We find that SNr becomes particularly responsive to the characteristic burst-like activity seen in both direct and indirect pathway striatal medium spiny neurons (MSN). As expected by the standard model, direct pathway MSNs are responsible for decreasing the activity in SNr. In particular, our simulations indicate that bursting in only a few percent of the direct pathway MSNs is sufficient for completely inhibiting SNr neuron activity. The standard model also suggests that SNr activity in the indirect pathway is controlled by MSNs disinhibiting the subthalamic nucleus (STN) via the globus pallidus externa (GPe). Our model rather indicates that SNr activity is controlled by the direct GPe-SNr projections. This is partly because GPe strongly inhibits SNr but also due to depressing STN-SNr synapses. Furthermore, depressing GPe-SNr synapses allow the system to become sensitive to irregularly firing GPe subpopulations, as seen in dopamine depleted conditions, even when the GPe mean firing rate does not change. Similar to the direct pathway, simulations indicate that only a few percent of bursting indirect pathway MSNs can significantly increase the activity in SNr. Finally, the model predicts depressing STN-SNr synapses, since such an assumption explains experiments showing that a brief transient activation of the hyperdirect pathway generates a tri-phasic response in SNr, while a sustained STN activation has minor effects. This can be explained if STN-SNr synapses are depressing such that their effects are counteracted by the (known) depressing GPe-SNr inputs

The arbitration-extension hypothesis: a hierarchical interpretation of the functional organization of the basal ganglia

Based on known anatomy and physiology, we present a hypothesis where the basal gangliamotor loop is hierarchically organized in two main subsystems: the arbitration system andthe extension system. The arbitration system, comprised of the subthalamic nucleus, globuspallidus, and pedunculopontine nucleus, serves the role of selecting one out of several candidateactions as they are ascending from various brain stem motor regions and aggregated in thecentromedian thalamus or descending from the extension system or from the cerebral cortex.This system is an action-input/action-output system whose winner-take-all mechanism findsthe strongest response among several candidates to execute. This decision is communicatedback to the brain stem by facilitating the desired action via cholinergic/glutamatergic projectionsand suppressing conflicting alternatives via GABAergic connections. The extension system,comprised of the striatum and, again, globus pallidus, can extend the repertoire of responsesby learning to associate novel complex states to certain actions. This system is a state-input/action-output system, whose organization enables it to encode arbitrarily complex Booleanlogic rules using striatal neurons that only fire given specific constellations of inputs (BooleanAND) and pallidal neurons that are silenced by any striatal input (Boolean OR). We demonstratethe capabilities of this hierarchical system by a computational model where a simulatedgeneric animal interacts with an environment by selecting direction of movement basedon combinations of sensory stimuli, some being appetitive, others aversive or neutral. Whilethe arbitration system can autonomously handle conflicting actions proposed by brain stemmotor nuclei, the extension system is required to execute learned actions not suggested byexternal motor centers. Being precise in the functional role of each component of the system,this hypothesis generates several readily testable predictions

Deep brain stimulation of the subthalamic nucleus preferentially alters the translational profile of striatopallidal neurons in an animal model of Parkinson’s disease

Deep brain stimulation targeting the subthalamic nucleus (STN-DBS) is an effective surgical treatment for the motor symptoms of Parkinson’s disease (PD), the precise neuronal mechanisms of which both at molecular and network levels remain a topic of debate. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively identify changes in translational gene expression in either Drd1a-expressing striatonigral or Drd2-expressing striatopallidal medium spiny neurons (MSNs) of the striatum following STN-DBS. 6-hydroxydopamine lesioned mice received either 5 days stimulation via a DBS electrode implanted in the ipsilateral STN or 5 days sham treatment (no stimulation). Striatal polyribosomal RNA was selectively purified from either Drd2 or Drd1a MSNs using the TRAP method and gene expression profiling performed. We identified 8 significantly altered genes in Drd2 MSNs (Vps33b, Ppp1r3c, Mapk4, Sorcs2, Neto1, Abca1, Penk1 and Gapdh) and 2 overlapping genes in Drd1a MSNs (Penk1 and Ppp1r3c) implicated in the molecular mechanisms of STN-DBS. A detailed functional analysis, using a further 728 probes implicated in STN-DBS, suggested an increased ability to receive excitation (mediated by increased dendritic spines, increased calcium influx and enhanced excitatory post synaptic potentials) accompanied by processes that would hamper the initiation of action potentials, transport of neurotransmitters from soma to axon terminals and vesicular release in Drd2-expressing MSNs. Finally, changes in expression of several genes involved in apoptosis as well as cholesterol and fatty acid metabolism were also identified. This increased understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies for PD