Direct pathway Anatomy The
direct pathway within the basal ganglia receives excitatory input from the cortex, thalamus, and other brain regions. In the direct pathway, medium spiny neurons project to the
internal division of the globus pallidus (GPi) or the
substantia nigra pars reticula (SNpr or SNr). These nuclei project to the deep layer of the
superior colliculus and control fast
eye movements (saccades), and also project to the ventral thalamus, which in turn projects to upper motor neurons in the
primary motor cortex (precentral gyrus). The SNr and GPi outputs are both tonically active inhibitory nuclei and are thus constantly inhibiting the thalamus (and thus motor cortex). However, transient activity in (inhibitory) direct pathway medium spiny neurons ultimately disinhibits thalamus projections to the motor cortex and enables movement.
Indirect pathway Anatomy The
indirect pathway also receives excitatory input from various brain regions. Indirect pathway medium spiny neurons project to the
external segment of the globus pallidus (GPe). Like the GPi, the GPe is a tonically active inhibitory nucleus. The GPe projects to the excitatory
subthalamic nucleus (STN), which in turn projects to the GPi and SNr. This model is supported by experiments demonstrating that
optogenetically stimulating direct pathway medium spiny neurons increases locomotion, whereas stimulating indirect pathway medium spiny neurons inhibits locomotion. The balance of direct/indirect activity in movement is supported by evidence from
neurodegenerative disorders, including
Parkinson's disease (PD), which is characterized by loss of
dopamine neurons projecting to the striatum,
hypoactivity in direct pathway and hyperactivity in indirect pathway neurons, along with motor dysfunction. This results in loss of normal action selection, as loss of dopamine drives activity in the indirect pathway, globally inhibiting all motor paradigms. This may explain impaired action initiation, slowed actions (
bradykinesia), and impaired voluntary motor initiation in Parkinson's patients. On the other hand,
Huntington's disease, which is characterized by preferential degradation of indirect pathway medium spiny neurons, results in unwanted movements (
chorea) that may result from impaired movement inhibition and predominant direct pathway activity. An alternative related hypothesis is that the striatum controls action initiation and selection via a 'center-surround' architecture, where activation of a subset of direct pathway neurons initiates movements while closely related motor patterns represented by surrounding neurons are inhibited by
lateral inhibition via indirect pathway neurons. This specific hypothesis is supported by recent
calcium-imaging work showing that direct and indirect pathway medium spiny neurons encoding specific actions are located in spatially organized ensembles. Despite the abundance of evidence for the initiation/termination model, recent evidence using
transgenic mice expressing calcium indicators in either the direct or indirect pathway demonstrated that both pathways are active at action initiation, but neither are active during inactivity, a finding which has been replicated using simultaneous two-channel calcium imaging. This has led to somewhat of a paradigm shift in models of striatal functioning, such that newer models posit that the direct pathway facilitates wanted movements, whereas the indirect pathway simultaneously inhibits unwanted movements. Indeed, more sophisticated techniques and analyses, such as state-dependent optogenetics, have revealed that both pathways are heavily involved in action sequence execution, and that specifically, both striatal pathways are involved in element-level action control. However, direct pathway medium spiny neurons mostly signal sequence initiation/termination and indirect pathway medium spiny neurons may signal switching between subsequences of a given action sequence. Other evidence suggests that the direct and indirect pathway oppositely influence the termination of movement—specifically, the relative timing of their activity determines if an action will be terminated. Recent experiments have established that the direct and indirect pathways of the dorsal striatum are not solely involved in movement. Initial experiments in an
intracranial self-stimulation paradigm suggested opposing roles in
reinforcement for the two pathways; specifically, stimulation of direct pathway medium spiny neurons was found to be reinforcing, whereas stimulation of indirect pathway medium spiny neurons was aversive. However, a subsequent study (using more physiologically relevant stimulation parameters) found that direct and indirect pathway stimulation was reinforcing, but that pathway-specific stimulation resulted in the development of different action strategies. Regardless, these studies suggest a critical role for reinforcement in the dorsal striatum, as opposed to the striatum only serving a role in movement control. ==Ventral striatal MSNs==