Basal Ganglia Study Notes

Basal Ganglia

Anatomy of the Basal Ganglia

• The basal ganglia (or basal nuclei) are a group of brain structures deep within the cerebrum and midbrain.
• They receive inputs from the cerebral cortex and project back to motor areas of the cerebral cortex, similar to the cerebellum.
• The basal ganglia are involved in various functions beyond motor control and are implicated in neurological disorders.
• Understanding the circuitry of the basal ganglia is crucial for insights into these disorders and their therapeutic approaches.
• The basal ganglia are bilaterally paired structures.

Key Structures:

• Putamen: An oval-shaped structure, the most lateral component, receives input from the cerebral cortex (Latin for "nutshell").
• Caudate Nucleus: A long, curved, tail-like structure extending from the dorsal putamen, also receiving cortical input (meaning "tail").
• Globus Pallidus: Situated medially to the putamen, has complex functions, divided into:
  • Globus Pallidus External (GPe): A processing station within the basal ganglia.
  • Globus Pallidus Internal (GPi): An output structure of the basal ganglia.
• Thalamus: Located near the midline (but not part of the basal ganglia).
• Striatum: Collective term for the putamen and caudate, referring to their striped appearance due to gray matter bridges between white matter bundles.
• Subthalamic Nucleus: Located ventral to the thalamus.
• Substantia Nigra: A nucleus in the midbrain, divided into:
  • Substantia Nigra Pars Reticulata (SNpr): Functions similarly to the GPi, with a loose meshwork cell architecture.
  • Substantia Nigra Pars Compacta (SNpc): Densely packed, darkly pigmented cells that release dopamine into the striatum; degeneration is a key feature of Parkinson’s disease.

Functional Entities:

• GPi/SNpr: Act as the output station of the basal ganglia.
• Internal Capsule (IC): A white matter tract carrying axons between the cerebral cortex, brainstem, and spinal cord, separating the GPi and SNpr.

Flow of Information Through the Basal Ganglia

• Inputs to the basal ganglia come from a wide area of the cerebral cortex.
• Outputs are directed to nuclei in the thalamus, which project back to:
  • Supplementary Motor Area (SMA): Involved in planning internally generated movements.
  • Prefrontal Cortex: Participates in high-level cognitive processes like reasoning, decision-making, and short-term memory; also linked to personality, social behavior, speech control, and eye movements.
• The basal ganglia's operations are similar across disparate functions but occur in distinct, parallel pathways.
• Motor pathway inputs are primarily from the premotor, primary motor, and somatosensory cortex.
• The striatum receives cortical input, and the GPi/SNpr provides output to thalamic nuclei, which project to the SMA.

Direct and Indirect Pathways

• Information flows from the striatum to the GPi–SNpr via two routes:
  • Direct Pathway: Direct connections from the striatum to the GPi–SNpr.
  • Indirect Pathway: Information flows from the striatum to the GPe, then to the subthalamic nucleus (STN), and finally to the GPi–SNpr.

Functional Organization of the Basal Ganglia

• Input from the cerebral cortex to the striatum is excitatory (glutamatergic).
• Output from the GPi–SNpr to the thalamus is inhibitory (GABAergic).
• The GPi–SNpr is persistently active, suppressing the thalamus from engaging the SMA to promote internally generated movements.
• Greater output from the basal ganglia reduces the likelihood of internally generated movements.

Direct Pathway (Go Pathway)

• Striatal neurons projecting directly to the GPi–SNpr are inhibitory (GABAergic).
• When active, this pathway suppresses the GPi/SNpr, lessening inhibition of the thalamus and increasing excitation of the SMA.
• This disinhibition leads to excitation of downstream targets, promoting movements.

Indirect Pathway (Stop Pathway)

• A different set of striatal neurons receive excitatory input from the cortex and project to the GPe; these neurons are also inhibitory (GABAergic).
• The GPe sends inhibitory inputs to the STN, reducing activity in the intrinsically active STN.
• The STN provides excitatory input (glutamatergic) to the GPi–SNpr.
• Increased STN activity further excites the GPi/SNpr, suppressing thalamic excitation of the SMA, reducing the likelihood of movement.
• Inhibitory inputs from the GPe temper the STN's activity, preventing excess activation of the GPi/SNpr.
• Activation of striatal neurons in the indirect pathway removes the tempering action of the GPe, increasing the STN's excitatory drive to the GPi/SNpr.
• Increased activity in the indirect pathway suppresses movement production.

Role of the Substantia Nigra Pars Compacta (SNpc)

• The direct and indirect pathways converge on the GPi/SNpr with opposing influences.
• The SNpc releases dopamine into the striatum, acting as a neuromodulator via G-protein-coupled metabotropic receptors.
• The ventral tegmental area (VTA) is another dopamine source, supplying dopamine to areas like the prefrontal cortex and acting as a reward signal.
• Dopamine's release in the striatum has differential effects:
  • Neurons with Dopamine-1 receptors (D1R) are excited by dopamine, underlying the direct pathway.
  • Neurons with Dopamine-2 receptors (D2R) are inhibited by dopamine, mainly driving the indirect pathway.
• Dopamine release boosts activity in the direct pathway and suppresses it in the indirect pathway, promoting movement.

Inputs Regulating the SNpc

• The SNpc receives excitatory, inhibitory, and neuromodulatory inputs from various brainstem and cerebrum structures, including feedback from basal ganglia nuclei.
• The amygdala, which identifies the emotional value of stimuli, inputs to the SNpc.
• Sensory inputs inform the amygdala of "what" is occurring, while prefrontal cortex inputs indicate the significance of circumstances.
• Amygdala output to the SNpc can motivate action by enhancing dopamine release, facilitating the direct pathway and inhibiting the indirect pathway.

Activation of the Direct Pathway

• Stimulation of the direct pathway involves delivering a puff of glutamate to the striatum to mimic cortical release.
• This increases the firing rate of striatal neurons, inhibiting the GPi/SNpr.
• The suppressed output of the GPi/SNpr relieves the thalamus from inhibition, increasing its firing rate.
• Increased thalamic activity excites the SMA, increasing the likelihood of movement.

Interruption of the Indirect Pathway

• Damage to the STN, a critical element of the indirect pathway, leads to uncontrolled movements (dyskinesias).
• Lesions of the STN reduce activity in the GPi, lessening inhibition of the thalamus.
• This highlights the indirect pathway's role in preventing unwanted movements.

Optogenetics

• Optogenetics allows precise activation or suppression of specific cells using light.
• Genes from algae or bacteria that express light-sensitive ion channels (channelrhodopsins [ChRs]) are introduced into mammalian neurons using non-toxic viruses.
• A genetic switch (promoter) drives expression of the ChR protein only in cells with specific genetic features.
• Two main types of light-sensitive systems: blue light to open channels (Na+ influx, excitation) and yellow light to activate ion pumps (Cl− entry, inhibition).
• Fiber optic cables deliver light to the brain region to manipulate targeted neurons.

Optogenetic Control of Direct and Indirect Pathways

• Mice engineered to express ChR in striatal neurons with D1 or D2 receptors.
• Blue laser light delivered to the striatum.
• In D1 mice (ChR in D1 receptor neurons), SNpr activity decreased.
• In D2 mice (ChR in D2 receptor neurons), SNpr activity increased.
• This supports the direct–indirect pathway hypothesis.
• Bilateral illumination of the striatum with fiber optic cables in freely moving mice.
• Activation of the D1 pathway increased locomotor activity, while activation of the D2 pathway caused the animal to stop.

Hyperkinetic Disorders Associated with Dysfunction of the Indirect Pathway

• When the stop pathway is disrupted, unintended movements or behaviors occur (hyperkinetic disorders).
• Hemiballism: Ballistic or flinging motions of a limb due to damage to the STN contralateral to the affected limb.
• Huntington’s Disease: Genetic disorder causing degeneration of striatal neurons projecting to the GPe (indirect pathway).
  • Symptoms include chorea (uncontrollable writhing movements) and cognitive/personality disorders.
  • As the disease progresses, direct pathway neurons also degenerate, leading to hypokinetic symptoms.
• Tourette’s Syndrome: Genetic disorder with repetitive motor and vocal tics, possibly due to dysfunction of the indirect pathway.
• Obsessive–Compulsive Disorder (OCD): Invasive thoughts (obsessions) leading to repetitive behaviors (compulsions), involving the basal ganglia and often treated with dopamine antagonists.

Parkinson’s Disease

• Prototypical hypokinetic disorder caused by degeneration of dopamine-producing cells in the SNpc.
• Symptoms include akinesia (paucity of movement), bradykinesia (slowed movement), facial masking, and tremor.
• Cognitive and personality disorders may arise.
• Dopamine depletion undercuts the ability to move, mainly impairing internally generated movements.
• Externally guided movements are less affected.

Treatments for Parkinson’s Disease

• Pallidotomy: Surgical ablation of part of the globus pallidus.
• Levodopa (L-DOPA): A precursor of dopamine that crosses the blood–brain barrier and is synthesized into dopamine in the striatum.
  • Efficacy diminishes over time, and patients may develop dyskinesias.
• Fetal Tissue Transplants: Dopamine-producing cells from aborted human fetuses transplanted into the striatum.
  • Showed mixed results and raise ethical concerns.
• Stem Cell Therapy: Stem cells induced to differentiate into dopamine-producing cells.
• Deep Brain Stimulation (DBS): High-frequency stimulation of the STN.
  • The gold standard therapy for Parkinson’s disease.
  • Mechanism of action is not fully understood.
  • Possible explanations include suppression of STN activity or excitation of inhibitory inputs to the STN.

Summary

• The basal ganglia promote movement and regulate cognitive functions.
• Inputs are from the cerebral cortex, and outputs target the SMA and prefrontal cortex via the thalamus.
• The direct path promotes movements, and the indirect path restrains movements.
• Dopamine facilitates movement by promoting the direct pathway and inhibiting the indirect pathway.
• Basal ganglia are implicated in movement related neurological disorders like Parkinson's and Huntington's Disease.
• Treatments for Parkinson’s disease include surgical ablation, dopamine replacement, and DBS, but no cure has been developed.