JD

Subcortical Structures and Motor Systems

Subcortical Structures & Review

  • Basal ganglia
  • Cerebellum
  • Reticular formation

Motor Processing

  • "Simple" reflex circuits (involuntary movement)
    • Spinal cord anatomy & neuromuscular junction
    • Muscle contraction and relaxation
    • Muscle fibers, stretch reflex, withdrawal reflex
  • Voluntary movement
    • Primary motor cortex and other motor cortical areas
    • Basal ganglia - selection of movement
    • Cerebellum - modulation of movement

Normal Basal Ganglia Circuit

  • Components:
    • Thalamus
    • Striatum
    • External Pallidum
    • Subthalamic Nucleus
    • Internal Pallidum
    • Substantia Nigra
  • Pathways:
    • Direct Pathway
    • Indirect Pathway
  • Projections:
    • To Frontal Cortex
    • To Thalamus

Dopamine as a Neuromodulator

  • Binds to two metabotropic receptors with different G-proteins.
  • Glutamate receptor: depolarizes the cells
  • D1 receptors: Increases the excitability of cells
  • D2 receptors: Decreases the excitability of cells
  • Dopamine supports cortical excitation (D1) and reduces cortical excitation (D2).

D1 & D2 Receptors Location

  • D1 receptor (direct pathway) & D2 receptors (indirect pathway) are intermixed within the striatum
  • Receptors are located on the dendrites and cell bodies of the D1 and D2 neurons
  • Both receive dopamine input
  • D2 receptor also on terminals (autoreceptor)

Normal Basal Ganglia Circuit with Dopamine (DA)

  • Direct Pathway:
    • Cerebral Cortex projects to Striatum (Caudate/Putamen).
    • Striatum projects to Globus Pallidus, internal segment.
    • Globus Pallidus projects to VA/VL complex of Thalamus.
    • Thalamus projects to Frontal Cortex.
    • Substantia Nigra pars compacta modulates the striatum.
  • Indirect Pathway:
    • Involves additional connections through the Globus Pallidus external segment and Subthalamic nucleus.
    • Modulated by Substantia Nigra pars compacta

Basal Ganglia Pathways and Dopamine

  • SNc (Substantia Nigra pars compacta), Caudate/Putamen, GPe (Globus Pallidus external), GPi (Globus Pallidus internal), STN (Subthalamic Nucleus)
  • D1+ and D2- neurons.
  • GABA (-) is the primary inhibitory neurotransmitter.
  • Glutamate (+) is the primary excitatory neurotransmitter.
  • Thalamus is tonically active and excites the Cortex with glutamate (+).
  • Disinhibition: Inhibition of an inhibitory input cancels out the inhibitory input.
  • Under normal conditions:
    • Dopamine (DA) release activates D1R neurons & inhibits D2R neurons
    • Activates the direct pathway & inhibits the indirect pathway
  • Two pathways connect cortex to striatum:
    1. Direct pathway excites cortex (movement).
    2. Indirect pathway inhibits cortex (no movement).

Hyperkinetic and Hypokinetic Circuits

  • Hyperkinetic movements: direct pathway > indirect pathway (Huntington’s).
  • Hypokinetic movements: indirect pathway > direct pathway (Parkinson’s).
  • Balance between the two is key!

Huntington’s Disease

  • Degeneration of caudate and putamen, particularly GABAergic and ACh-ergic neurons via apoptosis due to abnormal huntingtin (htt) gene.
  • Progressive chorea (jerky, random, uncontrollable movements).
  • No current treatment but possible treatment with small interfering RNA (siRNA) to interrupt transcription of htt gene.

Parkinson’s Disease: Hypokinetic Circuit

  • Second most common neurodegenerative condition (Alzheimer’s is most common).
  • Symptoms: Tremor, rigidity, mask-like facial expression.
  • Bradykinesia (slow movement and loss of spontaneous movement).

Parkinson's Pathology

  • Diminished substantia nigra, indicating a decrease in dopaminergic projection to the striatum.

Normal BG vs. Parkinson’s Disease BG

  • Normal BG: DA input present = balance between pathways & appropriate action selection/action initiation.
  • Parkinson’s Disease BG: DA input diminished or absent = imbalance between pathways & slow or absent action selection/initiation.

Parkinson’s Disease BG

  1. Loss of Dopamine = decreased direct pathway activity & increased indirect pathway activity (Hypokinetic state).
  2. Inhibition of Thalamus and Cortex.

Treatment Options for Parkinson’s Disease (PD)

  • L-Dopa to “top up” dopamine levels and hopefully restore normal modulation of basal ganglia; unwanted side effects and not long-term solution.
  • Stereotactic surgery: selective lesions (pallidotomy, STN) and/or deep brain stimulation to try and restore the balance in the pathways.

Experimental Confirmation of BG Circuit Model

  • Optogenetically activating D2R neurons in the striatum (indirect pathway) causes mice to stop moving.
  • Kravitz et al. (2010).

The Cerebellum

  • "Little brain".
  • 10% volume of the brain.
  • Over 50% of the neurons in the brain.
  • Anatomical Features:
    • Anterior lobe
    • Posterior lobe
    • Vermis
    • Purkinje cell layer
    • Folia
    • Deep white matter

Cerebellum Connections

  • Connects ipsi-laterally to the body and contra-laterally to the cortex.
  • Right cerebellar damage affects the right side of the body.
  • Left cerebellar damage affects the left side of the body.

Cerebellum and Movement

  • Control of movement and posture.
  • Coordination, accuracy of movement.
  • Accurately timed sequences of muscle contractions required for rapid, skilled movements.
  • “Supervised” motor learning – error-driven modification of movement.

Cerebellar Motor Syndrome

  • Clumsy, uncoordinated movements.
  • Incoordination characterized by overshoot and undershoot.
  • Slow, scanning speech.
  • Staggering, wide-based (drunken) gait, clumsiness, falling side to side without loss of strength.
  • “Disordered site, magnitude, and timing of muscle contractions”.
  • The brain’s autopilot

Connections: Loops with Cortex & Cord

  • Cerebellum interacts with:
    • Pontine nuclei
    • Ventral lateral thalamic nucleus
    • Spinal cord
    • Brain stem nuclei
  • Can thus modify movements to be more accurate, successful based on feedback.

Features of Motor Systems

  • Depends on hierarchical processing by many structures.
  • Multisensory integration.
  • Feedback.

Functional Systems and Behaviors

  • Sensory Systems (Vision, Hearing, Somatosensory, Smell, Taste)
  • Motor System (Spinal and cortical contributions to movement)
  • Sensory and Motor integration
    • Sense your environment
    • Interact with your environment

Functional System Definition

  • A collection of connected neuronal populations that is involved in a behavior.
  • Can also be called a functional pathway, behavioral pathway, behavioral circuit.
  • Connections (or information flow) are between anatomically distinct areas.
  • Connections can involve several different neurotransmitters.
  • Flow of information can be serial and/or parallel.

What 'Involved in a Behavior' means

  • Some evidence that a neuronal population is contributing to or processing information that is relevant to the production or refinement of a behavior.
  • Goal is to understand the details of the contribution (Whether? How? When?).
    • Manipulation:
      • Loss of behavior: When neurons are inactivated or damaged, a behavior is lost or altered.
      • Gain of behavior: When neurons are stimulated, a behavior is produced or altered.
    • Measurement:
      • Neural activity correlates with behavior: The activity at some level is correlated with a behavior.
    • Anatomy:
      • Anatomical connections & division (physical, chemical, genetic) can inspire and explain manipulation and measurement experiments.

Thalamus

  • It is on either side of the third ventricle and is involved in relaying sensory information and signals from the basal ganglia.

Forebrain: Diencephalon

  • Thalamus: relay station for sensory information; sends information to cortex.
  • Hypothalamus: Controls autonomic nervous system and the endocrine system (hormone system); organizes behaviors related to survival like fighting, fleeing, feeding, and mating.

Single-Unit Recording

  • indicate the level of individual neuron activity

Receptive Fields

  • On-center
  • Off-center
  • Center-surround, antagonistic organization
  • Central Spot, Peripheral Spot, Central Illumination, Surround Illumination, Diffuse illumination

Center-Surround Antagonism

  • Likely supported by convergent retinal anatomy.
  • Many photoreceptors converging onto a single retinal ganglion cell.
  • Lateral connections allowing cells in one part of the retina to influence the activity of cells in another part of the retina.

Motor Cortex Areas and Behaviors

  • Locating oneself in space: parietal cortex
  • Feeling an urge or desire to move your leg: pre-SMA
  • Generating goals and plans: prefrontal cortex
  • Dancing in response to the verbal instruction to “do the single ladies dance”: premotor cortex
  • Watching someone reach for a cup: ventral premotor cortex & inferior parietal lobule
  • Playing some remembered tune on the piano: SMA