Neurobiology Exam 3

Why did brains evolve? (2 arguments)

1. Movement is how animals affect the world.
   Wolpert argues that things like sensation, memory, thinking, speech, etc. are useful because they ultimately help produce or suppress future movements.

2. If an animal no longer needs to move, it may no longer need a brain.
   His example is the sea squirt: when young, it swims and has a nervous system; once it attaches permanently to a rock, it digests its own brain/nervous system. He uses that as evidence that the brain’s adaptive value is strongly tied to movement.

Even in the most simple organisms, membrane potential and ion-channel activity controls movement. Explain this in the example of the paramecium (a single-celled organism).

If it bumps into something with its front/anterior end:

• Ca²⁺ channels open

• Ca²⁺ causes a depolarizing action potential

• the cilia reverse direction

• the paramecium backs up/reverses movement

If stimulation is at the posterior end:

• K⁺ channels open

• K⁺ causes hyperpolarization

• cilia keep driving it forward

How does movement compare between single-celled organisms (e.g. paramecium) and vertebrates (e.g. humans)?

Ion channels are still the basic mechanism of movement. But in vertebrates, lots of neurons are connected into circuits across different brain regions. Neurons are connected by excitatory and inhibitory synapses. So one neuron might increase activity in the next neuron, while another connection suppresses activity.

How are the motor areas organized around the central sulcus?

• M1 = primary motor cortex = Area 4

  • located just anterior to the central sulcus

  • directly involved in executing voluntary movement

• Premotor cortex = Area 6

  • lies anterior to M1

  • includes:

    • PMA = premotor area in ventrolateral Area 6

    • SMA = supplementary motor area in dorsomedial Area 6

• S1 = primary somatosensory cortex

  • lies just posterior to the central sulcus

Primary motor cortex — M1

• Located in the pre-central gyrus

• AKA Brodmann area 4

• Contralateral

• Responsible for executing movement

• Pyramidal neurons in layer V are the upper motor neurons (MN)s of this area

  • axons project to brainstem and to spinal cord

  • each can influence multiple muscles

• population coding for direction of movement

Premotor cortex — Area 6

The premotor cortex is anterior to M1 and contains the PMA and SMA.

PMA = premotor area

• Planning the move

• More bilateral

• Just anterior to M1

• Lateral portion of Brodmann’s area 6

• Selects appropriate movements based on external cues

• Activity in the PMA PRECEDES that of M1

SMA = supplementary motor area

• just anterior to M1

• medial portion of Brodmann’s area 6

• selects appropriate movements based on internal cues

• Activity in the SMA PRECEDES that of M1

What comes first: PMA activity or M1 activity? Explain using the monkey experiment.

When would you expect to see an increase in activity in M1?

• The monkey gets the 1st signal: A red light tells it what movement will eventually be required. But it is not allowed to move yet. At this point: PMA activity increases because PMA is preparing/planning the movement. The monkey knows: “I’m going to have to move my arm there.” but has not executed it.

• Then, the 2nd signal: The blue trigger says: “NOW move.” At that point: M1 activity increases strongly because M1 is tied much more closely to movement execution.

• When would you expect to see an increase in activity in M1? Activity in M1 would correlate with the actual movement itself (just slightly in advance of the movement).

Is M1 and PMC contra-, ipsi-, or bi- lateral? How does the corpus callosum contribute to this?

• M1 = contralateral

• Premotor cortex = bilateral

  • The left and right premotor cortices communicate through cortico-cortical axons that cross the midline through the corpus callosum, allowing more bilateral coordination of movement planning.

What are the differences in effects of damage to PMC vs M1?

M1 DAMAGE = Paralysis: no movement; Paresis: weak movement

PMC DAMAGE = Apraxia

• Selective inability to perform complex (but not simple) motor acts. It stems from an inability to perform learned movements on command, even though the command is understood and there is a willingness to perform the movement.

• Apraxia is usually from damage to the premotor areas. It often affects bilateral motor acts, which suggests strong connections between left and right premotor cortex.

Ideamotor vs Ideational Apraxia

• Ideomotor apraxia (IMA) is the impaired ability to perform a skilled gesture with a limb upon verbal command and/or by imitation. It can be shown for both meaningful motor acts that do not imply objects and gestures that imply object use.

• Ideational apraxia is a condition in which an individual is unable to plan movements related to interaction with objects, because they have lost the perception of the object's purpose. Characteristics of this disorder include a disturbance in the

How does the M1 topographic map differ from S1?

• M1 does have a rough topographic map

  • nearby body parts often have nearby representations

  • for example, finger-related movements are grouped together and are near hand-related movements

• BUT M1 is organized more by movements and population coding than by single muscles or perfectly separated body parts

• the representations overlap a lot so M1 is not as cleanly segregated as S1

A movement like reaching for a cup uses several muscles across the shoulder, arm, wrist, and hand. M1 is better thought of as coordinating the movement pattern rather than having one tiny region for each individual muscle.

That connects to the “muscle field” idea: One M1 neuron can influence multiple muscles, so you wouldn’t expect perfectly separate muscle-by-muscle zones.

What are the three different ways the brain influences movement?

1. Motor cortex sends commands DOWN to the spinal cord

2. Basal ganglia loop back to premotor cortex to help select/facilitate motor programs

3. Cerebellum loops back to M1 to help coordinate/correct movement

The big thing is that basal ganglia and cerebellum do NOT directly replace the descending motor pathways. They modify what motor cortex does.

Motor loop through the Basal Ganglia

The basal ganglia receive input from almost all of cerebral cortex, with most from prefrontal cortex and motor cortex and least from sensory cortex.

The basal ganglia motor loop includes projections from basal ganglia – through the thalamus – back to premotor cortex (Area 6)

The thalamic nucleus involved is a portion of the ventral lateral nucleus – VLo (pars oralis).

Also, BG projects to SNpr which projects to superior colliculus to influence head/eye movements)

Motor loop through the Cerebellum

The cerebellum receives input from almost all of cerebral cortex, but most from sensory cortex and motor cortex and least from prefrontal cortex.

The cerebellar motor loop includes projections from cerebellum - through the thalamus - back to motor cortex (Area 4).

The thalamic nucleus involved is the caudal portion of the ventral lateral nucleus - VLc.

Later - cerebellum also gets some sensory info more directly (vestibular and proprioceptive)

AND projects to all upper MN areas (not just cerebral cortex) meaning the cerebellum can influence multiple descending motor systems. So it can affect motor output through:

• motor cortex

• brainstem motor areas

• other upper motor neuron systems

Why does the cerebellum get so much sensory information?

Because the cerebellum needs to compare: “What movement did I intend to make?”

with: “What is my body actually doing?”

The cerebellum also receives some sensory information more directly, especially:

• vestibular

• proprioceptive

That makes sense because:

• vestibular info tells it about balance/head position

• proprioception tells it where the limbs/body are

So if you reach for a cup, the cerebellum can use sensory feedback to adjust the movement while it is happening.

The BASAL GANGLIA!

Describe its function, explain what dorsal striatum/caudate/putamen are, and explain parallel circuits.

Function: varies by which part of basal ganglia is being considered, but in general it evaluates/modulates cortical commands

The dorsal striatum/caudate/putamen:

• Required for normal initiation of voluntary movements

• Helps in switching movement on and off, and controlling/modulating various motor patterns

The BG has parallel circuits, meaning it has multiple separate loops running simultaneously, instead of just one pathway for movement

• Executive loop: Helps with cognition

• Limbic loop: Helps with emotion

  • This loop includes the ventral striatum, especially the nucleus accumbens core and shell

• Motor loop: Movement

  • Indirect loop

  • Direct loop

Are the basal ganglia present on one side or both sides of the brain?

The basal ganglia are present on both sides of the brain. There is a left basal ganglia and a right basal ganglia.

What is the difference between dorsal striatum and ventral striatum?

• Dorsal striatum = caudate + putamen → mostly motor control

• Ventral striatum = nucleus accumbens → mostly reward/motivation/emotion

BG Direct VS Indirect Pathway

• The direct pathway acts to facilitate motor output/stimulate particular motor programs.

• The indirect pathway acts to inhibit motor output/to suppress competing motor programs.

• Neurons in these pathways are active at the same time to trigger the correct movement, and inhibit all other movements.

Explain the DG Direct Pathway. Describe how disinhibition plays a role in this path, and dopamines role in this pathway.

Cortex → excites striatum → striatum inhibits internal GP/SNpr → less inhibition of VL thalamus → VL thalamus excites motor cortex more.

The internal GP/SNpr normally inhibits the thalamus. The direct pathway inhibits this inhibition (aka disinhibition).

Dopamine turns up the direct pathway, so there is more stimulation of movement and more movement can occur.

Explain Dopamine's role in the Basal Ganglia Motor Loop

There are 5 dopamine receptors (D1-5), and they are all metabotropic GPCRs. D1 and D2 receptors are highly expressed in striatum.

• D1 activation = increases cAMP, excites direct pathway

• D2 activation = decreases cAMP, inhibits indirect pathway

Dopamine cell bodies are NOT in the striatum! Just the terminals!

In general, dopamine facilitates the initiation of motor programs

Explain the DG Indirect Pathway

Cortex excites striatum → striatum inhibits external GP → external GP inhibits subthalamic nucleus less → subthalamic nucleus excites internal GP more → internal GP inhibits VL thalamus more → VL thalamus excites motor cortex less

Dopamine turns down the indirect pathway, so there is less inhibition of movement and more movement can occur.

How would a lesion to the substantia nigra pars compacta (SNpc) affect motor cortex output?

There is less excitation of the DIRECT PATHWAY; there is less inhibition of the INDIRECT PATHWAY

This shifts the balance toward the INDIRECT pathway

The result is an overall decrease in motor output → Parkinson’s Disease

Parkinson’s Disease: Causes, Symptoms, Treatment

Caused by: Loss of neurons in SNpc, the locus coeruleus (norepinephrine), and the dorsal raphe (serotonin). Typically 30-50% of neurons are lost BEFORE motor symptom onset. Sometimes up to 70%!

Symptoms:

• onset typically in 60s

• resting tremor

• bradykinesia = slow movements

• loss of smell

• cognition (especially depression)

• mood disorders

• bowel control

• akinesia - lack of movements (difficulty starting movements)

Treatment: L-DOPA

Why does Parkinson’s also involve cognitive problems and mood disorders?

• Neurons that make norepinephrine and serotonin also die.

• Dopamine also regulates cognition

Why can Parkinson’s cause tremor?

• Parkinson’s changes the pattern of basal ganglia activity.

• Increased synchronization of oscillatory discharge contributes to tremor

Why is L-DOPA used for Parkinson’s, as opposed to other alternatives (e.g. dopamine, tyrosine)?

• Dopamine can't be used because Catecholamines are easily oxidized in the blood-brain barrier

• Tyrosine can't be used because the rate limiting step is TH

  • tyrosine → [rate-limiting TH step] → L-DOPA → dopamine

  • Giving L-DOPA skips the rate limiting step

Therefore, L-DOPA is used because it is a precursor to dopamine. However, its effectiveness depends on having some surviving dopamine neurons in the SNpc, so the treatment becomes less effective as these neurons continue to die. By the time Parkinson’s disease is diagnosed, many of these dopamine neurons have already been lost.

What are common problems with using L-DOPA as a treatment for Parkinson’s?

• Loses effectiveness or effectiveness varies (on/off)

  • L-DOPA may work less well over time.

  • Its effects can also fluctuate, so patients may switch between periods where movement is better and periods where symptoms return.

• Side effects — abnormal movements (dyskinesia), psychiatric disturbances including impulse control

  • Long-term L-DOPA can cause dyskinesia, meaning abnormal involuntary movements.

• Due to synapse/circuit plasticity AND lots of other dopamine pathways than just the one in the striatum

  • L-DOPA does not affect only the motor pathway.

  • Dopamine is used in other brain circuits too, so increasing dopamine can affect those pathways as well.

  • Long-term treatment can also change how the circuits respond over time.

What are alternative Parkinson’s treatment options?

• transplant dopamine-producing neurons

• inactivate the subthalamic nucleus or internal globus pallidus

• use deep brain stimulation

• change treatment regimens or add other drugs

Deep Brain Stimulation

DBS disrupts abnormal electrical activity patterns in the basal ganglia so the circuit can function more normally. DBS relieves symptoms; it does not cure Parkinson’s.

It can reduce:

• resting tremor

• rigidity

• bradykinesia

• gait problems

What happens to motor output if neurons in the indirect basal ganglia pathway are lost?

• The indirect pathway normally inhibits motor output.

• Loss of indirect pathway neurons → less inhibition of movement → increased motor output.

• This shifts the balance toward the direct pathway.

The loss of neurons that project from striatum to external GP is part of the mechanism underlying Huntington’s disease.

Huntington’s Disease: Causes, Symptoms

Causes:

• Mutant huntingtin (HTT) gene → neuronal death

• Loss of indirect pathway neurons projecting from striatum → external GP

• Less indirect pathway activity → increased motor output

Symptoms:

• Autosomal dominant

• Usually begins in the 40s–50s

• Progressive

• Death often occurs within 10–20 years from associated complications

• Chorea = involuntary, rapid, jerky movements (different from L-DOPA induced dyskinesia)

• Personality changes and Dementia (caused by loss of neurons elsewhere, like in the frontal/temporal lobes)

What happens to motor output if there is a lesion of the subthalamic nucleus?

Ballism or ballismus

• violent, involuntary limb movements

• usually caused by a stroke

Hemiballismus = one side

Ballism vs Huntington’s symptoms

• Ballism:

  • Tends to be much more violent and sudden

  • Violent, involuntary movements

  • Defined as limb movements

• Huntington’s:

  • Tends to start more subtly and increases in intensity over time

  • Chorea = involuntary, rapid, jerky movements

  • Can affect more than just the limbs

    • Ex: face twitches and stutters

Where does the cerebellum develop from, and why is this important?

• The cerebellum develops from the hindbrain, so it has a different origin than the cerebral cortex.

• It has its own embryological and evolutionary origin.

• Because of this, it can act independently of the cortex.

• This is important in animals like electric fish that do not have a cerebral cortex.

What are the main features of the cerebellum?

• 3-layered cerebellar cortex

• 2 hemispheres + midline vermis

• Deep cerebellar nuclei

• Different regions have different functions

• Fractured somatotopic maps mainly represent ipsilateral movements

What are the three layers of the cerebellar cortex?

• Molecular layer = outermost layer; contains dendritic arbors of Purkinje neurons

• Purkinje cell layer = contains Purkinje cell somas

• Granule cell layer = contains granule cells

What are the main features of a Purkinje neuron’s dendritic arbor?

• Dendrites are covered with dendritic spines.

• Receives hundreds of thousands of synaptic inputs—as many as any neuron in the nervous system.

• Dendritic tree is fan-shaped and almost two-dimensional.

  • 2D shape allows more neurons to fit into a smaller space

How does the cerebellum receive and send motor information, and which side of the body does it control?

• Much of the information is gated through the pons area of the brainstem.

• The cerebellum receives information from the brainstem/spinal cord and sends output back through the thalamus to cerebral cortex.

• An efferent copy of the motor command is sent toward the cerebellum.

• The cerebellum controls ipsilateral movements.

How do parallel fibers and climbing fibers connect to Purkinje cells?

• Parallel fibers:

  • Come from granule cells

  • Run perpendicular

  • Synapse onto many Purkinje cells

  • Excitatory

• Climbing fibers:

  • Come from the contralateral inferior olivary nucleus in the brainstem

  • One climbing fiber synapses many times onto a single Purkinje cell

  • Very strong excitatory input

What information do climbing fibers and parallel fibers carry to Purkinje cells?

• Climbing fibers carry muscle proprioceptive information

• Parallel fibers carry information from the cerebral cortex and other sources

What happens when parallel fibers and climbing fibers are active together?

• The active parallel fiber synapses become weaker and less effective

• This is long-term depression (LTD)

What is input specificity in cerebellar long-term depression (LTD)?

• Only parallel fiber synapses that are active at the same time as climbing fibers show LTD.

• Those active parallel fiber synapses become weaker.

Why is cerebellar LTD important?

• These synaptic changes may be important for learning and memory.

• Especially important for repeated, coordinated motor programs.

What information does the cerebellum use to control movement?

• Gets information from ipsilateral motor cortex about the movement to be performed.

• Gets lots of sensory information from ipsilateral sensory cortex and spinal cord about the movement actually made

What is the primary function of the cerebellum?

• Error reduction.

• Detects the difference between intended movement and actual movement, then acts to reduce the error.

• This occurs during movement and as part of learning over time.

What are the effects of cerebellar damage?

• Cerebellar ataxia = jerky, inaccurate, poorly coordinated movements

• Can be caused by:

  • autoimmunity to Purkinje cells

  • stroke

  • toxin damage

  • genetic disorders

  • cerebellar cancer

• Control is ultimately ipsilateral

• Specific movements affected depend on the cerebellar region damaged

What is an intention tremor, and how is it different from a Parkinson’s tremor?

• Intention tremor is one expression of cerebellar ataxia

• Tremor occurs with initiation/attempted movement

• Parkinson’s is associated with a resting tremor

What happens with damage to specific cerebellar regions?

• Vestibulocerebellum lesion → impaired eye fixation

• Korsakoff’s syndrome / long history of alcohol abuse:

  • degeneration of anterior lower-body spinocerebellum

  • wide, staggering gait

  • later difficulty walking at all

What are the two motor systems?

• Visceral (autonomic) motor system

  • Smooth and cardiac muscle

  • Not covered further in this class

• Somatic motor system

  • Skeletal muscle

What are upper motor neurons, and how do they differ from lower motor neurons?

• Upper motor neurons originate in the motor region of the cerebral cortex or brainstem.

• They carry motor information down to lower motor neurons.

• Lower motor neurons synapse directly onto muscle.

• Upper motor neurons do not synapse directly onto muscle.

Where are the four major groups of upper motor neurons located?

• Primary motor cortex

• Vestibular nuclei

• Reticular formation

• Red nucleus

• Superior colliculus

What are the four major upper motor neuron groups and their functions?

1. Body posture

   • Vestibular nuclei = feedback

   • Vestibulospinal tract

   • Reticular formation = feedforward

   • Reticulospinal tract

   • Controls axial and proximal limb muscles

2. Arm movements

   • Red nucleus in midbrain

   • Rubrospinal tract

   • Controls proximal arm muscles

3. Orienting head and eye movements

   • Superior colliculus in midbrain

   • Tectospinal tract

4. Complex voluntary movement sequences

   • Primary motor cortex in contralateral frontal lobe

   • Corticospinal tract

• Tracts are named by their origin and destination.