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SMP - APP Part 2 > Lectures 5 & 6 - Basal Ganglia Pathophysiology I & II > Flashcards

Lectures 5 & 6 - Basal Ganglia Pathophysiology I & II Flashcards

1
Q

What is the entryway into the basal ganglia in rodents?

A

Striatum

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2
Q

2 components of the striatum in higher primates?

A
  1. Caudate nucleus

2. Putamen

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3
Q

What is the input nucleus of the basal ganglia?

A

Striatum

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4
Q

What is the output nucleus of the basal ganglia?

A

Globus pallidus internus

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5
Q

What are 4 diseases associated with the basal ganglia?

A
  1. Huntington’s Disease
  2. Gilles de La Tourette’s Syndrome
  3. Parkinson’s Disease
  4. Dementia Pugilistica
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6
Q

List the 5 structures of the basal ganglia.

A
  1. Caudate nucleus
  2. Putamen
  3. Globus pallidus
  4. Subthalamic nucleus
  5. Substantia nigra
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7
Q

Cortex to striatum of basal ganglia: excitatory or inhibitory?

A

Excitatory

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8
Q

What are the 2 parts of the globus pallidus?

A
  1. Internus

2. Externus

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9
Q

Striatum to globus pallidus internus AND externus: excitatory or inhibitory?

A

Inhibitory

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10
Q

Globus pallidus externus of basal ganglia on subthalamic nucleus: excitatory or inhibitory?

A

Inhibitory

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11
Q

Globus pallidus internus of basal ganglia on thalamus: excitatory or inhibitory?

A

Inhibitory

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12
Q

Subthalamic nucleus of basal ganglia on globus pallidus internus: excitatory or inhibitory?

A

Excitatory

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13
Q

Substantia nigra of basal ganglia on thalamus: excitatory or inhibitory?

A

Inhibitory

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14
Q

Thalamus on cortex: excitatory or inhibitory?

A

Excitatory

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15
Q

Describe the direct pathway of the basal ganglia. Other name?

A

Motor cortex and substantia nigra stimulate striatum → Ascending dopaminergic input from SNc will bind D1 receptors on medium spiny neurons in striatum → Striatum inhibits GPi/substantia nigra pars reticulata → Decreased GPi inhibition of the the ventral lateral pars oralis of the thalamus → Thalamus stimulates motor cortex → Increase in motor behavior

= striatonigral pathway

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16
Q

Describe the indirect pathway of the basal ganglia. Other name?

A

Motor cortex and substantia nigra stimulate striatum → Ascending dopaminergic input from SNc will bind D2 receptors on medium spiny neurons in striatum → Striatum inhibits GPe → Decrease of GPe inhibition of subthalamic nucleus → Subthalamic nucleus stimulates GPi → GPi inhibits ventral lateral pars oralis of the thalamus → Decreased stimulation of motor cortex by thalamus → Decrease in motor behavior

= striatopallidal pathway

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17
Q

What 4 inputs does the striatum of the basal ganglia receive?

Type and source

A
  1. Glutamergic input from corticostriatal tract
  2. Dopaminergic from substantia nigra
  3. Acetylcholinergic from striatum itself (intrinsic control)
  4. GABAergic from striatum itself (intrinsic control)
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18
Q

What output does the globus pallidus internus of the basal ganglia send out?

Type, target, and pathway

A

GABAergic output to the cortex via the ventral lateral pars oralis of the thalamus

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19
Q

What output does the striatum of the basal ganglia send out?

Type and targets?

A

GABAergic to:

  1. Globus pallidus internus
  2. Globus pallidus externus
  3. Substantia nigra
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20
Q

What separates the caudate nucleus from the putamen?

A

Internal capsule

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21
Q

What are the basal ganglia neurons called? Why?

A

Spiny neurons because they each make 11K unique synaptic connections

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22
Q

What is the role of the dorsal striatum?

A

Convergence of multiple inputs to dictate striatal outflow of information important for the initiation of movement and habitual repertoires

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23
Q

Which cells of the substantia nigra synthesize dopamine?

A

Pars compacta cells

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24
Q

What are D1 and D2? Describe how they work.

A

2 dopamine receptor subtypes on the striatum:

  1. D1 + dopamine => increase cAMP => increase intracellular Ca++ => striatum stimulation to inhibit GPi MORE => more muscle movements
  2. D2 + dopamine => decrease cAMP => increase K+ channels and decrease Ca++ channels => striatum stimulation to inhibit GPe MORE => less muscle movements
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25
Q

Describe what happens in the basal ganglia pathways in Parkinson’s disease.

A

Damage to pars compacta cells of the substantia nigra:

  1. Substantia nigra cannot activate the direct pathway through dopamine D1 receptors to cause increased motor activity (PRIMARILY)
  2. Substantia nigra cannot inhibit the indirect pathway through dopamine D2 receptors

RESULT: decreased voluntary muscle movements

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26
Q

2 types of striatum neurons? Which are more numerous?

A
  1. ***Principal neurons => projecting medium spiny neurons = striatopallidal or striatonigral neurons (95% of neurons)
  2. Aspiny interneurons => non-projecting cholinergic or GABAergic neurons
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27
Q

Role of aspiny neurons of the striatum? Describe their firing.

A

Function to adjust and modulate firing to dictate striatal outflow

Fire APs in a steady, yet irregular fashion (3-10Hz)

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28
Q

What are the 2 states of medium spiny neurons when they are not firing APs in the striatum?

A
  1. Up: -60–50 mV => able to fire APs
  2. Down: -90–75 mV = hyperpolarized

Oscillations between these two states

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29
Q

Which neurons degenerate in Huntington’s disease?

A

Medium spiny neurons of the striatum

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30
Q

What are MSNs very permeable to in their basal resting state?

A

K+

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31
Q

Describe the FS type of interneuron of the striatum.

A

Fire fast APs (up to 100/second) and their axons richly innervate MSNs and can regulate their activity by dampening their signal

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32
Q

What is one subtype of MSNs?

A

Low threshold spiny neurons

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33
Q

What are cholinergic interneurons in the striatum characterized by? Other name?

A

Large soma

= tonically active interneurons

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34
Q

What are 4 types of cortical-basal ganglia loops? Which part of the BG does each innervate?

A
  1. Motor: putamen
  2. Oculomotor: caudate nucleus
  3. Prefrontal: caudate nucleus
  4. Limbic: caudate nucleus
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35
Q

5 associated disorders with the motor cortical-basal ganglia loop?

A
  1. Parkinson’s Disease
  2. Dystonia
  3. Huntington’s Disease
  4. Tourette’s
  5. Hemiballismus
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36
Q

2 associated disorders with the oculomotor cortical-basal ganglia loop?

A
  1. Parkinson’s Disease

2. Huntington’s Disease

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37
Q

2 associated disorders with the prefrontal and limbic cortical-basal ganglia loop?

A
  1. OCD

2. Addictive disorders

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38
Q

2 types of neurons in the globus pallidus? Majority?

A
  1. Projection neurons***

2. Interneurons

39
Q

What is important to note regarding the GABAnergic neurons of the GP?

A

Long pause between signaling from one neuron to another suggesting the convergence of multiple GABA synapses

40
Q

What output does the subthalamic nucleus of the basal ganglia send out?

Type and targets?

A

Glutaminergic to the GPi

41
Q

Only neurons in the basal ganglia that are glutaminergic?

A

Subthalamic nucleus neurons

42
Q

Describe the firing of the neurons of the subthalamic nucleus of the basal ganglia.

A

Pattern of autonomous firing between 20 and 50 Hz

43
Q

What is distinctive about the substantia nigra of the basal ganglia?

A

Black color

44
Q

2 major divisions of the substantia nigra?

A
  1. Pars compacta

2. Pars reticulata

45
Q

What are the firing patterns of the substantia nigra regulated by?

46
Q

Neuromodulator used by substantia nigra?

47
Q

3 types of GABA receptors? Describe each.

A
  1. GABAA receptors: pentameric ligand gated ion receptors that are targets for barbiturates and benzodiazepines
  2. GABAB receptors: metabotropic receptors that affect secondary messenger cascades
  3. GABAC receptors: ligand gated ion receptors located in the retina
48
Q

3 types of glutamate receptors? Describe each.

A
  1. NMDA receptors
  2. Non-NMDA receptors: AMPA and kainite receptors and are tetrameric receptors that allow for the non-selective passage of monovalent and divalent cations
  3. Metabotropic receptors: couple with intracellular secondary messenger systems and affect membrane potential via other ion channels
49
Q

Type of dopamine receptors?

50
Q

Where are the basal ganglia brain nuclei located?

A

Forebrain and midbrain

51
Q

What striatal neurons secrete acetylcholine? What to note?

A

Giant aspiny neurons

NOTE: levels of the neurotransmitter acetylcholine are among the highest of any brain structure

52
Q

Where does the striatum get its name from?

A

The axons of spiny neurons are bundled into fascicles that perforate the gray matter of the nucleus, giving it a striated appearance

53
Q

What are the firing patterns of dopaminergic neurons of the basal ganglia associated with?

54
Q

Describe the firing of the neurons of the globus pallidus of the basal ganglia.

A

Homogeneous and exhibit tonic activity in frequency ranges from 50-100 Hz

55
Q

Describe the firing of the dopaminergic neurons of the substantia nigra of the basal ganglia.

A

Slow spontaneous activity patterns that range from pacemaker-like firing, to random patterns, and burst firing patterns that have been correlated with ‘reward’ signal

56
Q

3 functional roles of the basal ganglia?

A
  1. Smooth execution of voluntary movements by involvement in planning
  2. Suppression of unwanted movements
  3. Higher level cognitive processes
57
Q

When do PD symptoms appear?

A

When ~80% of dopaminergic neurons of the substantia nigra are lost

58
Q

Cause of Huntington’s disease?

A

Single autosomal dominant mutation in which multiple CAG repeats are inserted into the normal gene (normal repeat length: 9-34 vs 38-100), termed huntingtin, which has the following proposed functions:

  • Mitochondrial dysfunction, ATP generation
  • Aberrant transcriptional regulation
  • Mitochondrial positioning in neurons
59
Q

Cause of hemiballism? What is it characterized by?

A

Unilateral lesions of subthalamic nucleus (due to stroke, tumor, or infection), and is characterized by uncontrolled flinging movements of the contralateral arm or leg (more severe hyperkinetic disorder than HD) and associated with decreased levels of GP output

60
Q

5 clinical aspects of diseases of the basal ganglia?

A
  1. Tremor
  2. Changes in posture and muscle tone
  3. Poverty of movement without paralysis
  4. Hyperkinetic involuntary movements
  5. Obsessive-compulsive disorders
61
Q

Where is the substantia nigra located in the brain?

62
Q

Theory behind PD?

A

Unbalanced activity of the direct and indirect pathway

63
Q

Theory behind the development of PD?

A

Coincides with the industrial revolution

64
Q

4 clinical manifestations of PD?

A
  1. Bradykinesia = slow movements
  2. Muscle rigidity
  3. Resting tremor: usually abates during voluntary movement
  4. Poor postural balance leading to disturbances in gait/falling episodes
65
Q

Demographics of PD patients?

A
  1. 1-1.5 million Americans (> multiple sclerosis, muscular dystrophy, Lou Gehrig’s disease combined)
  2. Usually occurs in late middle age (μ=60 yrs) in both ♀♂ equally
  3. Caucasian > Asian, African
66
Q

Is there a genetic correlation with PD? What to note?

A

YUP, mostly involved in mitochondrial function

BUT 95% of cases are idiopathic

67
Q

Is there a conclusive diagnosis of PD?

A

NOPE - only post-mortem

68
Q

Effect of PD on the striatum?

A

Dopamine transport (DAT) disappears

69
Q

Environmental factor in PD?

A

Chronic pesticide exposure may lead to PD features

70
Q

Parkinson therapy? How does it work?

A

Levodopa (L-dopa)

Metabolic precursor of dopamine that is largely inert (won’t interfere with other dopamine receptors, for example on the kidneys) and can pass the blood-brain barrier => within the brain, L-Dopa is taken up by dopaminergic neurons via the DAT transporter and converted to dopamine in dopamine neurons

In modern practice it is co-administered with inhibitor of L-amino acid decarboxylase (AAD) called ”carbidopa” (Sinemet, Atamet) to inhibit that enzyme in our blood

71
Q

Disadvantages of current PD treatment?

A

Repetitive, aimless movements occur over time = dyskinesia

72
Q

What 2 enzymes in our blood act on L-dopa when administered to PD patients? What happens then?

A
  1. Catechol-O-methyl transferase (COMT): converts L-dopa to 3-OMD
  2. L-amino acid decarboxylase (AAD): converts L-dopa to dopamine
73
Q

Describe the treatment of PD using dopamine receptor agonists. Side effects?

A

Bromocryptine and pergolide are used: no enzymatic activity required and we can target receptor subtype D1

Side effects include dyskinesias, orthostatic hypotension, nausea, hallucinations/confusion

74
Q

Describe the treatment of PD using MAO-B inhibitors. What to note?

A

Monoamine oxidase-B expressed in the CNS and inhibitors can decrease the metabolism of existing dopamine using selegiline and ELDEPRYL

NOTE: benefits are modest and more efficacious early in PD progression

75
Q

Describe the treatment of PD using ablation surgery.

A

Ablation targeting:

  1. Thalamus: can improve tremor
  2. Globus pallidus: can improve levodopa-induced dyskinesia, rigidity and sometimes tremor: UNILATERAL
  3. Subthalamic nucleus: can improve tremor, slowness and stiffness, and may allow PD medication to be reduced, BILATERAL
76
Q

Describe the treatment of PD using deep brain stimulation surgery. What to note?

A

Exact mechanism remains uncertain but targets the
STN or GPi bilaterally

NOTE: patients with more ‘mild’ symptoms are better
candidates

NOTE: has largely replaced ablation surgeries: less invasive, reversible and adjustable

77
Q

Other name for Huntington’s disease?

A

Huntington’s Chorea

78
Q

8 nonmotor features of PD?

A
  1. Cognitive impairment (e.g. memory)
  2. Visual hallucinations
  3. Mood disorders
  4. Olfactory deficit
  5. Pain
  6. Sleep disorders
  7. Orthostasic hypotension
  8. Constipation, urine and erectile dysfunction
79
Q

Which is more affected in HD: direct or indirect pathway?

80
Q

Symptoms of HD?

A
  1. Twitching movements of head
  2. Grimacing movements in face, lips, tongue
  3. Gesticulating movements in distal parts of upper limbs
  4. Jerking movements in distal parts of lower limbs
81
Q

Is HD fatal?

82
Q

What do CAG repeats code for?

A

Polyglutamine

83
Q

Can current medications slow the progression of HD?

84
Q

Is the movement disorder in HD treated?

A

Only rarely

85
Q

What is treated in HD?

A

Depression, irritability, and paranoia using fluoxetine (SSRI) and carbamazepine

86
Q

What is Tourette’s syndrome? What do patients usually also have?

A

Neurological disorder characterized by childhood onset and motor and vocal ‘tics’, where limbic cortical-basal ganglia loop is impaired

High percentage of TS patients suffer from OCD, ADHD, and depression

87
Q

Treatment for Tourette’s syndrome?

A

Hyper-dopaminergic disease so treatments include dopamine antagonists

88
Q

What do addictions have in common?

A

Cocaine, amphetamines, nicotine, alcohol: all share common mechanism of elevating dopamine in ventral striatum

89
Q

What is the purpose of the striatum inhibiting the pars reticulata of the substantia nigra in the direct pathway?

A

To help select movements and get movement going

90
Q

Are ACh striatal neurons segregates? What does this mean?

A

NOPE - only one type of them

91
Q

What are Lewy bodies?

A

Abnormal aggregates of protein that develop inside nerve cells in Parkinson’s disease

92
Q

Can dopamine cross the BBB?

A

Not efficiently

93
Q

What does “tonic” activity of neurons mean?

A

Always firing action potentials at a slow rate.

SMP - APP Part 2 (7 decks)

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