11/20: Basal Ganglia Flashcards Preview

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Flashcards in 11/20: Basal Ganglia Deck (60):
1

Basal ganglia circuitry is basically a _____ involving a projection from the cerebral cortex to a collection of _____ which project back to the cortex via the thalamus.

Output of the basal ganglia does NOT directly influence ____ involved in motor control or lower motor neurons.

Basal ganglia circuitry is basically a feedback loop involving a projection from the cerebral cortex to a collection of subcortical nuclei which project back to the cortex via the thalamus.

Output of the basal ganglia does NOT directly influence brainstem nuclei involved in motor control or lower motor neurons.

2

FUNCTION OF THE BASAL GANGLIA:

Initially, it was thought that the basal ganglia initiated movement, based on deficits seen following lesions of the system. Likely not this simple.

Lesions produce both paucity and enhancement of movement, sometimes simultaneously within a single disorder.

The basal ganglia may “condition” cortical output and set the gain of movement (amplitude, velocity, etc.).
There is no direct input from the periphery; the main excitatory input is from the cerebral cortex.

Inhibitory output may act selectively to inhibit competing motor programs (e.g., those to agonist & antagonist muscles).

3

Many regions of the cerebral cortex project to the striatum in a topographic pattern.

Further, projections within the basal ganglia also are topographically organized.

4

BASAL GANGLIA Structures in the FOREBRAIN

Striatum:
- Caudate Nucleus
- Putamen

Globus Pallidus
- External Segment (GPe)
- Internal Segment (GPi)

5

LENTICULAR NUCLEI

Putamen

Globus Pallidus
- External Segment (GPe)
- Internal Segment (GPi)

6

BASAL GANGLIA Structures in the DIENCEPHALON

Subthalamic Nucleus

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BASAL GANGLIA Structures in the MIDBRAIN

Substania Nigra
- Compact Part (SNc)
- Reticular Part (SNr)

8

STRIATUM

Caudate + Putamen

Input nuclei in the basal ganglia – receive excitatory input from cerebral cortex

Striatum means "striped"

The 1st part of the Basal Ganglia that receives incoming info from the cortex

9

Caudate

primarily related to prefrontal regions of the cerebral cortex and is involved in cognitive processing.

10

Putmen

primarily related to motor cortex and is involved in controlling movement.

11

Before the Lesion – Honor Student, Employed, Lived Independently, Engaged To Be Married.

Symptoms: Abnormal Behaviors Including Vulgarity, Impulsiveness, Easy Frustration, Violent Outbursts, Hypersonmia, Indifference, Wandering, Increased Appetite, Hypersexuality, Shoplifting.

Patient With Bilateral Damage To Head Of Caudate.

8 Months Later, Caudate Was No Longer Present and Ventricles Appeared Enlarged.

12

Output of striatum

Medium spiny neuron - GABAergic

Also distinguished by the type of dopamine receptor they express.
Some express D1 and some D2 type receptor.

13

GABA/ D2 Receptors

Project to GPe

Medium spiny neurons

Binding of dopamine to a D2 receptor results in hyperpolarization and inhibition of the neuron.

14

GABA/D1 Receptors

Project to GPi

Medium spiny neurons

Binding of dopamine to neurons expressing the D1 receptor causes depolarization and excitation of the neuron.

15

medium spiny neurons

All medium spiny neurons are GABAergic (inhibitory to their targets)

16

NEUROCHEMICAL MAKEUP OF MEDIUM SPINY NEURONS

There are 2 populations of medium spiny neurons in the striatum (caudate & putamen).
Both populations are GABAergic.
However, they express different types of dopamine receptors.

Some medium spiny neurons express Type 2 dopamine receptor or D2.
Others express the type 1 dopamine receptor of D1.

Binding of dopamine to these 2 receptors has very different effects.

When dopamine binds to a D2 receptor, it results in hyperpolarization and inhibition of the neuron.

In contrast, binding of dopamine to neurons expressing the D1 receptor causes depolarization and excitation of the neuron.

This is due to the fact that these are metabotropic receptors that activate distinct intracellular pathways leading to different effects.

One more difference is noted:

Neurons expressing the D1 receptor project to the internal segment of the globus pallidus and the substantia nigra pars reticulata.

Neurons expressing D2 project to the external segment of the globus pallidus.

In addition to these projection neurons, there also is a population of interneurons that are cholinergic.

17

DOPAMINE _____ Neurons With D1 Receptor On Cells Giving Rise to the ____ Pathway

DOPAMINE Excites Neurons With D1 Receptor On Cells Giving Rise to the Direct Pathway

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DOPAMINE ____ Neurons With D2 Receptor On Cells Giving Rise To ____ Pathway

DOPAMINE Inhibits Neurons With D2 Receptor On Cells Giving Rise To Indirect Pathway

19

EFFECT of DOPAMINE (DA) on MEDIUM SPINY NEURONS IS DEPENDENT on the TYPE of DOPAMINE RECEPTOR EXPRESSED by the NEURON.

DA Excites Neurons With D1 Receptor: On Cells Giving Rise To Direct Pathway

DA Inhibits Neurons With D2 Receptor: On Cells Giving Rise To Indirect Pathway

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GLOBUS PALLIDUS

EXTERNAL (Lateral) & INTERNAL (Medial) segments

Neurons in both segments are GABAergic

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INTERNAL SEGMENT

PRIMARY OUTPUT OF BASAL GANGLIA FOR LIMB MOVEMENTS

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SN – Pars Reticulata
(SNpr)

is primary output of basal ganglia for eye movements

23

Subthalamus

In the Diencephalon

Between thalamus & substantia nigra

Glutamaterigic neurons:
only intrinsic source of excitation in basal ganglia

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Substantia Nigra

Midbrain

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only intrinsic source of excitation in basal ganglia

Glutamaterigic neurons of the Subthalamus

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SNpc

Substantia Nigra nuclei

dorsal to pars reticulata and contains dopaminergic neurons.

These cells are lost in Parkinson’s disease

27

SNpr

Substantia Nigra nuclei

analogous to GPi, controls eye movements

Contains large GABAergic neurons

28

BASIC FEEDBACK LOOP

Motor cortex
---> Putamen
---> GPi
---> Thalamus
---> back to the Motor Cortex

29

The motor (primary, premotor, and supplementary motor) cortex projects to:

Putamen
Subthalamus
SNc

This is an excitatory projection

There is no direct projection from the cortex to the globus pallidus.

30

Output of basal ganglia

Output of basal ganglia is via GPi and SNpr to thalamus.

This is an INHIBITORY projection that suppresses the activity of thalamic neurons.

31

Thalamus and Cerebral Cortex

Thalamus projects back to cerebral cortex.
This is an excitatory projection.

If neurons in the thalamus are inhibited, there is a decreased drive on cortical neurons and decreased activity in descending pathways.

32

Circuitry Is Made Up of Opposing Parallel Pathways that Adjust the Magnitude of the Inhibitory ____ Output in order to Increase or Decrease _____.

Circuitry Is Made Up of Opposing Parallel Pathways That Adjust the Magnitude of the Inhibitory GPi Output In Order to Increase or Decrease Movement.

33

DIRECT PATHWAY

CORTEX --> PUTAMEN --> GPi --> THALAMUS --> CORTEX

NET EFFECT: DISINHIBITION (excitation) of thalamus and motor cortex

34

INDIRECT PATHWAY

CORTEX
----> PUTAMEN
----> GPe
----> SUBTHALAMUS
----> GPi
----> THALAMUS
----> CORTEX

NET EFFECT: Suppression of thalamus and DISFACILITATION (inhibition) of cortex

35

There is a ____ in GPi activity in response to Striatum Activation
????

There is a Decrease in GPi activity in response to Striatum Activation
????

36

Basal ganglia control of movement represents an integration of the direct and indirect pathway

1. Cortical activity increases at onset of movement.

2. Activity in some GPi neurons increases, but some decrease:
Cells in GPi controled by direct pathway decrease activity.
Cells in GPi controled by indirect pathway increase activity.

3. Neurons in GPi that show Decrease in activity may be critical for gating or facilitating cortically initiated movement. (Increased thalamic output)

4. Neurons in GPi that show Increase in activity may be critical in suppressing antagonist muscles or decreasing competing movements.
(Decreased thalamic input)

37

INFLUENCE OF DOPAMINERGIC PROJECTION FROM SNpc

Effect on target neurons is
dependent on type of receptor expressed by neuron

DA excites neurons with D1 receptor: On cells giving rise to direct pathway

DA inhibits neurons with D2 receptor: On cells giving rise to indirect pathway

REGARDLESS, NET EFFECT of DOPAMINE is DISINHIBITION of THALAMIC NEURONS and a FACILITATION of ACTIVITY in THALAMOCORTICAL CIRCUITS

38

SN (DA) EFFECT ON DIRECT PATHWAY

INCREASED ACTIVITY IN CORTICOSPINAL NEURONS

39

CHOLINERGIC NEURONS IN THE STRIATUM

Basically, the cholinergic neurons have the opposite effects of DA.

They
inhibit neurons in the Direct pathway, and
excite neurons in the Indirect pathway.

The net effect is increased output from GPi and an ultimate decrease in motor activity.

We have 2 chemically defined systems with opposite effects.

Acetylcholine turns down motor activity.
Dopamine turns up motor activity.

These opposing systems contribute to the symptoms seen in Parkinson’s disease.

40

ACh _____ MOTOR ACTIVITY

ACh TURNS DOWN MOTOR ACTIVITY

41

ACh inhibits striatal cells in the ____ loop

ACh inhibits striatal cells in the direct loop

42

ACh excites striatal cells in the ____ loop

ACh excites striatal cells in the indirect loop

43

DA TURNS ___ MOTOR ACTIVITY

DA TURNS UP MOTOR ACTIVITY

44

DA excites striatal cells in the ___ loop via D__ receptors

DA excites striatal cells in the direct loop via D1 receptors

45

DA inhibits striatal cells in the ____ loop via D__ receptors

DA inhibits striatal cells in the indirect loop via D2 receptors

46

DA inhibits striatal cells in the ____ loop via D_ receptors

DA inhibits striatal cells in the indirect loop via D2 receptors

47

CAUDATE-PUTAMEN
(STRIATUM)

TRANSMITTER OF NEURONS IN NUCLEUS:
1. GABA FOR STRIATAL OUTPUT NEURONS
2. ACETYLCHOLINE FOR INTERNEURONS

INPUT FROM - EFFECT:
1. CEREBRAL CORTEX
–EXCITATORY
2. SNc (DA) EXCITATORY (D1) OR INHIBITORY (D2)

PROJECTS TO - EFFECT:
D1 to GPi – INHIBITORY
D2 to GPe – INHIBITORY

48

GLOBUS PALLIDUSe&i

GABA FOR BOTH GPe & GPi

INPUT FROM - EFFECT:
STRIATUM –INHIBITORY
SUBTHALAMUS – EXCITATORY

PROJECTS TO - EFFECT:
GPi: THALAMUS –INHIBITORY
GPe: SUBTHALAMUS
–INHIBITORY

49

SUBSTANTIA NIGRA
COMPACTA

TRANSMITTER OF NEURONS IN NUCLEUS: DOPAMINE

INPUT FROM, EFFECT:
CEREBRAL CORTEX, EXCITATORY

PROJECTS TO, EFFECT
GPi, EXCITATORY

50

SUBTHALAMUS

TRANSMITTER OF NEURONS IN NUCLEUS: GLUTAMATE

INPUT FROM, EFFECT:
CEREBRAL CORTEX, EXCITATORY.
GPe, INHIBITORY.

PROJECTS TO, EFFECT
GPi, EXCITATORY.

51

PARKINSON’S DISEASE

One of the most common movement disorders
(~1 million cases in USA)

Linked to changes in 2 genes: α-synuclein and Parkin;
function of these genes is yet to be determined.

Also linked to environmental toxins, especially some used in agriculture

Net effect is a loss of dopaminergic neurons in SNpc

Characterized by wide range of deficits including:
Tremor at rest (4-5/sec)
Cogwheel rigidity
Akinesia

52

Cogwheel rigidity

thought to be due to decreased descending control of inhibitory interneurons that control gamma motor neurons.

If gamma motor neuron activity increases, both agonist & antagonist muscles may be hypersensitive and active at the same time.

53

Akinesia

impaired initiation of movement

54

bradykinesia

reduced amplitude & velocity of voluntary movement

55

Based on data from MPTP studies in primates:
It now appears that the effect is primarily on the ___ pathway, resulting in ____ activity in the subthalamus and subsequent decreased activity in the thalamo-cortical pathway.

Based on data from MPTP studies in primates:
It now appears that the effect is primarily on the indirect pathway resulting in increased activity in the subthalamus and subsequent decreased activity in the thalamo-cortical pathway.

56

Lesions of ____ reduces motor symptoms in MPTP treated monkeys.

Lesions of the subthalamus reduce motor symptoms in MPTP treated monkeys.

57

PARKINSON’S DISEASE BRAIN

The Substantia Nigra is barely there.

The SN is normally full of dopaminergic neurons, but in Parkinson's patient, these cells are dead.

58

In Parkinson's, Dopamine systems are broken, leaving the cholinergic system unchecked

This is why Parkinson's patient are so slow.

59

TREATMENTS FOR PARKINSON’S DISEASE

Several treatments including:

1. Ingestion of a precursor of dopamine: L-dopa.
Not localized in specific terminals.
The presence of dopamine in the vicinity of neurons is adequate to obtain some relief.

Potential problems of this type of therapy?
- Systemic effects
- Difficult to titrate drugs
- While blocking rigidity, it may induce hyperkinesia

2. Lesioning of GPi or subthalamus

3. Deep brain stimulation

60

DEEP BRAIN STIMULATION

FDA approved for treatment of Parkinson’s disease in 2002.

Covered by medicare in many states.

There is a 60-80% improvement in symptoms, such as tremor and slowness of movement.

Patients, on average, report a 50% improvement in their walking and balance.

Patients with involuntary movements (dyskinesia) due to their medications, experience over 80% reduction in their involuntary movements.

Most patients are able to significantly reduce their medications following deep brain stimulation.