11/20: Basal Ganglia

Question 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.

Answer 1

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.

Question 2

FUNCTION OF THE BASAL GANGLIA:

Answer 2

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).

Question 3

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

Answer 3

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

Question 4

BASAL GANGLIA Structures in the FOREBRAIN

Answer 4

Striatum:

• Caudate Nucleus
• Putamen

Globus Pallidus

• External Segment (GPe)
• Internal Segment (GPi)

Question 5

LENTICULAR NUCLEI

Answer 5

Putamen

Globus Pallidus

• External Segment (GPe)
• Internal Segment (GPi)

Question 6

BASAL GANGLIA Structures in the DIENCEPHALON

Answer 6

Subthalamic Nucleus

Question 7

BASAL GANGLIA Structures in the MIDBRAIN

Answer 7

Substania Nigra

• Compact Part (SNc)
• Reticular Part (SNr)

Question 8

STRIATUM

Answer 8

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

Question 9

Caudate

Answer 9

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

Question 10

Putmen

Answer 10

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

Question 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.

Answer 11

Patient With Bilateral Damage To Head Of Caudate.

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

Question 12

Output of striatum

Answer 12

Medium spiny neuron - GABAergic

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

Question 13

GABA/ D2 Receptors

Answer 13

Project to GPe

Medium spiny neurons

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

Question 14

GABA/D1 Receptors

Answer 14

Project to GPi

Medium spiny neurons

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

Question 15

medium spiny neurons

Answer 15

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

Question 16

NEUROCHEMICAL MAKEUP OF MEDIUM SPINY NEURONS

Answer 16

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.

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

GLOBUS PALLIDUS

Answer 20

EXTERNAL (Lateral) & INTERNAL (Medial) segments

Neurons in both segments are GABAergic

Question 21

INTERNAL SEGMENT

Answer 21

PRIMARY OUTPUT OF BASAL GANGLIA FOR LIMB MOVEMENTS

Question 22

SN – Pars Reticulata

SNpr

Answer 22

is primary output of basal ganglia for eye movements

Question 23

Subthalamus

Answer 23

In the Diencephalon

Between thalamus & substantia nigra

Glutamaterigic neurons:
only intrinsic source of excitation in basal ganglia

Question 24

Substantia Nigra

Answer 24

Midbrain

Question 25

only intrinsic source of excitation in basal ganglia

Answer 25

Glutamaterigic neurons of the Subthalamus

Question 26

SNpc

Answer 26

Substantia Nigra nuclei dorsal to pars reticulata and contains dopaminergic neurons. These cells are lost in Parkinson’s disease

Question 27

SNpr

Answer 27

Substantia Nigra nuclei analogous to GPi, controls eye movements Contains large GABAergic neurons

Question 28

BASIC FEEDBACK LOOP

Answer 28

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

Question 29

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

Answer 29

Putamen Subthalamus SNc This is an excitatory projection There is no direct projection from the cortex to the globus pallidus.

Question 30

Output of basal ganglia

Answer 30

Output of basal ganglia is via GPi and SNpr to thalamus. This is an INHIBITORY projection that suppresses the activity of thalamic neurons.

Question 31

Thalamus and Cerebral Cortex

Answer 31

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.

Question 32

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

Answer 32

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

Question 33

DIRECT PATHWAY

Answer 33

CORTEX --> PUTAMEN --> GPi --> THALAMUS --> CORTEX NET EFFECT: DISINHIBITION (excitation) of thalamus and motor cortex

Question 34

INDIRECT PATHWAY

Answer 34

CORTEX - ---> PUTAMEN - ---> GPe - ---> SUBTHALAMUS - ---> GPi - ---> THALAMUS - ---> CORTEX NET EFFECT: Suppression of thalamus and DISFACILITATION (inhibition) of cortex

Question 35

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

Answer 35

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

Question 36

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

Answer 36

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)

Question 37

INFLUENCE OF DOPAMINERGIC PROJECTION FROM SNpc

Answer 37

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

Question 38

SN (DA) EFFECT ON DIRECT PATHWAY

Answer 38

INCREASED ACTIVITY IN CORTICOSPINAL NEURONS

Question 39

CHOLINERGIC NEURONS IN THE STRIATUM

Answer 39

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.

Question 40

ACh _____ MOTOR ACTIVITY

Answer 40

ACh TURNS DOWN MOTOR ACTIVITY

Question 41

ACh inhibits striatal cells in the ____ loop

Answer 41

ACh inhibits striatal cells in the direct loop

Question 42

ACh excites striatal cells in the ____ loop

Answer 42

ACh excites striatal cells in the indirect loop

Question 43

DA TURNS ___ MOTOR ACTIVITY

Answer 43

DA TURNS UP MOTOR ACTIVITY

Question 44

DA excites striatal cells in the ___ loop via D__ receptors

Answer 44

DA excites striatal cells in the direct loop via D1 receptors

Question 45

DA inhibits striatal cells in the ____ loop via D__ receptors

Answer 45

DA inhibits striatal cells in the indirect loop via D2 receptors

Question 46

DA inhibits striatal cells in the ____ loop via D_ receptors

Answer 46

DA inhibits striatal cells in the indirect loop via D2 receptors

Question 47

CAUDATE-PUTAMEN | STRIATUM

Answer 47

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

Question 48

GLOBUS PALLIDUSe&i

Answer 48

GABA FOR BOTH GPe & GPi INPUT FROM - EFFECT: STRIATUM –INHIBITORY SUBTHALAMUS – EXCITATORY PROJECTS TO - EFFECT: GPi: THALAMUS –INHIBITORY GPe: SUBTHALAMUS –INHIBITORY

Question 49

SUBSTANTIA NIGRA | COMPACTA

Answer 49

TRANSMITTER OF NEURONS IN NUCLEUS: DOPAMINE INPUT FROM, EFFECT: CEREBRAL CORTEX, EXCITATORY PROJECTS TO, EFFECT GPi, EXCITATORY

Question 50

SUBTHALAMUS

Answer 50

TRANSMITTER OF NEURONS IN NUCLEUS: GLUTAMATE INPUT FROM, EFFECT: CEREBRAL CORTEX, EXCITATORY. GPe, INHIBITORY. PROJECTS TO, EFFECT GPi, EXCITATORY.

Question 51

PARKINSON’S DISEASE

Answer 51

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

Question 52

Cogwheel rigidity

Answer 52

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.

Question 53

Akinesia

Answer 53

impaired initiation of movement

Question 54

bradykinesia

Answer 54

reduced amplitude & velocity of voluntary movement

Question 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.

Answer 55

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.

Question 56

Lesions of ____ reduces motor symptoms in MPTP treated monkeys.

Answer 56

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

Question 57

PARKINSON’S DISEASE BRAIN

Answer 57

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

Question 58

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

Answer 58

This is why Parkinson's patient are so slow.

Question 59

TREATMENTS FOR PARKINSON’S DISEASE Several treatments including:

Answer 59

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

Question 60

DEEP BRAIN STIMULATION

Answer 60

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.