Basal Ganglia (Week 4--Chesselet)

Question 1

Basal ganglia

Answer 1

Ensemble of interconnected brain regions

Striatum: caudate nucleus and putamen

Globus pallidus (external and internal segments)

Substantia nigra (pars compacta and pars reticulata)

Subthalamic nucleus (only recently included in definition of basal ganglia)

Question 2

Lentiform nucleus

Answer 2

Putamen and globus pallidus

(just because they are close together)

Question 3

Are the caudate and putamen separate structures?

Answer 3

Not really, the caudate and putamen are two parts of the same structure (the striatum)

However, the internal capsule (white myelinated fibers) go through this structure to create the caudate medially (near ventricles) and the putamen laterally

Caudate and putamen have same connections, except for somatotopic arrangements

Question 4

External globus pallidus (GPe) vs. Internal globus pallidus (GPi)

Answer 4

Have VERY different connections and functions

GPe: projects within the basal ganglia; uses GABA; gets input from medium spiny neurons from striatum that use enkephalin; indirect pathway, uses D2 receptors, inhibitory

GPi: projects outside the basal ganglia; uses GABA; gets input from medium spiny neurons from striatum that use substance P; major output pathway of striatum (projects to/inhibits VA,VL of thalamus); direct pathway, uses D1 receptors, excitatory

Question 5

Substantia nigra pars compacta (SNc) vs. Substantia nigra pars reticulata (SNr)

Answer 5

Very different

SNc: contains dopaminergic neurons projecting to caudate-putamen (striatum)

SNr: contains GABAergic neurons projecting outside the basal ganglia

Question 6

Ansa lenticularis

Answer 6

Output from the internal pallidum (GPi) to the thalamus

Lenticular fasciculus, or “H2 field of Forel” is same?

Question 7

Inputs to the basal ganglia

Answer 7

The main “entry” into the basal ganglia is input to striatum

These inputs come mainly from the cerebral cortex

Question 8

What regions of the cortex project to what regions of the striatum?

Answer 8

Medial cerebral cortex projects to caudate nucleus (more medial!)

Lateral cerebral cortex projects to putamen (more lateral!)

Question 9

Two things about the cortex to striatum connections that are important to remember

Answer 9

1) Convergence: a huge region of cortex (almost the whole thing) projects to a small striatum
2) Topographical organization: medial cortex projects to caudate and lateral cortex projects to putamen

Question 10

Inputs to the striatum

Answer 10

Cerebral cortex (not directly though!): uses glutamate

Nigrostriatal pathway (SNc to both putamen and caudate): uses dopamine; modulates input, not direct input (?)

Thalamus (centrum medianum/parafascicular nucleus): uses glutamate

Dorsal raphe: uses serotonin; modulates input, not direct input

Basolateral nucleus of amygdala: uses glutamate

Question 11

Basal ganglia “loops”

Answer 11

Inputs, outputs and internal connections are topographically organized which results in “parallel circuits”

Motor loop

Oculomotor loop

Prefrontal loop

Limbic loop

So patient with basal ganglia disorder will have symptoms in multiple regions (not just motor!)

Question 12

Motor loop

Answer 12

1) Motor, premotor, somatosensory cortex
2) Putamen
3) Lateral globus pallidus internal (GPi)
4) Ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus
5) Primary motor, premotor, supplementary motor cortex

Question 13

Oculomotor loop

Answer 13

1) Posterior parietal, prefrontal cortex
2) Caudate
3) Globus pallidus internal (GPi), substantia nigra pars reticulata (SNr)
4) Mediodosal and ventral anterior (VA) nuclei of the thalamus
5) Frontal eye field, supplementary eye field

Question 14

Prefrontal loop

Answer 14

1) Dorsolateral prefrontal cortex
2) Anterior caudate
3) Globus pallidus internal (GPi), substantia nigra pars reticulata (SNr)
4) Mediodorsal (MD) and ventral anterior (VA) nuclei of the thalamus
5) Dorsolateral prefrontal cortex

Question 15

Limbic loop

Answer 15

1) Amygdala, hippocampus, orbitofrontal, anterior cingulate, temporal cortex
2) Ventral striatum
3) Ventral pallidum
4) Mediodorsal nucleus of the thalamus
5) Anterior cingulate, orbital frontal cortex

Question 16

Neurons in the cortex vs. neurons in the striatum

Answer 16

Cortex: pyramidal neuron

Striatum: medium spiny neuron

Question 17

What are the neurons of the striatum?

Answer 17

95% efferent neurons (medium spiny neurons): use GABA; 50% to GPi/SNr use GABA/substance P; 50% to GPe use GABA and enkephalin

5% interneurons: use GABA or ACh; few but important

Note: see that most of the efferent neurons out of the striatum are inhibitory

Question 18

Main outputs of basal ganglia

Answer 18

Main “exits” are outputs from internal pallidum (GPi) and substantia nigra pars reticulata (SNr)

Question 19

Types of inputs to caudate vs. putamen

Answer 19

Caudate = cognitive = inputs from limbic prefrontal areas

Putamen = motor = inputs from motor and sensory regions

Question 20

Medium spiny neuron and output of striatum

Answer 20

Neurons of the striatum

Very spiny dendrites

Spines receive inputs from the cortex (use glutamate)

Shafts receive dopaminergic inputs from SNc (use dopamine)

GABAergic and project outside the striatum

Two main classes based on their output projections (enkephalin output to GPe and substance P output to GPi/SNr)

Question 21

Interneurons of the striatum

Answer 21

Few interneurons (5%) but they are important functionally

Drugs that block muscarinic ACh receptors help in Parkinson’s disease (“dopamine/ACh balance” important therapeutically)

Important in processing cortical info within the striatum

Question 22

Input to the subthalamic nucleus (of the basal ganglia)

Answer 22

Cortex directly projects to subthalamic nucleus and is excitatory

Called “hyperdirect pathway” and is functionally important

Question 23

Outputs from the basal ganglia originate from which two regions?

Answer 23

Internal palladium (GPi)

Substantia nigra pars reticulata (SNr)

Question 24

Outputs from basal ganglia (originating from GPi and SNr) use which NT?

Answer 24

GABA

Question 25

Where do outputs from GPi project to?

Answer 25

Thalamic motor nuclei (VA, VL) Reticular formation

Question 26

Where do outputs from SNr project to?

Answer 26

Thalamic nuclei of the thalamus (VA, VL and dorsomedial nucleus) Reticular formation **Superior colliculus**

Question 27

How does the basal ganglia send information back to the cortex

Answer 27

Via the thalamic motor nuclei (VA, VL)

Question 28

Dorsal vs. ventral part of internal palladium

Answer 28

Neurons in **dorsal** part of internal pallidum more involved in movements based on **internal cues** (**remembered sequences**) Neurons in **ventral** part of internal pallidum more involved in movements guided by **external** **cues**

Question 29

Conections within the basal ganglia

Answer 29

Striatum sends GABAergic projections to GPe, GPi, SNc (just a little), SNr Two distinct pathways: 1) Striatum --\> GPi and SNr (contains GABA and substance P) 2) Striatum --\> GPe (contains GABA and enkephalin)

Question 30

Subthalamic nucleus

Answer 30

Only **excitatory** pathway **WITHIN** the basal ganglia (uses **glutamate**)

Question 31

Direct and indirect pathways of output neurons of the striatum

Answer 31

Direct: SNc onto D1 receptors in striatum --\> input of GABA and substance P from medium spiny neurons of striatum --\> GPi/SNr --\> VA/VL of thalamus --\> frontal cortex to increase movement Indirect: SNc onto D2 receptors in striatum --\>input of GABA and enkephalin from medium spiny neurons of striatum --\> GPe --\> subthalamic nucleus --\> GPi --\> VA/VL of thalamus --\> frontal cortex to decrease movement

Question 32

Is there tonic activity in the indirect and direct pathways?

Answer 32

Yes! Direct pathway has tonic inhibition of GPi to thalamus but when cortex fires to cause striatum to inhibit GPi, you get **movement** Indirect pathway has tonic inhibition of GPe to subthalamic nucleus but when cortex fires to inhibit this inhibition, the subthalamic nucleus is free to stimulate the GPi which inhibits the VA/VL of the thalamus which **decreases movement**

Question 33

How does the indirect pathway act as a "brake" to suppress competing movements?

Answer 33

It's a brake because it inhibits movement 1) Because of **additional synapses**, the effect of inhibiting movement will be **delayed** compared to the direct pathway 2) **Anatomical** **organization** creates a "center/surround" effect with direct pathway affecting a small group of neurons in output regions and indirect pathway a large number of "surrounding" neurons; this focuses facilitation of **specific** motor units (via direct pathway) while **inhibiting competing, unwanted movement** (via indirect pathway)

Question 34

How does dopamine act on direct and indirect pathways?

Answer 34

Dopamine exerts **opposite** effects on the direct and indirect pathways in the striatum, but same consequence of actually **increasing movement** **Direct** pathway: dopamine stimulates **GPi/SNr** by acting on **D1** receptors (facilitates **movement**) **Indirect** pathway: dopamine inhibits **GPe** by acting on **D2** receptors (**inhibits inhibition** to cause **movement**)

Question 35

Role of basal ganglia disinhibition in the generation of saccadic eye movements

Answer 35

Stimulate **caudate** nucleus --\> inhibition of **SNr** --\> now **superior colliculus** free to fire --\> stimulation of **horizontal** and **vertical** **gaze** **centers** (eye movements!)

Question 36

Major diseases of the basal ganglia

Answer 36

**Parkinson's disease** **Huntington's disease** Dystonia Restless Leg Syndrome Psychiatric diseases (OCD)

Question 37

Parkinson's disease

Answer 37

1-2% of population, more men, onset before 50 years old Loss of nigrostriatal dopaminergic neurons (loss of melanin pigment of SNc) Symptoms: akinesia (difficulty initiating movements)/bradykinesia (slowness of movement), muscle rigidity (cogwheel sign), resting tremor, postural imbalance (can have stooped posture and gait disorder)

Question 38

Triad of symptoms in Parkinson's Disease

Answer 38

Akinesia/bradykinesia Muscle rigidity Resting tremor

Question 39

Which neurons are lost in PD?

Answer 39

Dopaminergic neurons of the substantia nigra pars compacta (SNc) Other dopaminergic neurons in the brain are fine!

Question 40

What part of the brain is first affected in PD and what does this mean?

Answer 40

Putamen is the first brain region to be affected in PD Since putamen = motor (putamen is part of "motor loop"), the first symptoms you have are motor symptoms

Question 41

How does PD affect the direct vs. indirect pathways to decrease movement?

Answer 41

**Direct**: decreased activity of caudate/putamen to GPi/SNr because less stimulation by dopamine --\> decreased inhibition of GPi/SNr --\> **increased activity of GPi/SNr** --\> increased inhibition of VA/VL of thalamus --\> **less movement** **Indirect**: decreased inhibition of caudate/putamen --\> increased activity of caudate/putamen --\> increased inhibition of GPe --\> decreased activity of GPe --\> decreased inhibition of subthalamic nucleus --\> **increased activity of subthalamic nucleus** --\> **increased activity of GPi** --\> increased inhibition of VA/VL --\> **less movement**

Question 42

General consequences of loss of dopamine in the brain of someone with PD

Answer 42

1) **Striatum** has **loss of "balanced"** control 2) **GPi/SNr** has **disorganized** firing 3) **Subthalamic** **nucleus** has **hyperactivity/bursts** Note: easy to think about increases/decreases but in reality it's the disorganization of firing that causes the basal ganglia not to be able to regulate thalamocortical neurons that causes PD symptoms

Question 43

Treatments for PD

Answer 43

**L-dopa therapy** **Surgery**: lesions of GPi, high frequency stimulation to inhibit **GPi** or **subthalamic nucleus**

Question 44

How might deep brain stimulation (DBS), or high frequency STIMULATION actually reduce the activity of structures??

Answer 44

1) Induce "depolarization block" because you've stimulated so much that the cells just stop firing 2) Stimulates the release of GABA from nearby axons which inhibits the structure itself from firing

Question 45

What causes the tremor in PD

Answer 45

We don't really know yet! Animal models of PD don't show tremor, only akinesia so no good way to study it

Question 46

Lewy body

Answer 46

Main neuropathological "signature" of PD **Cytoplasmic inclusion** made of various **proteins** Mainly made of **alpha-synuclein**, which is **toxic** when it accumulates and misfolds within the neuron (sometimes called a "synucleopathy") Present in **dopaminergic** **neurons** **of substantia nigra**

Question 47

Possible etiology of PD

Answer 47

Mutations in **genes** linked with the **proteasome** or **toxins** (pesticides) altering function of proteasome Proteins can't be degraded as well and get **accumulation of proteins** and **misfolding of proteins** Proteasome dysfunction may affect mitochondria function also --\> **free radicals** and **oxidative stress**

Question 48

Treatments for Parkinson's disease

Answer 48

Currently only symptomatic and for motor symptoms 1) Give drug that becomes dopamine in the brain 2) Give agonists at dopamine receptors 3) Change brain activity with implanted electrode

Question 49

The many systems that PD can affect

Answer 49

Akinesia Rigidity Tremor Postural imbalance Olfactory loss Cognitive disorders (implicit memory) Affective disorders (depression/anxiety/apathy) Sleep disturbances Autonomic disorders (hypotension) Digestive symptoms (constipation)

Question 50

Environmental factors that may cause PD

Answer 50

**MPTP** (in heroine addicts, see Melega lecture) **Rotenone** in experimental studies Pesticides, heavy metals

Question 51

Environment vs. genes in PD

Answer 51

Environmental **pesticides** increase the **risk** of PD but this effet is **modulated** by a person's **genes** Genes for **VMAT2** and **DAT** (which control amount of dopamine in cell/synapse) altered in those who have been exposed to pesticides