11/20: Basal Ganglia Flashcards
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.
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).
Many regions of the cerebral cortex project to the striatum in a topographic pattern.
Further, projections within the basal ganglia also are topographically organized.
BASAL GANGLIA Structures in the FOREBRAIN
Striatum:
- Caudate Nucleus
- Putamen
Globus Pallidus
- External Segment (GPe)
- Internal Segment (GPi)
LENTICULAR NUCLEI
Putamen
Globus Pallidus
- External Segment (GPe)
- Internal Segment (GPi)
BASAL GANGLIA Structures in the DIENCEPHALON
Subthalamic Nucleus
BASAL GANGLIA Structures in the MIDBRAIN
Substania Nigra
- Compact Part (SNc)
- Reticular Part (SNr)
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
Caudate
primarily related to prefrontal regions of the cerebral cortex and is involved in cognitive processing.
Putmen
primarily related to motor cortex and is involved in controlling movement.
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.
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.
GABA/ D2 Receptors
Project to GPe
Medium spiny neurons
Binding of dopamine to a D2 receptor results in hyperpolarization and inhibition of the neuron.
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.
medium spiny neurons
All medium spiny neurons are GABAergic (inhibitory to their targets)
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.
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
DOPAMINE ____ Neurons With D2 Receptor On Cells Giving Rise To ____ Pathway
DOPAMINE Inhibits Neurons With D2 Receptor On Cells Giving Rise To Indirect Pathway
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
GLOBUS PALLIDUS
EXTERNAL (Lateral) & INTERNAL (Medial) segments
Neurons in both segments are GABAergic
INTERNAL SEGMENT
PRIMARY OUTPUT OF BASAL GANGLIA FOR LIMB MOVEMENTS
SN – Pars Reticulata
SNpr
is primary output of basal ganglia for eye movements
Subthalamus
In the Diencephalon
Between thalamus & substantia nigra
Glutamaterigic neurons:
only intrinsic source of excitation in basal ganglia
Substantia Nigra
Midbrain
only intrinsic source of excitation in basal ganglia
Glutamaterigic neurons of the Subthalamus
SNpc
Substantia Nigra nuclei
dorsal to pars reticulata and contains dopaminergic neurons.
These cells are lost in Parkinson’s disease
SNpr
Substantia Nigra nuclei
analogous to GPi, controls eye movements
Contains large GABAergic neurons
BASIC FEEDBACK LOOP
Motor cortex
- –> Putamen
- –> GPi
- –> Thalamus
- –> back to the Motor Cortex
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.
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.
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.
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.
DIRECT PATHWAY
CORTEX –> PUTAMEN –> GPi –> THALAMUS –> CORTEX
NET EFFECT: DISINHIBITION (excitation) of thalamus and motor cortex
INDIRECT PATHWAY
CORTEX
- —> PUTAMEN
- —> GPe
- —> SUBTHALAMUS
- —> GPi
- —> THALAMUS
- —> CORTEX
NET EFFECT: Suppression of thalamus and DISFACILITATION (inhibition) of cortex
There is a ____ in GPi activity in response to Striatum Activation
????
There is a Decrease in GPi activity in response to Striatum Activation
????
Basal ganglia control of movement represents an integration of the direct and indirect pathway
- Cortical activity increases at onset of movement.
- 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. - Neurons in GPi that show Decrease in activity may be critical for gating or facilitating cortically initiated movement. (Increased thalamic output)
- Neurons in GPi that show Increase in activity may be critical in suppressing antagonist muscles or decreasing competing movements.
(Decreased thalamic input)
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
SN (DA) EFFECT ON DIRECT PATHWAY
INCREASED ACTIVITY IN CORTICOSPINAL NEURONS
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.
ACh _____ MOTOR ACTIVITY
ACh TURNS DOWN MOTOR ACTIVITY
ACh inhibits striatal cells in the ____ loop
ACh inhibits striatal cells in the direct loop
ACh excites striatal cells in the ____ loop
ACh excites striatal cells in the indirect loop
DA TURNS ___ MOTOR ACTIVITY
DA TURNS UP MOTOR ACTIVITY
DA excites striatal cells in the ___ loop via D__ receptors
DA excites striatal cells in the direct loop via D1 receptors
DA inhibits striatal cells in the ____ loop via D__ receptors
DA inhibits striatal cells in the indirect loop via D2 receptors
DA inhibits striatal cells in the ____ loop via D_ receptors
DA inhibits striatal cells in the indirect loop via D2 receptors
CAUDATE-PUTAMEN
STRIATUM
TRANSMITTER OF NEURONS IN NUCLEUS:
- GABA FOR STRIATAL OUTPUT NEURONS
- 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
GLOBUS PALLIDUSe&i
GABA FOR BOTH GPe & GPi
INPUT FROM - EFFECT:
STRIATUM –INHIBITORY
SUBTHALAMUS – EXCITATORY
PROJECTS TO - EFFECT:
GPi: THALAMUS –INHIBITORY
GPe: SUBTHALAMUS
–INHIBITORY
SUBSTANTIA NIGRA
COMPACTA
TRANSMITTER OF NEURONS IN NUCLEUS: DOPAMINE
INPUT FROM, EFFECT:
CEREBRAL CORTEX, EXCITATORY
PROJECTS TO, EFFECT
GPi, EXCITATORY
SUBTHALAMUS
TRANSMITTER OF NEURONS IN NUCLEUS: GLUTAMATE
INPUT FROM, EFFECT:
CEREBRAL CORTEX, EXCITATORY.
GPe, INHIBITORY.
PROJECTS TO, EFFECT
GPi, EXCITATORY.
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
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.
Akinesia
impaired initiation of movement
bradykinesia
reduced amplitude & velocity of voluntary movement
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.
Lesions of ____ reduces motor symptoms in MPTP treated monkeys.
Lesions of the subthalamus reduce motor symptoms in MPTP treated monkeys.
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.
In Parkinson’s, Dopamine systems are broken, leaving the cholinergic system unchecked
This is why Parkinson’s patient are so slow.
TREATMENTS FOR PARKINSON’S DISEASE
Several treatments including:
- 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
- Lesioning of GPi or subthalamus
- Deep brain stimulation
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.
