L-27 Basal Ganglia I: Anatomy And Cell Physiology

Front 1

Inputs to striatum

Back 1

Dopaminergic from substantia nigra, pars compacta

D1 receptor - excitatory (Gs)

D2 receptor - inhibitory (Gi/O coupled)

Cerebral cortex glutamatergic input

Front 2

Direct pathway of basal ganglia

Back 2

D1 neurons have direct GABAergic projection to output part of basal ganglia, the internal globus pallidus. Internal pallidum then has inhibitory GABAergic projection to thalamus.

Thus, D1 activation by cerebral cortex and striatum leads to disinhibition of the thalamus. Thalamus has excitatory glutamatergic projections to cerebral cortex, promoting movement.

Front 3

Indirect pathway of basal ganglia

Back 3

D2 has GABAergic inhibitory projection to external globus pallidus, which in turn has GABAergic inhibitory projection to subthalamic nucleus. Disinhibited subthalamic nucleus excites internal globus pallidus. Internal pallidum inhibits thalamus via GABAergic projection. Thalamus then inhibits cortex to inhibit movement.

Front 4

Parkinson's Disease

Back 4

Lose dopamine neurons in substantia nigra, pars compacta. Loss of dopaminergic tone in the striatum. Promotes the indirect pathway (actually not true - creates poison pattern of synchronous events leading to simultaneous activation of "go" and "no go" = ridigity)

Front 5

Block D2 Dopamine receptor with haloperidol antipsychotic

Back 5

Parkinsonism due to dopamine receptor supersensitivity

Causes tandive dyskinesia

Front 6

Unilateral lesion in suthalamic nucleus

Back 6

Results in contralateral ballistic movement - hemiballismus

Front 7

Basal ganglia definition

Back 7

Series of interconnected subcortical structures that process reentrant cortical information for successful execution of action (and cognitive) sequencing, timing and selection; a functionality that allows for smooth, accurate, purposeful movements (and thoughts) with optimal posture that can be perfected through repetition.

Front 8

Back 8

Caudate nucleus

Putamen

Globus pallidus, external and internal segments

Subthalamic nuclei

Substantia nigra pars compacta

Subthalamic nucleus

Front 9

Neostriatum

Back 9

Caudate + putamen

Essentially same structure bisected by white matter

Front 10

Output nuclei of basal ganglia

Back 10

Internal globus pallidus

Sustantia nigra pars reticulata

Front 11

Rostral view of basal ganglia

Back 11

Putamen and head of caudate bisected by internal capsule

Front 12

Lenticular nucleus

Back 12

Putamen + globus pallidus

Front 13

Corpus striatum

Back 13

Caudate + Putamen + accumbens + globus pallidus

Front 14

Striatum

Back 14

Caudate, putamen, accumbens

Front 15

Eye Saccade circuit from basal ganglia

Back 15

Internal pallidus also has GABAergic input to superior colliculus, which controls eye saccades.

Front 16

Supplemental motor area feedback loop

Back 16

Supplementary motor area sends input to striatum, goes through basal ganglia, and heads back to same part of cortex.

Front 17

Reentrant cortical input

Back 17

Topographical

Motor cortex projects to one part of striatum, to one part of globus pallidus and substantia nigra to one part of thalamus, for instance.

Front 18

What part of cortex projects to basal ganglia

Back 18

Almost every cortical region, with exception of auditory cortex and primary visual cortex (weak projections)

Front 19

Huntington's Disease

Back 19

Arises from degeneration of output cells of striatum, medium spiny neurons, that give rise to direct and indirect pathway.

Age of onset is 30-40 years

Trinuleotide repeat

Motor dysfunction, choreiform movements

Front 20

Pattern of events in Huntington's disease

Back 20

Early on, dysplasticity - plastic patterns that usually do not occur are occuring - more than degeneration.

Later, degeneration including of cortex occurs, leading to cognitive symptoms like psychosis/hallucination, dementia, anxiety, and depression.

Front 21

Hemiballismus

Back 21

Results from unilateral lesion to subthalamic nucleus. Results in ballistic movements on contralateral side of body, causing injury and fatigue.

Front 22

Neurotransmitter release from dopaminergic substantia nigra pars compacta neurons

Back 22

Co-release dopamine and GABA

Front 23

Thalamus also projects to striatum.

Front 24

Serotonergic input onto basal ganglia

Back 24

All parts of basal ganglia receive serotonergic input from dorsal raphe nucleus

Front 25

Noradrenergic input onto basal ganglia

Back 25

All of basal ganglia except caudate and putamen receive noradrenergic input from locus ceruleus.

Front 26

Baseline firing of caudate and putamen

Back 26

Do not fire at rest until receive stimulus from cerebral cortex

Front 27

Baseline firing of substantia nigra pars compacta

Back 27

Fire at 2 Hz at rest, undergo bust of phasic firing of 20 Hz with novel stimulus or reward. Interface between motor function and reward.

Front 28

Baseline firing of globus pallidus external segment

Back 28

Part of indirect pathway. Has irregular firing of 10-70 Hz

Front 29

Baseline firing of globus pallidus internal segment

Back 29

Tonic firing of 60-80 Hz. Movement related

Front 30

Baseline firing of subthalamic nucleus

Back 30

Tonic firing of 20 Hz, movement-related.

Front 31

Firing in direct pathway when cortex active and inactive

Back 31

Inactive cortex -> inactive striatum. Tonically active globus pallidus which inhibits thalamus. No output to UMNs in cortex.

Active cortex -> active striatum. Tonically active globus pallidus is inhibited, which releases inhibition on thalamus so thalamus is active. Excited upper motor neurons in cortex.

Front 32

Disinhibitory basal ganglia circuit for eye saccades

Back 32

Active cortex -> active caudate nucleus (striatum). Inhibits substantia nigra pars reticularis output pathway, which disinhibits superior colliculus causing eye movements.

Front 33

Synapse between caudate nucleus and substantia nigra pars reticulata

Back 33

GABA/inhibitory

Front 34

Synapse between Substantia nigra parts reticulata and superior colliculus

Back 34

GABA/inhibitory

Front 35

Disinhibitory circuit of direct pathway

Back 35

Cortical inputs excite striatum which inhibits globus pallidus to disinhibit thalamus, driving excitation of motor cortex UMNs.

Front 36

Striatum

Back 36

Input nucleus of basal ganglia

Site of enormous convergence, must also have tons of processing. Large dendritic trees on principal projection neurons.

Front 37

Ratio of cells in parts of basal ganglia

Back 37

Cortex - 150,000,000

Striatum - 30,000 (500:1)

Globus Pallidus external - 100 (300:1)

Globus Pallidus internal - 1 (100:1)

Front 38

Morphology of striatal medium spiny neurons

Back 38

Large dendritic trees studded with many dendritic spines.

Each spine receives cortical input, neck of spine receives dopaminergic input.

Front 39

Number of synapses on each medium spiny neuron

Back 39

10,000 cortex synapses onto each medium spiny neuron

Front 40

Inputs on Medium Spiny Neurons

Back 40

Cortex - glutamatergic

Intralaminar nuclei of thalamus - glutamatergic

Fast spiking interneurons - GABA

Low threshold spiking interneurons - GABA

Other medium spiny neurons - GABA

Globus pallidus - GABA

Cholinergic interneurons in striatum - ACh

Substantia nigra pars compacta - Dopamine

Dorsal raphe nucleus - Serotonin

Front 41

Population of medium spiny neurons in striatum

Back 41

95% of cells in striatum

Front 42

GABAergic inputs onto medium spiny neurons

Back 42

Fast spiking interneurons - GABA

Low threshold spiking interneurons - GABA

Other medium spiny neurons - GABA

Globus pallidus - GABA

Front 43

Glutamatergic inputs onto medium spiny neurons

Back 43

Cortex - glutamatergic

Intralaminar nuclei of thalamus - glutamatergic

Front 44

Types of medium spiny neurons

Back 44

D1 expressing - direct pathways - send projections directly to output structures via internal pallidus

D2 expressing - indirect pathway - globus pallidus external to subthalamic to internal pallidus to thalamus.

Front 45

Three basal ganglia circuits

Back 45

1) Direct

2) Indirect

3) Hyperdirect pathway

Front 46

Hyperdirect pathway

Back 46

Information directly fed into subthalamic nucleus, which communicates to internal pallidus, thalamus, then cortex.

Front 47

Direct and indirect pathways of basal ganglia

Back 47

Front 48

Compartments within striatum

Back 48

Patch - express mu opioid receptor. Process limbic inputs.

Matrix - devoid of mu opioid receptors. Process motor inputs.

Also differential expression of acetylcholinesterase between the two.

Front 49

Organization of basal ganglia cell firing

Back 49

Basal ganglia "chunks" information. Instead of encoding each individual component, different basal ganglia cells fires either beginning of sequence, during sequence, or at end of sequence.

E.x. - if mice presses lever 6 times, some dopaminergic neurons fire at first press, some right before first press, some at last press, some at beginning and end.

Front 50

Role of dopaminergic neurons in substantia nigra

Back 50

Appear to be active at start or stop of action - may explain inability to start or stop movements in Parkinson's disease.

Front 51

Parkinson's disease

Back 51

Loss of dopaminergic neurons in substantia nigra pars compacta (causing loss of dopaminergic tone in striatum).

Causes bradykinesis, rigidity, tremor at rest, and impairment of action initiation and termination.

Other symptoms - festination (shuffling gait), postural instability, pain, depression, autonomic dysfunction, and sleep disruption.

Front 52

Effect of dopamine in striatum

Back 52

Controls corticostriatal plasticity

Glutamatergic input from cortex on D1 or D2 spiny neurons.

When dopamine binds to receptor on MSN, induces long-term depression of glutamate release from cortex presynaptic terminal.

Front 53

Conditions needed for LTD of corticostriatal synapse

Back 53

1. D2 dopamine receptor tone

2. Glutamate release from cortex cell hitting mGluR5

3. Ca2+ entry into postsynaptic cell after striatum depolarizes.

Front 54

Mechanism of dopamine effect on corticostriatal plasticity

Back 54

Dopamine binding to D2 receptor results in production of endocannabanoid that retrogradely hits presynaptic CB1 receptor which is GiO coupled. Results in LTD of glutamate release from presynaptic cortical cell.

Front 55

Effect of monoamine depletor and D2 agonist on plasticity.

Back 55

Strength of synapse at baseline is 100%

Treat with reserpine which depletes monoamine stores so no dopamine - then do not observe plasticity

If treat with both reserpine and quinpriole (agonist of D2 receptors), do get LTD

Front 56

Effect of dopamine neuron toxin on plasticity

Back 56

Treat with dopamine neuron toxin (6-OHDA) -> no plasticity

Rescue with quinpriole (agonist of D2 receptors) = LTD

Front 57

Effect of URB597 (inhibits endocannabanoid degradation) on plasticity

Back 57

Boost endocannabanoid levels. Induce LTD even without dopamine.

Front 58

Effect of dopamine neuron toxin on movement

Back 58

if treat with 6-OHDA, animals cannot move.

If treat with UR597 (endocannabanoid booster), also cannot move.

If add quinpriole (D2 agonist) as well, then animal can move

Front 59

Caudate vs putamen functions

Back 59

Caudate - dorsomedial striatum - responsible for goal directed action. When goal is gone, action halts.

Putamen - dorsolateral striatum. Responsible for habit-formation or stimulus-response action strategies.

Front 60

Basal ganglia influence in cognition

Back 60

Mediate action selection and sequencing for cognition as well as movement.

Parkinson's - dementia and depression

Huntington's - dementia, depression, psychosis

Schizophrenia - psychosis

Tourette's syndrome - echolalia, palilalia, corprolalia

OCD - intrusive, compulsive thoughts

ADD - impulsivity/"dyskinesia of thought"

Front 61

How are striatum neurons organized to perform actions?

Back 61

Neuron ensembles - groups of neurons - in striatum fire synchronously to control a particular action.

Same organization downstream - i.e. in globus pallidus.