Basal ganglia

Question 1

Anatomical and functional organization of the basal ganglia

Answer 1

• Basal ganglia (BG) refers to a group of connected subcortical nuclei that are reciprocally connected to the frontal cortex via thalamus
• Plays an essential role in the regulation and learning of cognitive and motor behaviors
• Damage to basal ganglia result in disturbances in both motor and cognitive functions
• Also leads to the inability to carryout smoothly executed skilled movements, but not paralysis

Question 2

Structures of the basal ganglia 1

Answer 2

• They are grey matter masses located w/in the white matter of the cerebral hemispheres
• 4 principle structures: striatum, globus pallidus, substantia nigra, and subthalamus
• Striatum can be divided into dorsal striatum (caudate and putamen) and the ventral striatum (nucleus accumbens)
• Globus pallidus is subdivided into external segment (GPe) and internal segment (GPi)
• Putamen and GP together form the lenticular nucleus and is just lateral to internal capsule

Question 3

Structures of the basal ganglia 2

Answer 3

• Subthalamic nucleus (STN) is just lateral to the hypothalamus, it functions w/ GPe to modulate BG output
• Substantia nigra (SN) is just dorsal to the crus cerebri in midbrain
• SN is subdivided into dorsal strip the pars compacta (SNpc, contains pigmented DA neurons), and ventral strip the pars reticulata (SNpr, contains non-pigmented GABA neurons)
• Pigmentation of SNpc due to neuromelanin (autooxidation of DA and lipofuscin)

Question 4

Circuitry of the BG

Answer 4

• BG efferents do not descend to communicate w/ LMNs, instead they ascend and communicate w/ the motor cortex to influence the UMNs (the connections are ipsilateral)
• Since the UMNs in the cortex control LMNs on the contralateral side, BG on one side influences motor activity on the contralateral side
• When there is PD pathology on one side of the brain, there is hemiparkinsonism on the contralateral side

Question 5

Pathways of BG 1

Answer 5

• Input to BG comes from all parts of cerebral cortex and terminates on striatum (excitatory)
• Output of BG arises from the GPi and SNpr neurons and terminates on thalamus (on ventral anterior, VA neurons and ventral lateral, VL, neurons)
• These terminal fibers on the VL and VA release GABA and have a tonic inhibitory effect on VL and VA
• Thalamocortical efferents from VL and VA project back to the same areas of the cortex where the cortical input originated

Question 6

Pathways of BG 2

Answer 6

• Thalamocortical efferents use glutamate on the cortex and are excitatory, thus VA/VL activity increase the activity of motor areas (reinforcement of actions)
• Since the GPi and SNpr axons to VL and VA are inhibitory, there must be a decrease in GPi and SNpr activity to disinhibit the VA/VL to reinforce the activity
• GPi and SNpr are influenced by parallel inhibitory and excitatory pathways arising from striatum (direct and indirect)

Question 7

Direct pathway

Answer 7

• Arises from a subset of striatal neurons that project to the GPi and SNpr and are inhibitory (GABA)
• Thus activation of the direct pathway reduces inhibitory BG output to thalamus, disinhibiting it and increasing thalamic feedback to cortex to sustain wanted movements
• Overall: the direct pathways facilitates cortical activation by VA/VL nuclei activation (thru GPi/SNpr inhibition)
• This effect sustains wanted motor programs and desired motor activity

Question 8

Indirect pathway

Answer 8

• Arises from a subset of striate neurons whose axons project to GPe. These neurons use GABA and thus inhibit the GPe
• The GPe projects to the STN and also are inhibitory
• Thus activation of the striatum from the cortex leads to inhibition of GPe and resultant disinhibition of the STN
• This activates STN, which sends excitatory axons to the GPi/SNpr
• Activation of the GPi/SNpr inhibits the VA/VL in the thalamus to suppress unwanted movements
• Thus the indirect pathway serves to increase inhibitory BG output, inhibit thalamic (VA/VL) activity, and suppress unwanted movements by reducing cortical activation

Question 9

Corticostriatal pathways of segregated circuits

Answer 9

• 2 motor, 2 non-motor
• Motor: one originates from motor cortex (primary, supplementary, and premotor) and one originates from oculomotor (FEF, supplementary FEF)
• Non-motor: one originates in prefrontal cortex (dorsolateral prefrontal [DLPFC], lateral orbitofrontal [LOFC]) and one originates from limbic cortex (anterior cingulate area [ACA], medial orbiofrontal cortex [MOFC])

Question 10

Functions of corticostriatal motor circuits

Answer 10

• Motor areas: action selection, preparation for movement, sequencing of movements, control of parameters (direction, velocity) and movement reinforcement
• Oculomotor areas: coordination of voluntary and saccadic eye movements

Question 11

Functions of corticostriatal non-motor circuits 1

Answer 11

• Executive/associative (DLPFC): working memory, learning new info, planning, temporal ordering of recent events
• Clinical syndrome: impaired reasoning, easily distracted, poor organization
• Test for syndrome: tower of london test

Question 12

Functions of corticostriatal non-motor circuits 2

Answer 12

• Executive/associative (LOFC): projects to nucleus accumbens and is involved in reinforcement of an action when performing the action results in reward (acted on in drug addiction)
• Functions in personality, emotional stability, determining appropriateness for social behaviors (phineas gage)
• Lesions lead to inability to learn from mistakes and myopia of the future (can’t think long-term)
• Anterior cingulate: part of the limbic striatum, involved in motivated behavior
• Syndrome: lack of motivation and communication

Question 13

Function of BG in corticostriatal circuits

Answer 13

• Integrates info from all of the corticostriatal circuits to carry out the appropriate goal-oriented motor or social behavior
• By definition is not involved in voluntary motor activity

Question 14

Role of DA on BG function 1

Answer 14

• Changes in corticostriatal circuits are important for learning to chose the response that leads to reward/avoid punishment
• These changes are mediated by DA-dependent changes in strength of stratal synapses
• They reshape the cortical motor map in order to carry out smoothly executed motor behaviors

Question 15

Role of DA on BG function 2

Answer 15

• DA terminals synapse on dendritic spines of target neurons that also receive glutamatergic input
• This forms the synaptic triad, that DA serves a modulatory role in fine tuning the excitatory input from other afferents
• DA axons innervate both direct and indirect stratal neurons via D1 (direct) and D2 (indirect) receptors

Question 16

D1 family of DA receptors (D1 and D5)

Answer 16

• Are excitatory (drives LTP) receptors (depolarize the cell) that respond only to peak bursts of DA
• They are expressed by the direct pathway striatal neurons
• Activation of the receptors not only depolarizes the cell, it also elevates cAMP thru Gs (GPCR) stimulation which increases PKA signaling
• The increase in PKA activity results in incorporation of AMPA receptors into the membrane
• DA binding to D1 opens Ca channels, thus allowing for LTP induction
• Function to activate the direct pathway upon bursts of DA release from the SNpc and VTA

Question 17

D2 family of DA receptors (D2, D3, and D4)

Answer 17

• Are both pre and postsynaptic receptors that are inhibitory and thus drive LTD
• They are expressed by indirect striatal neurons and VTA/SNpc (?) DAminergic neurons
• D2 family receptors respond to low, tonic levels of DA release, and binding decreases cAMP by inhibition of the GPCR (Gi)
• Thus, D2 receptors diminish the indirect pathway’s effect of blocking thalamus activity to the cortex (continuously)
• Decreasing cAMP leads to removal of AMPA receptors from postsynaptic membrane
• Binding of DA to D2 receptors also inhibits glutamate release on the striatum (from cortex) via the endocannabinoid pathway

Question 18

Overall function of DA on striatum and indirect pathway 1

Answer 18

• When there is no DA release on the striatum, there is activation of the indirect pathway via cortical activation of striatum-> indirect, and cortical activation of the STN directly (also leads to thalamic inhibition thru GPi/SNpr)
• This means that w/o DA there is constant inhibition of the thalamus and therefore no movements can be reinforced/modulated

Question 19

Overall function of DA on striatum and indirect pathway 2

Answer 19

• Physiologically there is tonic release of DA on the striatum, which inhibits the indirect pathway (no effect on direct)
• This results in partial removal of inhibitory input on thalamus, which allows the motor plan to be carried out
• This process is important to monitor cellular excitability on a moment-moment basis, to allow smooth motor movements to be carried out by selectively disinhibiting the desired ones (positive feedback to cortex)

Question 20

Overall function of DA on striatum and direct pathway 1

Answer 20

• In order to learn new motor skills (via reinforcement), there must be an increase in positive feedback to the cortex by changing the strength of the corticostriatal synapses for that behavior
• When we want to reinforce a rewarding behavior there is a large burst of DA on the striatum, leading to activation of the direct pathway (also inhibits indirect pathway)

Question 21

Overall function of DA on striatum and direct pathway 2

Answer 21

• Because of the effects of D1 receptors on LTP induction, bursts of DA on striatum result in increased strength of corticostriatal synapses responsible for a rewarding behavior (also decreases indirect pathway influence)
• This overall results in more thalamic activation and positive feedback to the cortex regarding the rewarding behavior (reinforcement)

Question 22

Regulation of DA-releasing centers

Answer 22

• DA neurons of the SNpc increase their firing rate and release a burst of DA on striatum in association w/ learning a new motor skill/performing appropriate social behavior
• NA neurons release DA on striatum in a greater amount (bursts) in response to unpredictable stimuli
• However, as a new task is learned, DA activity on striatum decreases as the task is transformed from goal-oriented behavior to a reproducible habit

Question 23

Reasons for DA release

Answer 23

• Change in DA activity measures the difference btwn what we expected to happen and what really happens (not how good something is)
• Thus, the rate of learning depends on the estimated value of the difference btwn the true reward and predicted reward (prediction error)

Question 24

Predictive errors

Answer 24

• Prediction error positive: things are better than I thought. Leads to increase in DA firing
• Prediction error negative: things are worse than I thought. Leads to a decrease (pause) in DA firing
• Prediction error 0: things are just as I thought. Leads to no change in baseline DA firing

Question 25

Translating predictive errors to learning

Answer 25

• As we learn a new motor/behavior skill we unexpectedly do somethings better than we anticipated and DA firing is increased
• This activates the direct pathway to positively feedback on the cortex and strengthen the circuit for that action
• Simultaneously the D2 receptors are being activated more to have a greater inhibitory effect on the indirect pathway
• As the skill is learned the expectation of the reward aligns with what the actual reward is, the predictive error is 0, and the skill becomes a habit
• Addictive drugs artificially produce spikes of DA release, resulting in reinforcement and addiction

Question 26

Parkinson’s disease

Answer 26

• Neuropathology of PD is about 75% loss of DAminergic neurons
• Can be seen grossly by loss of melanin containing cells in the SN
• There is also formation of lewy bodies in monoaminergic neurons (in the SN, LC, dorsal motor nucleus of vagus) and also the cholinergic neurons in the basal forebrain
• DA neurons in VTA are not affected

Question 27

Sx of PD

Answer 27

• Tremor at rest: DA neuron degeneration in SN leads to disinhibtion of pacemaker cells in thalamus
• Bradykinesia
• Muscle rigidity
• Postural instability

Question 28

Etiology of PD

Answer 28

• Idiopathic (90-95% of cases)
• Familial about 15% of cases have family history of d/o
• Onset before age 50: high likelihood of familial PD, but after 50 is probably idiopathic
• Genetic mutations (of PARK and UCHL for ubiquitin pathway, other proteins as well) likely contribute to the disease but not causal
• Mutations in the ubiquitin pathway reduces capability to breakdown proteins
• None of the mutations are specific to DA neurons

Question 29

Effect of DA neuron loss

Answer 29

• Loss of DA neurons leads to greater inhibition of VL/VA and thus reduced cortical facilitation
• Thus it is an over-activation of the indirect pathway due to decrease DA effect on D2 receptors

Question 30

Rx of PD

Answer 30

• Attempts to re-establish balance btwn indirect and direct pathways (want to decrease indirect pathway activity)
• Replenish DA by L-DOPA Rx (standard), this will reduce PD Sx by increasing DA binding to D2
• L-DOPA Rx also over-activates other, intact DA pathways
• DA agonists: D2 receptor agonists also improve Sx (better tolerated than L-DOPA in early onset Sx)
• Deep brains stimulation (DBS): GPi and STN are primary targets
• Doing DBS on the GPi and STN will silence these areas and allow for an increase in feedback to the cortex