Basal ganglia Flashcards
1
Q
Anatomical and functional organization of the basal ganglia
A
- 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
2
Q
Structures of the basal ganglia 1
A
- 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
3
Q
Structures of the basal ganglia 2
A
- 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)
4
Q
Circuitry of the BG
A
- 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
5
Q
Pathways of BG 1
A
- 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
6
Q
Pathways of BG 2
A
- 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)
7
Q
Direct pathway
A
- 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
8
Q
Indirect pathway
A
- 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
9
Q
Corticostriatal pathways of segregated circuits
A
- 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])
10
Q
Functions of corticostriatal motor circuits
A
- 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
11
Q
Functions of corticostriatal non-motor circuits 1
A
- 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
12
Q
Functions of corticostriatal non-motor circuits 2
A
- 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
13
Q
Function of BG in corticostriatal circuits
A
- 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
14
Q
Role of DA on BG function 1
A
- 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
15
Q
Role of DA on BG function 2
A
- 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
16
Q
D1 family of DA receptors (D1 and D5)
A
- 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
17
Q
D2 family of DA receptors (D2, D3, and D4)
A
- 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
18
Q
Overall function of DA on striatum and indirect pathway 1
A
- 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
19
Q
Overall function of DA on striatum and indirect pathway 2
A
- 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)
20
Q
Overall function of DA on striatum and direct pathway 1
A
- 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)
21
Q
Overall function of DA on striatum and direct pathway 2
A
- 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)
22
Q
Regulation of DA-releasing centers
A
- 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
23
Q
Reasons for DA release
A
- 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)
24
Q
Predictive errors
A
- 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
25
Q
Translating predictive errors to learning
A
- 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
26
Q
Parkinson’s disease
A
- 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
27
Q
Sx of PD
A
- Tremor at rest: DA neuron degeneration in SN leads to disinhibtion of pacemaker cells in thalamus
- Bradykinesia
- Muscle rigidity
- Postural instability
28
Q
Etiology of PD
A
- 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
29
Q
Effect of DA neuron loss
A
- 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
30
Q
Rx of PD
A
- 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
