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Anatomical and functional organization of the basal ganglia

-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


Structures of the basal ganglia 1

-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


Structures of the basal ganglia 2

-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)


Circuitry of the BG

-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


Pathways of BG 1

-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


Pathways of BG 2

-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)


Direct pathway

-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


Indirect pathway

-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


Corticostriatal pathways of segregated circuits

-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])


Functions of corticostriatal motor circuits

-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


Functions of corticostriatal non-motor circuits 1

-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


Functions of corticostriatal non-motor circuits 2

-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


Function of BG in corticostriatal circuits

-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


Role of DA on BG function 1

-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


Role of DA on BG function 2

-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


D1 family of DA receptors (D1 and D5)

-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


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

-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


Overall function of DA on striatum and indirect pathway 1

-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


Overall function of DA on striatum and indirect pathway 2

-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)


Overall function of DA on striatum and direct pathway 1

-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)


Overall function of DA on striatum and direct pathway 2

-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)


Regulation of DA-releasing centers

-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


Reasons for DA release

-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)


Predictive errors

-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


Translating predictive errors to learning

-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


Parkinson's disease

-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


Sx of PD

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


Etiology of PD

-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


Effect of DA neuron loss

-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


Rx of PD

-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

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