Basal Ganglia (Week 4--Chesselet) Flashcards Preview

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Flashcards in Basal Ganglia (Week 4--Chesselet) Deck (51)

Basal ganglia

Ensemble of interconnected brain regions

Striatum: caudate nucleus and putamen

Globus pallidus (external and internal segments)

Substantia nigra (pars compacta and pars reticulata)

Subthalamic nucleus (only recently included in definition of basal ganglia)


Lentiform nucleus

Putamen and globus pallidus

(just because they are close together)


Are the caudate and putamen separate structures?

Not really, the caudate and putamen are two parts of the same structure (the striatum)

However, the internal capsule (white myelinated fibers) go through this structure to create the caudate medially (near ventricles) and the putamen laterally

Caudate and putamen have same connections, except for somatotopic arrangements


External globus pallidus (GPe) vs. Internal globus pallidus (GPi)

Have VERY different connections and functions

GPe: projects within the basal ganglia; uses GABA; gets input from medium spiny neurons from striatum that use enkephalin; indirect pathway, uses D2 receptors, inhibitory

GPi: projects outside the basal ganglia; uses GABA; gets input from medium spiny neurons from striatum that use substance P; major output pathway of striatum (projects to/inhibits VA,VL of thalamus); direct pathway, uses D1 receptors, excitatory


Substantia nigra pars compacta (SNc) vs. Substantia nigra pars reticulata (SNr)

Very different

SNc: contains dopaminergic neurons projecting to caudate-putamen (striatum)

SNr: contains GABAergic neurons projecting outside the basal ganglia


Ansa lenticularis

Output from the internal pallidum (GPi) to the thalamus

Lenticular fasciculus, or "H2 field of Forel" is same?


Inputs to the basal ganglia

The main "entry" into the basal ganglia is input to striatum

These inputs come mainly from the cerebral cortex


What regions of the cortex project to what regions of the striatum?

Medial cerebral cortex projects to caudate nucleus (more medial!)

Lateral cerebral cortex projects to putamen (more lateral!)


Two things about the cortex to striatum connections that are important to remember

1) Convergence: a huge region of cortex (almost the whole thing) projects to a small striatum

2) Topographical organization: medial cortex projects to caudate and lateral cortex projects to putamen


Inputs to the striatum

Cerebral cortex (not directly though!): uses glutamate

Nigrostriatal pathway (SNc to both putamen and caudate): uses dopamine; modulates input, not direct input (?)

Thalamus (centrum medianum/parafascicular nucleus): uses glutamate

Dorsal raphe: uses serotonin; modulates input, not direct input

Basolateral nucleus of amygdala: uses glutamate


Basal ganglia "loops"

Inputs, outputs and internal connections are topographically organized which results in "parallel circuits"

Motor loop

Oculomotor loop

Prefrontal loop

Limbic loop

So patient with basal ganglia disorder will have symptoms in multiple regions (not just motor!)


Motor loop

1) Motor, premotor, somatosensory cortex

2) Putamen

3) Lateral globus pallidus internal (GPi)

4) Ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus

5) Primary motor, premotor, supplementary motor cortex


Oculomotor loop

1) Posterior parietal, prefrontal cortex

2) Caudate

3) Globus pallidus internal (GPi), substantia nigra pars reticulata (SNr)

4) Mediodosal and ventral anterior (VA) nuclei of the thalamus

5) Frontal eye field, supplementary eye field


Prefrontal loop

1) Dorsolateral prefrontal cortex

2) Anterior caudate

3) Globus pallidus internal (GPi), substantia nigra pars reticulata (SNr)

4) Mediodorsal (MD) and ventral anterior (VA) nuclei of the thalamus

5) Dorsolateral prefrontal cortex


Limbic loop

1) Amygdala, hippocampus, orbitofrontal, anterior cingulate, temporal cortex

2) Ventral striatum

3) Ventral pallidum

4) Mediodorsal nucleus of the thalamus

5) Anterior cingulate, orbital frontal cortex


Neurons in the cortex vs. neurons in the striatum

Cortex: pyramidal neuron

Striatum: medium spiny neuron


What are the neurons of the striatum?

95% efferent neurons (medium spiny neurons): use GABA; 50% to GPi/SNr use GABA/substance P; 50% to GPe use GABA and enkephalin

5% interneurons: use GABA or ACh; few but important

Note: see that most of the efferent neurons out of the striatum are inhibitory


Main outputs of basal ganglia

Main "exits" are outputs from internal pallidum (GPi) and substantia nigra pars reticulata (SNr)


Types of inputs to caudate vs. putamen

Caudate = cognitive = inputs from limbic prefrontal areas

Putamen = motor = inputs from motor and sensory regions


Medium spiny neuron and output of striatum

Neurons of the striatum

Very spiny dendrites

Spines receive inputs from the cortex (use glutamate)

Shafts receive dopaminergic inputs from SNc (use dopamine)

GABAergic and project outside the striatum

Two main classes based on their output projections (enkephalin output to GPe and substance P output to GPi/SNr)


Interneurons of the striatum

Few interneurons (5%) but they are important functionally

Drugs that block muscarinic ACh receptors help in Parkinson's disease ("dopamine/ACh balance" important therapeutically)

Important in processing cortical info within the striatum


Input to the subthalamic nucleus (of the basal ganglia)

Cortex directly projects to subthalamic nucleus and is excitatory

Called "hyperdirect pathway" and is functionally important


Outputs from the basal ganglia originate from which two regions?

Internal palladium (GPi)

Substantia nigra pars reticulata (SNr)


Outputs from basal ganglia (originating from GPi and SNr) use which NT?



Where do outputs from GPi project to?

Thalamic motor nuclei (VA, VL)

Reticular formation


Where do outputs from SNr project to?

Thalamic nuclei of the thalamus (VA, VL and dorsomedial nucleus)

Reticular formation

Superior colliculus


How does the basal ganglia send information back to the cortex

Via the thalamic motor nuclei (VA, VL)


Dorsal vs. ventral part of internal palladium

Neurons in dorsal part of internal pallidum more involved in movements based on internal cues (remembered sequences)

Neurons in ventral part of internal pallidum more involved in movements guided by external cues


Conections within the basal ganglia

Striatum sends GABAergic projections to GPe, GPi, SNc (just a little), SNr

Two distinct pathways:

1) Striatum --> GPi and SNr (contains GABA and substance P)

2) Striatum --> GPe (contains GABA and enkephalin)


Subthalamic nucleus

Only excitatory pathway WITHIN the basal ganglia (uses glutamate)


Direct and indirect pathways of output neurons of the striatum

Direct: SNc onto D1 receptors in striatum --> input of GABA and substance P from medium spiny neurons of striatum --> GPi/SNr --> VA/VL of thalamus --> frontal cortex to increase movement

Indirect: SNc onto D2 receptors in striatum -->input of GABA and enkephalin from medium spiny neurons of striatum --> GPe --> subthalamic nucleus --> GPi --> VA/VL of thalamus --> frontal cortex to decrease movement


Is there tonic activity in the indirect and direct pathways?


Direct pathway has tonic inhibition of GPi to thalamus but when cortex fires to cause striatum to inhibit GPi, you get movement

Indirect pathway has tonic inhibition of GPe to subthalamic nucleus but when cortex fires to inhibit this inhibition, the subthalamic nucleus is free to stimulate the GPi which inhibits the VA/VL of the thalamus which decreases movement


How does the indirect pathway act as a "brake" to suppress competing movements?

It's a brake because it inhibits movement

1) Because of additional synapses, the effect of inhibiting movement will be delayed compared to the direct pathway

2) Anatomical organization creates a "center/surround" effect with direct pathway affecting a small group of neurons in output regions and indirect pathway a large number of "surrounding" neurons; this focuses facilitation of specific motor units (via direct pathway) while inhibiting competing, unwanted movement (via indirect pathway)


How does dopamine act on direct and indirect pathways?

Dopamine exerts opposite effects on the direct and indirect pathways in the striatum, but same consequence of actually increasing movement

Direct pathway: dopamine stimulates GPi/SNr by acting on D1 receptors (facilitates movement)

Indirect pathway: dopamine inhibits GPe by acting on D2 receptors (inhibits inhibition to cause movement)


Role of basal ganglia disinhibition in the generation of saccadic eye movements

Stimulate caudate nucleus --> inhibition of SNr --> now superior colliculus free to fire --> stimulation of horizontal and vertical gaze centers (eye movements!)


Major diseases of the basal ganglia

Parkinson's disease

Huntington's disease


Restless Leg Syndrome

Psychiatric diseases (OCD)


Parkinson's disease

1-2% of population, more men, onset before 50 years old

Loss of nigrostriatal dopaminergic neurons (loss of melanin pigment of SNc)

Symptoms: akinesia (difficulty initiating movements)/bradykinesia (slowness of movement), muscle rigidity (cogwheel sign), resting tremor, postural imbalance (can have stooped posture and gait disorder)


Triad of symptoms in Parkinson's Disease


Muscle rigidity

Resting tremor


Which neurons are lost in PD?

Dopaminergic neurons of the substantia nigra pars compacta (SNc)

Other dopaminergic neurons in the brain are fine!


What part of the brain is first affected in PD and what does this mean?

Putamen is the first brain region to be affected in PD

Since putamen = motor (putamen is part of "motor loop"), the first symptoms you have are motor symptoms


How does PD affect the direct vs. indirect pathways to decrease movement?

Direct: decreased activity of caudate/putamen to GPi/SNr because less stimulation by dopamine --> decreased inhibition of GPi/SNr --> increased activity of GPi/SNr --> increased inhibition of VA/VL of thalamus --> less movement

Indirect: decreased inhibition of caudate/putamen --> increased activity of caudate/putamen --> increased inhibition of GPe --> decreased activity of GPe --> decreased inhibition of subthalamic nucleus --> increased activity of subthalamic nucleus --> increased activity of GPi --> increased inhibition of VA/VL --> less movement


General consequences of loss of dopamine in the brain of someone with PD

1) Striatum has loss of "balanced" control

2) GPi/SNr has disorganized firing

3) Subthalamic nucleus has hyperactivity/bursts

Note: easy to think about increases/decreases but in reality it's the disorganization of firing that causes the basal ganglia not to be able to regulate thalamocortical neurons that causes PD symptoms


Treatments for PD

L-dopa therapy

Surgery: lesions of GPi, high frequency stimulation to inhibit GPi or subthalamic nucleus


How might deep brain stimulation (DBS), or high frequency STIMULATION actually reduce the activity of structures??

1) Induce "depolarization block" because you've stimulated so much that the cells just stop firing

2) Stimulates the release of GABA from nearby axons which inhibits the structure itself from firing


What causes the tremor in PD

We don't really know yet!

Animal models of PD don't show tremor, only akinesia so no good way to study it


Lewy body

Main neuropathological "signature" of PD

Cytoplasmic inclusion made of various proteins

Mainly made of alpha-synuclein, which is toxic when it accumulates and misfolds within the neuron (sometimes called a "synucleopathy")

Present in dopaminergic neurons of substantia nigra


Possible etiology of PD

Mutations in genes linked with the proteasome or toxins (pesticides) altering function of proteasome

Proteins can't be degraded as well and get accumulation of proteins and misfolding of proteins

Proteasome dysfunction may affect mitochondria function also --> free radicals and oxidative stress


Treatments for Parkinson's disease

Currently only symptomatic and for motor symptoms

1) Give drug that becomes dopamine in the brain

2) Give agonists at dopamine receptors

3) Change brain activity with implanted electrode


The many systems that PD can affect




Postural imbalance

Olfactory loss

Cognitive disorders (implicit memory)

Affective disorders (depression/anxiety/apathy)

Sleep disturbances

Autonomic disorders (hypotension)

Digestive symptoms (constipation)


Environmental factors that may cause PD

MPTP (in heroine addicts, see Melega lecture)

Rotenone in experimental studies

Pesticides, heavy metals


Environment vs. genes in PD

Environmental pesticides increase the risk of PD but this effet is modulated by a person's genes

Genes for VMAT2 and DAT (which control amount of dopamine in cell/synapse) altered in those who have been exposed to pesticides

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