The Basal Ganglia

The Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt
http://login.ncmir.ucsd.edThe Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt