Late-stage Huntington's is characterized by a loss of ENK+ and SP+ striatal neurons, and GPe neurons. What tx would be the best choice to combat the hypokinesia of late Huntington's?
A lesion of the subthalamic nucleus
D2 type neurons are INH, and preferentially found on ENK+ striatal neurons. What would be the effect of a D2 antagonist on enkephalinergic neurons?
- INC activity and INC enkephalin production
- When a neuron is active, it is making more transmitter; will make less when it is inactive
- If you hit it with a D2 agonist, enkephalin and activity would go down
- NOTE: D1 type dopamine receptors are excitatory, and preferentially found on SP+ striatal neurons
Is subthalamic input to GPi INH or excitatory?
What is ballismus? What causes it?
- Ballismus: person afflicted w/unwanted movements
- Caused by destruction of the subthalamic nucleus, which leads to INC activity of motor thalamus neurons
Apomorphine (non-specific dopamine receptor agonist) produces hyperactivity. What would the effects of this drug be?
Diminished activity of GPi neurons
What is Haloperidol? How does it affect the basal ganglia?
- Haloperidol: dopamine (D2) receptor antagonist
- INC activity of GPi neurons
How does the profound loss of dopamine neurons acting on the basal ganglia motor circuit produce hypokinesia?
Via INC activity of subthalamic nucleus neurons
Huntington’s: enkephalinergic neurons lost before substance P neurons, leading to a progression from chorea to rigidity. What therapy would be desirable to combat the hyperkinesia of early Huntington’s?
Tx with a D2 receptor antagonist
What are the parts of the basal ganglia? What other brain structures are associated with them?
- Caudate nucleus (yellow)
- Putamen (green)
- Globus pallidus (purple)
- Subthalamic nucleus: interconnected with the basal ganglia
- Substantia nigra: in midbrain, interconnected with basal ganglia
1. Black bc neurons in substantia nigra contain the black pigment melanin
What are the main structures composing the basal ganglia? Where are they located anatomically?
- Caudate: medial, and located along the lateral wall of the lateral ventricle
- Putamen: lateral and ventral to the caudate nucleus, and separated from it by the internal capsule
1. NOTE: caudate and putamen are part of the same structure, but separated by the internal capsule
- Globus pallidus: external (GPe) and internal (GPi) parts
What are the 2 divisions of basal ganglia, and their functions (in general)?
- SOMATIC (dorsal) basal ganglia: caudate, putamen, globus pallidus -> movement control
- LIMBIC (ventral) basal ganglia: nucleus accumbens, olfactory tubercle, ventral pallidum -> motivation, reward, and affect
Describe the 3D relationship of the caudate and putamen.
- Head of the caudate (tail) and putamen (peach pit) are confluent, evidence they are part of same thing
- Fibers of internal capsule develop b/t putamen and head of caudate moving caudally
- Caudate nucleus has a long tail that sweeps posteriorly, bends and comes forward, and curls under main body of the caudate, ending rostrally at the amygdaloid nucleus (if one cuts slice through middle of caudate, head and tail will be in that slice)
- Thalamus is medial to the putamen
Why is the globus pallidus called this?
- Does not have many cells in it, so it looks pale when sliced and stained with a stain that reveals cells
- Globus name because it is rounded like a globe
- NOTE: also can be referred to just as the pallidus
What is another name for caudate + putamen?
Striatum (because many nerve fibers pass through them, giving them a striped appearance)
What are some outdated names for the basal ganglia that should NOT be used (table)?
I can't imagine this is actually important
When stained with dopamine, what features of the basal ganglia will be enhanced?
- Dark region near bottom of image shows dopamine neurons of SUBSTANTIA NIGRA, at the base of the midbrain
- PUTAMEN, and head/tail of CAUDATE all brown bc substantia nigra has axons that travel to head and tail of caudate, and putamen and form dopaminergic terminals there
- Terminals present in all of those areas that are dark
- Globus pallidus does not receive many dopamine terminals, so it is pale
- NOTE: attached image shows rhesus monkey brain stained IHC for enzyme that reveals which neurons make dopamine
1. Note the cerebral peduncle, which is the midbrain continuation of the internal capsule
What are the two divisions of the substantia nigra? What is the significance of this division?
- PARS COMPACTA: dopaminergic neurons arranged in a compact layer in the upper part of the substantia nigra -> neurons contain the black pigment (melanin)
- PARS RETICULATA: net-like, meshwork of fibers below the pars compacta that contains few dopaminergic neurons -> resemble neurons in globus pallidus in their chemistry, shape, and function
- NOTE: image is close-up of substantia nigra in a rat
Where is the subthalamic nucleus located in the human brain?
- Above the cerebral peduncle, and below the bulk of the thalamus
What are the 2 types of neurons in the striatum?
- Aspiny (A): about 5% of neurons in the striatum
1. Dendrites that do NOT possess stubby protrusions (spines) on them
- Spiny (SN): 95% of neurons in striatum -> typically smaller than aspiny neurons
What is this? Why does it look like this?
- Close-up view of a spiny neuron (about 15 microns in width; aspiny are about 30 microns in width at their cell bodies): projection neuron of the striatum
- Dendrites w/stubby protrusions (spines) specialized for receiving terminals from o/brain regions -> neurons that need to integrate information from diverse sources possess dendritic spines
- Dendrites of some neurons are smooth, and receive their input on their smooth surface (aspiny)
What is the role of the spiny neurons in the striatum?
- Spiny neurons have a long axon that leaves the striatum (in contrast to the short axons of aspiny neurons that do NOT leave the striatum)
- Spiny neurons = projection neurons; aspiny neurons = local circuit/interneurons
- Whatever the striatum decides based on pattern of input it receives, it is spiny neurons that transmit that decision to other brain areas
- NOTE: there is further functional and neurochem diversity within these two types of neurons
What are the 2 major subtypes of projection neurons in the striatum? Where do they project?
- All spiny (projection) neurons in the striatum use the nuerotransmitter, GABA
- 2 major subtypes based on different neuropeptides (adjunct NT's that neurons often use, and can be neurochem signatures for defining subtypes):
1. Opioid neuropeptide, enkephalin (ENK): red in the illustration; nearly all project to GPe
2. Substance P (green): many project to GPi (there are add'l subtypes of striatal substance P neurons)
What does this image show?
- Dark labeling in GPi represents substance P-containing terminals of those substance P neurons in striatum that project to GPi (note: no noteworthy labeling of substance P terminals in GPe)
- Enkephalinergic neurons in caudate and putamen project to GPe, resulting in many terminals in GPe that can be visualized by enkephalin IHC (GPi largely devoid of enkephalin)
- NOTE: rhesus monkey basal ganglia
What does this image show?
- Substance P image: substance P terminals located in upper shelf in substantia nigra where dopaminergic neurons are located (pars compacta) and in region of substantia nigra below dopaminergic neurons (pars reticulata)
1. Substance P neurons in striatum project to GPi, SNc, and SNr
- Enkephalin neurons in striatum have only a hint of a projection to substantia nigra, and only to very most medial part -> bc it is minor, we will disregard it
- NOTE: rhesus monkey brain
How are the different striatal projection neurons distributed in the caudate/putamen?
- Substance P and enkephalin neurons in the striatum are INTERMINGLED (see image)
- Substance P neurons, in addition to containing SP, contain a second neuropeptide -> the opioid, dynorphin (SWEATMAN: kappa, OP-2 receptors)
- NOTE: red neurons in this image project to GPi and substantia nigra pars reticulata, and the blue neurons, the enkephalin neurons, project to the GPe
What are the 4 striatal projection neuron types (table)? Describe their dendrite traits, where they project, their main NT/NP, DA receptor type, and main function.
- All 4 types are medium-sized and spiny, and main NT of each is GABA
- Enkephalinergic striato-GPe neurons have D2 type dopamine receptor; substance P-containing striatal neurons have D1 dopamine receptor (these function differently)
- NOTE: can substitute "initiate" for "promote" in the main function column
What are the 4 types of interneurons in the striatum?
- Distinguished by their neurochemistry, size of their cell body, which neuron in the striatum they project to, and which parts of the brain they receive input from
- Each type makes up about 1% of the neurons in the striatum, and together they make up about 5%
- CHOLINERGIC: has been the target of txs directed at basal ganglia disease -> big cell body, and NT = Ach
- PARVALBUMIN (Ca-binding protein): NT = GABA; larger than projection neurons, but smaller than cholinergic interneurons
- SOMATOSTATIN: main NT is GABA; cell bodies are same size as cell bodies of spiny neurons
- CALRETINERGIC (Ca-binding protein): cell body that is the same size as the cell body of the spiny neurons of the striatum; NT = GABA
What happens to the striatum in Huntington's Disease? Which neurons survive?
- Striatum sustains severe neuron loss and atrophy in HD, but several types of interneurons survive, NPY+ and cholinergic -> striatal projection neurons, which make up 90% of striatum, die
- Somatostatin interneurons = NPY+
- While the functional role of these interneurons is unknown, they are relevant to understanding the pathology of HD
- NOTE: parvalbuminergic are the only type of interneuron lost in HD
Describe the 4 striatal interneuron types, incl. dendrite traits, where they project, main NT/NP, and main function.
- NOTE: therapies to tx Parkinson's in the past were directed at modulating cholinergic interneurons bc cholinergic input in striatum opposes the action of dopaminergic input
1. So, if there is insufficient dopamine (like in PD), then DEC cholinergic activity should compensate for dopamine def
What is the major neuron type in the globus pallidus?
- GP interneurons have long, aspiny dendrites that form a disk-shaped tree that ramifies in vertical plane of globus pallidus (GPe and GPi)
- Many striatal neurons send their terminals onto the dendrites of any given GP neuron, and any given GP neuron integrates info from the many striatal neurons that project to it
- Both GPe and GPi neurons are GABAergic, and send their axons out of GP to their target area (2)