Basal Ganglia Flashcards
1
Q
Medium Spiny Neuron
A
- Dendrites are studded with spines, many projections, 95% of basal ganglia.
- Modal “balanced” state membrane potential (-78 to -60mV) **These are targeted in Huntington’s**
2
Q
OBJ 7: Functional role of the basal ganglia. (3)
A
- collection of subcortical structures that control movement. Regulate activities of motor cortical areas– allows voluntary movements to be performed smoothly, AND surpasses unwanted movements.
- allow us to do repetitive motions automatically (walking, chewing gum, typing)
- also contribute to higher level cognitive processing
3
Q
OBJ 1: Where are the 2 places that basal ganglia receive input from?
A
- Cortex– via descending pathway – excitatory via glutamate
- SNc – via ascending pathway – excitatory via dopamine (*Dopaminergic projections*)
4
Q
Basal ganglia connections
A
SNpc release dopa and cholinergic interneurons and Glu from cortex all influence the basal ganglia.
5
Q
OBJ 4: What does the striatum signal?
A
Striatum only sends INHIBITORY signals (GABA) to:
- GPe (indirect pathway)
- GPi/SNr (direct pathway)
6
Q
OBJ 4: What does the thalamus signal?
A
Sends EXCITATORY signals via glutamate to the CORTEX thereby completing the loop of the basal ganglia.
7
Q
What is the INDIRECT pathway from the striatum?(Remember: Stripes indirectly excite SIR Thalamus)
A
INDIRECT = Striato-pallidal pathway
** Striatum inhibits GPe **
Normally, GPe inhibits STN, and prevents this: STN→ excites GPi/SNr→ inhibit THALAMUS.
key: INHIBITION of GPe (by striatum) allows EXCITATION of STN, and then GPi/SNr, which INHIBIT thalamus.
8
Q
Clinical manifestation of Tourette’s syndrome (3)
A
- Neurological disorder characterized by childhood onset
- Motor and vocal “tics”
- Comorbidity with OCD, ADHD, depression
9
Q
OBJ 4: What does the subthalamic nucleus signal?
A
STN is unique in the basal ganglia because it is the only structure to send EXCITATORY signals via glutamate to:
- GPi/SNr
- GPe
10
Q
Treatments for Huntington’s
A
No treatment to slow or treat progression of Huntington’s. Can only treat depression, irritability, and paranoia symptoms with SSRI’s (Fluoxetine, carbamazepine).
11
Q
Inhibitory NT GABA has 3 receptors:
A
GABAA – ligand gated ion ch permeable to cations (Cl-)
GABAB – GPCR’s, metabotropic (?), opens K+ or Ca2+ channels to dampen the membrane potential.
GABAC – in retina
** All are inhibitory, dampens the membrane potential**
12
Q
OBJ 4: What is the role of the cortex in stimulation of the basal ganglia?
A
Cortex sends EXCITATORY signals (glutamate) to the STRIATUM
13
Q
Dorsal striatum
A
- Convergence of multiple inputs.
- receives inputs via Glu, Dopa, and Ach
14
Q
striatum RECEIVES _____ inputs from cortex, and SENDS output to ______ .
A
- topographic descending.
- Globus Pallidus and SNiagra.
15
Q
What are aspiny interneurons?
2 types? (location, NT, target, action)
A
5% of striatum, DO NOT project outward, entirety of neuron is within striatum, but may influence MSNs that send info out from striatum. Two types:
- Cholinergic interneurons
- GABAnergic interneurons (Fast-spiking and Low-threshold-spiking)
16
Q
Clinical manifestations of basal ganglia disease
A
- Tremor
- Changes in posture and muscle tone
- Poverty of movement without paralysis
- Hyperkinetic involuntary movements
- Obsessive compulsive disorders
… all tend to involve uncoordinated movement
17
Q
Cortical Basal Ganglia Loops
A
- Involved in associative, limbic mvmt, sensory, motor loops.
- a problem in a motor loop may be caused by a defect, Huntington’s, or eye movement???
18
Q
What causes Tourette’s syndrome? treatment?
A
- “Hyper-dopaminergic” neurons
- dopamine receptor antagonists
19
Q
Clinical manifestations of Parkinson’s disease (Motor symptoms)
A
- Muscle rigidity
- Bradykinesia (slowness of movement)
- Resting tremor (goes away during voluntary movement)
- hyperkinetic INVOLUNTARY mvmts (like reflexes)
- Poor postural balance leading to disturbances in gait and falling episodes
20
Q
Dopaminergic Modulation: Dopa is more of a neuromodulator than a NT, because ______
A
- b/c doesn’t have its own receptor, instead binds to GPCRs generally. (What the heck are D1 and D2 receptors then???)
- Send inputs to striatum (+/-) and thalamus (-).
21
Q
General Basal Ganglia Pathway goes from ____ to basal ganglia via _____
A
- Cortex to basal ganglia, via striatum.
- striatum RECIEVES topographic descending inputs from cortex, and SENDS input to GP and SN.
- All inputs go to the thalamus and feedback on cortex. It’s a loop!
22
Q
Direct vs Indirect pathway
A
- SMA/MC to putamen to GPi directly, or indirectly to GPe and eventually reach the GPi.
23
Q
What is “down-state”?
A
Resting state of the medium spiny neuron of striatum– at resting membrane potential.
24
Q
What are the firing patterns of the 2 types of GABAergic interneurons of striatum, in comparison to MSNs?
A
- Fast-spiking GABAergic interneurons – have a much greater frequency of action potential firing than MSNs (which have a consistent steady firing pattern).
- Low threshold spiking GABAergic interneurons – don’t need as much depolarization as the MSNs in order to reach threshold and fire an AP.
25
Potential causes of Parkinson's (3)
More than 95% are idiopathic. Some genetic ties.
Some chronic pesticide exposure may be correlated, due to mitochondria dysfunction
26
All addictions (cocaine, amphetamines, nicotine, alcohol) all share common mechanism of ....
elevating dopamine in Ventral Striatum/Limbic Loops -- probably hyperactive reward pathways.
27
Excitatory NT Glutatmate has 3 receptor:
- NMDA R (Na, Ca, K channels will be open)
- mGLURs (GPCRs - open channels to depolarize membrane potential- dampens memb potential, decreases probability of opening Ca channels)
- kainate receptors
28
Glutamate and its receptors
\*Major excitatory NT
_NMDA_ and _Non-NMDA receptors_ (AMPA, Kainate): Ionotropic non-selective ion channels that mediate influx of cations like Na+ and Ca++
_Metabotropic receptors_: coupled to intracellular excitatory pathways
29
The central event in Huntington's disease, aka \_\_\_, is the loss of \_\_\_\_\_. Which pathway is affected?
- aka Chorea
- Loss of striatal medium spiny projection neurons \*\*
- Indirect pathway affected more \*\*
- Interneurons and neighboring neurons unaffected.
30
OBJ 4: What is the DIRECT pathway from the striatum?
DIRECT = Striato-nigral pathway
Striatum → inhibits GPi/SNr
Normally, GPi/SNr → inhibits Thalamus
INHIBITION of GPi/SNr by the striatum removes inhibition and allows EXCITATION of Thalamus.
31
3 nonsurgical treatment for Parkinson's. \*Can't treat with dopamine bc \_\_\_\_
- dopamine doesn't cross BBB
1) L-dopa + Carbidopa (AADC inhibitor)
2) MAO-B inhibitor
3) Dopamine receptor agonists
32
Clinical manifestations of Parkinson's disease (non-motor symptoms)
(senses and intellect are spared until later in disease?)
- Cognitive impairment, hallucination, mood/sleep disorders, OCD
- Constipation/Erectile dysfunction
- Altered pain sensation
33
Parkinsonism
Many types of diseases. Substantial death of cells in SNpc. Theory: there is unbalanced activity of direct and indirect pathway to develop PD.
34
What are tonically active neurons (TAN)? (location, NT, target, action)
- TANS, cholinergic interneurons of striatum, modulate MSNs using acetylcholine (Ach binds to muscarinic M1 receptors on MSNs)
- large cell bodies, typical firing pattern and are tonically active WITHOUT cortical innervation. Even if you remove cortex, TAN cells continue to fire APs.
35
MAO-B inhibitor
- Used to treat Parkinson's disease.
- Prevents degradation of dopamine in the synapse by MAO-B.
- CONS: but modest affects, works early in disease
36
Why is the general basal ganglia pathway considered a loop?
bc pathway starts from cortex/thalamus, and all inputs go to the thalamus and feedback on cortex. It's a loop!
37
hyperactive reward pathways are characterized by \_\_\_
elevated dopamine levels in Ventral Striatum or Limbic Loops
38
Globus Pallidus
- Receive inputs from striatum
- majority are projection neurons, some interneurons
- uses GABA and targets thalamus
39
GABA and its receptors
Major inhibitory NT
- **GABA-A receptors**: ligand-gated ion channels selective for Cl-, thus hyperpolarize cells
- **GABA-B receptors**: GPCRs that acivate 2nd messenger cascades of cAMP
40
What causes Huntington's disease?
- HERITABLE fatal neurodegenerative disease, caused by abnormal number of CAG repeats in DNA (38-100 repeats in HD, normally 9-34).
- Huntingtin and other genes is involved.
41
What are medium spiny neurons (MSN)?
2 types? (location, NT, target, action)
**95%** striatal neurons. Project _out_ of striatum to communicate with other parts of basal ganglia. _2 types:_
1. Striato-pallidal (Striatum --\> GP)
2. Striato-nigral (Striatum --\> SN)
42
Dopaminergic neurons
- Found in the pars compacta of Substantia Nigra.
- firing pattern is regulated by SALIENCE -- determines if a sensory input is important to integrate or not.
- Known to be associated with rewards pathway
- Stimulate the direct pathway and inhibit the indirect pathway
- destruction of these neurons in parkinson's.
43
Dopamine and its receptors
Dopamine modulates the opening and closing properties of other types of ion channels (K+, Na+, Ca++).
- D1 receptor: GPCR coupled to G-s-alpha subunit and INCREASE cAMP to stimulate adenylyl cyclase. Present in the DIRECT pathway.
- D2 receptor: GPCR coupled to G-i-alpha subunit and DECREASE cAMP to inhibit adenylyl cyclase. Present in the INDIRECT pathway.
44
OBJ 4: What does the globus pallidus signal?
Globus pallidus only sends INHIBITORY signals (GABA).
- GPi/SNr-- inhibits THALAMUS
- GPe-- inhibits STN and GPi/SNr
45
OBJ 4: What do inputs to the basal ganglia tell them (in general terms)?
1. release of wanted movements (excitatory via glutamate) OR...
2. inhibition of unwanted movements (inhibitory via GABA)
46
manifestation of hemiballismus:
Hyperkinetic disease -- uncontrolled flinging movements of contralateral arm or leg.
47
symptoms of Huntington's
- uncontrolled head movement, twitchiness
- Grimacing movements of face, lips, tongue
- Gesticulating mvmt of limbs
- Jerking movements of lower limbs
- Paranoia, depression, irritability
Like Parkinson's, symptoms appear later in life
48
Central event of Parkinson's disease - neurons and pathways involved.
\*\* Degeneration and death of dopaminergic neurons in the Substantia Nigra (SNc) of the midbrain\*\*
- dopa neurons stimulate direct and INHIBIT indirect pathway, so in Parkinson's **direct pathway doesn't get stimulated** and **INDIRECT pathway is chronically OVERSTIMULATED (lack of inhibition).**
- GPe inhibited→ STN excited→ leading to excitation of GPi/SNr→ inhibition of thalamus.
49
OBJ 1: What is the basal ganglia composed of? (4 major structures + their substructures)
1. Striatum - gateway of info processing from cortex + thalamus. Contains Caudate Nucleus, Putamen, Nucleus Accubens.
2. Globus Pallidus - external and internal (GPe, GPi)
3. Subthalamic Nucleus (STN)
4. Substantia Niagra - Pars Compacta, Pars Reticulata (SNc, SNr)
50
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← ↑ → ↓ ↔ ∴ ∵ ∼ ≈ ° % ÷ × ± − + ½ ¼ ¾ ⁰ ¹ ³ ⁴ ⁵ ⁶ ⁿ ⁺ ⁻ ∧ ₀ ₁ ₂ ₃ ⊕ ⊗ ∑ Θ ƒ ∫ ‖ | ⊥ ∠ α β γ δ ε γ η θ π ∆ ∞ σ κ λ µ ∨ ℵ ∞ ∆
51
Carbidopa and levodopa
- used to treat Parkinson's Disease
- L-dopa CAN crosses BBB, converted to dopamine in the brain by AADC (Tyr→ L-dopa → dopamine).
- Carbidopa is a AADC inhibitor, CAN'T cross BBB, prevents L from being broken down/converted outside the brain.
52
Surgical therapies for Parkinson's (2)
-- Ablation of thalamus, GP (UNILATERAL), or STN (BILATERAL)-- may improve tremors, rigidity, slowness.
-- Deep brain stimulation-- Implant electrodes to stimulate dopaminergic neurons. Targets STN or GPi bilaterally. Less invasive, reversible, and adjustable.
53
Internal capsule separates the ____ and \_\_\_\_\_.
putamen and caudate nucleus.
54
Action Selection involves ___ neurons bringing input to ___ (area).
Tonically active Ach Neuron (TAN) inputs to striatum
55
What is hemiballismus? 3 causes?
- Hyperkinetic disease
- unilateral lesion of the subthalamic nucleus causes decresed output from Globus Pallidus.
- Often caused by stroke, tumor, or infections
56
\_\_\_\_ and _____ Loops within the Globus Pallidus all implicated in Parkinson's disease
Motor and oculomotor loops
57
Subthalamic Nucleus
- Project to globus pallidus
- uses Glu so it is excitatory.
- autonomous firing pattern (5-50Hz).
- It is driven by the cortex.
58
Demographics of Parkinson's patients
- 1-1.5 million Americans, more Caucasians.
- Onset in the elderly
- Some genetic correlation
- No conclusive diagnosis
59
D1 vs. D2 receptors
D1 Receptor: couples to Gs -- increase AC activity, increase cAMP
D2 Receptor: couples to Gi -- *_decrease_* AC activity, _decrease_ cAMP
60
Parts of the Striatum
Caudate nucleus (medial) Putamen (lateral).
They send inputs to other parts of the basal ganglia only.
61
Substantia Nigra
- Distinctive black color
- pars compacta uses dopamine and express melatonin
- firing patterns regulated by "salience"
- it degenerates in Parkinson's
62
Basal ganglia Injuries/Diseases
Tourette's Syndrome
Parkinson's Disease
Huntington's
63
Basal ganglia (caudate and putamen) neurons:
- Medium spiny neurons (95%) -- projecting neurons
- Aspiny Interneurons (5%) -- cholinergic and GABA-ergic, non-projecting, influence projecting neurons.
64
Dopamine receptor agonists
- Used to treat Parkinson's disease.
- PRO: No enzymatic activity required! targets receptor subtypes.
- CONS: doesn't work + side effects: dyskinesia, orthostatic hypotention, nausea, hallucinations/confusion
65
Obsessive-compulsive disorder
- likely associated with loops of basal ganglia
- things that give us pleasure (shopping, gambling) but when it's at the level of compulsiveness probably something wrong with the basal ganglia.
66
What is "up-state"??
- active state of the MSN of striatum, when it is _depolarized_ and firing action potentials.
- a MSN reaches the up-state (gets excited) via _glutamatergic_ innervation from the cortex.
