Basal ganglia = essential for movement
---> But there are NO direct connections
to motor neurons in spinal cord OR to brainstem that control movement
- lesions can produce both paucity and enhancement of movement
- Parkinson's = tremors and rigidity
- Basic loop = between subcortical nuclei and the cerebral cortex ---> Ultimate effect on motor neurons giving rise to Corticospinal Tract
- From cortex ---> BG ---> thalamus ---> Cortex ---> Corticospinal and corticobulbar tracts
- == indirect influence on Motor Neurons
- Theory 1 = they are critical for Self-initiated movements ---> can catch ball bc of reflex but cannot throw it when want to
- Theory 2 = inhibit competing motor programs ---> problem leads to rigidity
Terminology in the Basal Ganglia: what makes them up?
- All of these are in the Forebrain
- Striatum = Caudate Nucleus, Putamen, and Nucleus Accumbens (aka ventral striatum ---> no motor function, works in addiction/pleasure)
- Globus pallidus has External and Internal Segment
- Putamen and Globus pallidus = right next to eachother = Lenticular N.
- Subthalamus (part of basal ganglia)
- Midbrain = Substantia Nigra ---> Pars Compacta and Pars Reticulata
Relationships: basics = first, they are located deep to cortex and lateral to the Internal Capsule (IC)
- Striatum = BOTH function as input nuclei = information processing begins!!
- Caudate = lateral to the lateral ventricle!! Medial to the Putamen
- C-shape = head/body in frontal lobe, and tail in temporal lobe
- executive decision making, or emotions from Prefrontal cortex...
- lesion = outbursts, bad behavior, NO motor deficits
- Putamen = separated from the caudate by the internal capsule, located laterally on section
- not separated at their very most rostral poles!!
- Motor Cortex = comes to Putamen!!
- External Globus Pallidus + Subthalamus ---> NOT next to each other...
- Processing information as it moves through the BG
- Internal Globus Pallidus (medial to external) + Substantia Nigra Pars Reticulata = Spatially different again...
- == OUTPUT of BG ---> thalamus ----> motor cortex ----> control neurons giving rise to Corticospinal and Corticobulbar tracts
- Substantia Nigra Para Compacta = DOPAMINE source that modulates BG circuitry
Striatal Loop Circuitry : between BG and cortex involves thalamus
- output of BG to the thalamus is carried by neurons located in the INTERNAL segment of the Globus Pallidus or the Substantia nigra Pars Reticulata
- Motor Cortex Projects to the PUTAMEN
- OUTPUT of the Striatum = Medium Spiny Neuron
- GABAergic = Inhibitory to targets (also contain enkephalin and substance P)
- Huntington's Disease = LOSE these neurons, especially ENK+
- These are also Dopamingergic...and thus their function is altered when these dopamine inputs are lost in Parkinson's Disease
2 populations of Medium Spiny Neurons in the Striatum = Caudate and Putamen = Metabotropic receptors (are also interneurons that are cholinergic)
- D1 = binding of dopamine ---> Depolarization and excitation
- ---> INTERNAL Globus pallidus and Substantia Nigra Pars Reticulata
- D2 = binding of dopamine ---> HYPER polarization and inhibition
- ----> EXTERNAL Globus Pallidus
Globus Pallidus = both are GABAergic = inhibitory
- Internal GP = PRIMARY OUTPUT of the BG ---> to thalamus ---> Motor neurons in Cerebral Cortex
- GP-i = motor output that effects MOST of the body!!
- External GP = modulate the Internal GP via relay system in the Subthalamic Nucleus
- Cross Section = these are medial to the Putamen (ventral surface) = Lenticular N. together
- axons leaving the GP-i cross the internal capsule to reach Thalamus in tract called the Lencticular Fasciculus
Subthalamus = between the Thalamus (above) and Substantia Nigra (below)...separated from the Lenticular N. by the internal Capsule
- Glutamatergic = ONLY EXCITATORY source in the BG
Substantia Nigra = midline, lowest down....immediately dorsal to the Cerebral Peduncle (is the distal continuation of the internal capsule)
- Pars Compacta (dorsal) = Dopaminergic ----> Putamen and Caudate N.
- Lost in Parkinson's Disease
- Pars Reticulata = GABAergic ----> output of the BG to thalamus but only regarding EYE movement!!
Basic Loop ... ALL parts of Cerebral Cortex go to the Striatum ---> Cortical Axons == Glutamate = Excitatory = STARTS processing information
- Cortex also projects to the Subthalamus and the SN-PC
- NO direct cortical projection to the Globus Pallidus
- Ultimately, information leaves via the GP-i (for body) or the SN-PR for eyes
- these are INHIBITORY to the thalamus bc they are GABAergic ---> Thalamus projects back to the Cortex
- thalamus to the cortex = Excitatory based on how much inhibition was given
Opposing Parallel Pathways:
Direct pathway: 1) Excitatory Input from the CC to the PUTAMEN
- cortical neurons also Excite Dopaminergic neurons in the SN-PC ----> Project to Striatum
- = excite neurons expressing D1 receptor...just like the cortex is doing to the Striatum
- == increases excitation of D1 neuron
- 2) Cortical neuron terminates on D1 receptors on Striatum Putamen ----> directly to the GP-i and they are INHIBITORY
- "when striatal cell is silent the GP-i neurons are firing away" ---> inhibit thalamus
- "when striatal cell is excited, the GP-i activity is suppressed" --->
- 3) this suppresses the GP-i neurons = DECREASE inhibitory drive on thalamic neurons
- Disinhibition == thalamic neurons are released from Inhibition of GP-i
- = fire at higher rate = increased activity of Corticospinal tract ---> increased muscle tone
- Cortex ---> Putamen ---> GP-i ---> Thalamus ---> Cortex = INCREASED FIRING
- Disinhibition of an Excitatory neuron = increase in output of chain
- Disinhibition of an Inhibitory Neuron = DECREASE output of chain bc the inhibitory neuron is "not inhibited"
Indirect Pathway: Cortex --> Putamen --> GP-e ---> SUBTHALAMUS ---> GP-i ---> Thalamus ---> Cortex DECREASED
- Cortex = Excitatory input to Putamen + SN-PC
- but to D2 receptors!! ---> EXTERNAL globus pallidus and is INHIBITORY
- "when Striatal neuron is active, the GP-e cell is inhibited due to GABA release"
- "however, When DOPAMINE is present the firing of the Striatal cell is BLOCKED"
- ---> GP-e is now free to fire = supresses Subthalamus via GABA release
- = removes excitatory drive on GP-i (disfacilitation) --->
- less inhibitory output from the GP-i = increased firing of Thalmus = increase Cortical Firing
- == DOPAMINE causes greater cortical output in BOTH direct and indirect pathways!!!!
- this balance is upset in Parkinson's
- NO dopamine = GP-e goes to the Subthalamus...which normally it would inhibit...
- == now, the GP-e is inhibited by the Striatum = subthalamus is released from inhibition
- == Subthalamus fires at higher rate ---> EXCITATORY to the GP-i = increased GP-i output
- "subthalamus is a direct source of excitatory input to the GP-i"
- == Stronger Inhibition of the Thalamic Neurons and a DECREASED output to the cortex
- == NET effect --> enhanced output from GP-i = suppresses thalamus = DISFACILITATION of Cortical neurons
- Disfacilitate an excitatory neuron = LOWER output of the chain
- Disfacilitate an Inhibitory neuron = INCREASE output of the chain
Basal Ganglia Circuitry:
- under Basal conditions (no stimulation) =
- Putamen = Silent
- GP-i/SN-PR firing away = inhibiting the neurons of the thalamus ----> Disfacilitation of the Cortical Neurons
Center-Surround Organization = hypothesis that particular voluntary movement synapse on different Populations of the GP-i neurons
- D1 = direct pathway ---> increased cortical output = reinforce the ongoing movement
- D2 = indirect pathway ---> suppress cortical output for conflicting motor pathways
What about Cholinergic Receptors? Have opposite effects of Dopamine!
- INHIBIT striatal neurons w/ D1 in the Direct pathway
- EXCITE striatal neurons w/ D2 in the indirect pathway
- NET = increased output from GP-i == ultimately decreased cortical output
- AcH = decreased cortical output
- Dopamine = increases activity in cortical neurons giving rise to the corticospinal tract
Parkinson's Disease = loss of dopaminergic neurons in the SN-PC...primarily on Indirect pathways ==
- increased activity of subthalamus + decreased activity in the thalamo-cortico pathways!!
- when dopamine is depleted = profound loss of spines and Glutamatergic synapses coming from the cortex on Medium Spiny neurons expressing the D2 receptor (indirect)
- also loss of dendritic length and branching
- but not on those expressing D1...
- the depletion results in hyperexcitability of the remaining synapses
- Tremor at rest, Cogwheel Rigidity (tension on both sides of joint)
- thought to be from decreased descending control of inhibitory interneurons that control Gamma motor neurons
- ---> increase GMN = both agonist and antagonist mm. are hypersensitive and active at the same time
- Akinesia (cannot initiation movement), Bradykinesia (low amplitude once movement is started)
- Linked to a-synuclein, and Parkin...as well as pesticides in agriculture
Tx for Parkinson's
- Give Oral Precursor = L-dopa, can relieve symptoms
- systemic side effects like hallucinations, hard to titrate
- may reduce rigidity, but can also induce hyperkinesia = out of control movements
- Lesioning of the GP-i or Subthalamus = helps more with tremor, not so much for rigidity
- Deep brain stimulation = electrodes placed in subthalamus and neurons are stimulated at specific frequencies
- alleviates 60-80% = FDA approved...it works really well...