Basal Ganglia + Cerebellum
Vocabulary:
Basal ganglia: Consists of a group of nuclei deep in the cerebral hemispheres, has associated structures located within the midbrain and diencephalon. Contains subcortical loops involving the cortex. Controls motor decisions, cognitive function, and emotional functioning. Controls thought as it relates to body movement. Also involved in reward systems with DA, decision making, and habit formation. Contains corticocortical, corticothalamic, and corticospinal collaterals
Body movement loop: Understood the most, responsible for the selection of action plans and decisions to move toward a goal, not just the actual movements needed to get there. Regulates transition from one voluntary movement to another, also establishes habitual patterns of movement. Both direct and indirect pathways are modulated by DA input from the substantia nigra pars compacta (SNc) in the midbrain
Direct path: Prepares UMNs to initiate movements, cortex → corpus striatum → gpi → VA/VL of thalamus (converges with info from the cerebellum)→ motor cortex. Doesn’t receive signaling, the gpi → VA/VL is tonically inhibited by GABA so there aren’t excitatory signals from the VA/VL to the motor cortex. Due to cortical stimulation, cortical projections excite the caudate/putamen. From here GABA projections → gpi (inhibitory). The gpi GABA projections to the VA/VL thalamus are inhibited, allowing it to excite motor control (disinhibited/released from inhibition). Excitation of the corpus striatum results in disinhibition of the thalamus, the inhibitor (gpi) is inhibited so the VA/VL no longer receives GABA and can thus excite glutamatergically the motor cortex. DA is released onto D1 receptors in the VA/VL to enhance inhibition release when excited by cortical projections. Activation of D1 receptors onto a specific population of medium spiny neurons in the corpus striatum increases GABA stimulation to the gpi to release the VA/VL from inhibition, eventually leads to excitation of UMNs. Focuses cortical projection into the corpus striatum, to converge projections to the gpi
Hyperdirect path: Without cortical stimulation, the gpi inhibits the VA/VL, with the subthalamic nucleus having the potential to increase gpi inhibition. Cortical stimulation of the subthalamic nuclei are excitatory and control subthalamic glutamatergic projections to the gpi. The gpi then increases GABA release onto the VA/VL complex. Leads to increased GABA release from the gpi onto the VA/VL. Diffuses cortical projects to the corpus striatum, subthalamic projections to the gpi diffuse
Indirect path: Prevents the activation of UMNs associated with unwanted movements. Stimulation increases GABA signaling from the gpi to further decrease VA/VL excitation in the motor cortex. Without cortical stimulation, the globus pallidus external (gpe) diminishes the amount of GABA from gpi onto the VA/VL. Cortical signaling will decrease GABA release from the gpe to the gpi. When the gpi is disinhibited, more GABA is released onto the VA/VL. With no cortical signaling, the gpe prevents the subthalamic nucleus from increasing gpi and VA/VL inhibition. With cortical signaling, the gpe is stopped from preventing subthalamic nuclei from increasing gpi inhibition of the VA/VL. Dopamine is released onto D2 receptors of the gpe to reduce GABA release (inhibition). The gpi is inhibited by the gpe to reduce excitation by the subthalamic nuclei. The gpi releases less GABA onto the VA/VL. Activation of D2 receptors on a specific population of medium spiny neurons in the corpus striatum increases inhibition of tonic GABAergic neurons in the gpe, increasing the release of GABA from the gpi onto the VA/VL to inhibit UMNs. Diffuses cortical projects to the corpus striatum, subthalamic projections to the gpi diffuse
Oculomotor loops: Consists of the superior colliculus and SNc. Stimulation of the basal ganglia involved with this loop releases inhibition of UMNs in the superior colliculus
Oculomotor pathway: Targets UMNs of the superior colliculus which stimulate saccades, causing rapid orienting eye movements that are suppressed when fixating on a target. The substantia nigra pars reticula (SNr) tonically releases GABA onto UMNs in the superior colliculus (much like the gpi of body movement loops). This gets cortical inputs to the corpus striatum from multimodal association areas and the frontal eye fields. Palladium projection neurons go to the SNr to tonically inhibit the superior colliculus. Frontal eye fields | Multiple association area → (glutamatergically) caudate → (GABAergically) SNr → (GABAergic and tonic) Superior colliculus with UMNs for the extrinsic eye muscles. Inhibition of inhibition
Corpus striatum (neostriatum): Includes areas like the caudate and the putamen, gets input from the cortex glutamatergically, with multiple of these parallel corticostriatal paths. Has little spontaneous activity, inward rectifier K+ channels are open at RMP but many require glutamatergic synapses from cortical collaterals to generate APs. Topographically mapped with bands for different parts of the body. Interconnected cortical areas overlap in terms of function. Receives glutamatergic input from medium spiny neurons and projects to the gp, then to the cortex, interneurons, and the SNc for DA production. Compartmentalized based on neurotransmitters utilized, source of cortical input, and axon targets
Caudate nucleus: Part of the basal ganglia, contains multimodal association cortices, used in the oculomotor loop
Putamen: Contains S1 and S2, extrastriate cortices, motor cortices, and auditory association areas. Firing of MSNs here is associated with movement and termination of movement in the trunk/limbs
Globus pallidus internal (Gpi): Contains projection neurons going to the ventroanterior (VA) and ventrolateral (VL) complexes of the thalamus. Contains a subthalamic nuclei that is involved in the indirect path. Tonically releases GABA to inhibit the VA/VL thalamus. Functions with the corpus striatum
VA/VL complex: Ventrolateral and ventroanterior areas of the thalamus, integrates inputs from the cerebellum and basal ganglia. Tonically releases GABA from the gpi to inhibit glutamatergic projections to the motor cortex
Substantia nigra pars compacta (SNc): Synthesizes dopamine (DA), used in modulation of the corpus striatum
Medium spiny neurons (MSNs): Responsible for cortical input divergence, as many different collaterals synapse on spines of a single MSN. Each collateral makes only a few light synapses with multiple MSNs. They help modulate SNc dopaminergic neuron synapses at the base of the synapse, local circuit neuron synapses onto shafts close to the soma, and ACh. Projections are convergent to the gp, 100 MSNs per neuron in the gp. MSNs make many diffused synapses with multiple neurons, with preference for one in the gp
Parkinson’s disease: The 2nd most common degenerative disease of the nervous system, consists of hypokinesia (reduced movement), bradykinesia (slowed movement), rigid extremities/neck, minimal facial expressions, a shuffling gate with lack of arm swinging, resting tremors, micrographia (very small writing), dysphagia (difficulty swallowing), stooped posture, and cognitive/emotional issues like depression, anxiety, apathy, decreased processing speed and memory retrieval, and impaired visuospatial abilities. This may be associated with dementia, but does not directly culminate in death. Caused by a loss of dopaminergic neurons in the SNc and VTA of the midbrain. Can also be caused by MPTP exposure, though presents slightly different. With the body movement circuit, this is a loss of excitation to enhance the direct path, and a dampened inhibition of the indirect path
Parkinson’s treatments:
L-DOPA: Used as a treatment for Parkinson’s as it crosses the BBB. Ubiquitous decarboxylase reduces L-DOPA in peripheral blood, so this is often administered as carbadopa which is a substrate for the same decarboxylase and doesn’t cross the BBB, by using the enzymes, more L-DOPA can “sneak through”.
Drugs that target ACh: To balance DA/ACh signaling
Deep brain stimulation: Done to subthalamic nuclei to dampen enhancement of indirect path inhibition
Gene therapy: Implants cells in the caudate/putamen that are genetically modified to produce DA
Neural graft: Uses STEM cells, attempts to establish what causes them to become DA producing neurons
Huntington’s disease: A hyperkinetic disease passed genetically, displays alteration of mood (particularly depression), personality change (higher rates of suspicion, irritability, and impulsive/eccentric behavior), deficits in memory/attention, and chorea (rapid/jerky movements with no clear purpose). Doesn’t display weakness, ataxia, or deficits in sensory function. Arises around 40, results in death after 10-20 years. A selective loss of MSNs in the indirect path, resulting in loss of indirect path inhibition
Hemiballismus: A hyperkinetic disorder, involves involuntary movements of the limbs. A result of damage to the subthalamic nucleus, resulting in overstimulation of the motor cortex
Bicuculline: A GABA antagonist, when injected into monkey SNr the caudate is no longer able to release GABA to inhibit tonic activity to the superior colliculus, increasing tonic inhibition and leading to slower and fewer saccades (like Parkinson’s)
Muscimol: A GABA agonist, when injected into the SNr decreases inhibition of the superior colliculus and causes multiple spontaneous saccades
Cerebellum: Can influence motor behavior, detects the motor error (difference between intended and actual movements). Also reduces error by signaling UMNs during the course of movement causing motor learning when the correlation is stored. Also plays roles in cognition, emotion, and autonomic processes. Has 3 layers of cortex on the surface, contains nuclei deep in white matter, with each hemisphere (anterior and posterior) having 4 (fastigial, emboliform, globose, dentate) and divided by the vermis/primary fissure. Divided functionally into 3 sections (cerebrocerebellum, spinocerebellum, vestibulocerebellum). Gets input from the cortex via the pontine nuclei and red nucleus → inferior olive. Also receives proprioceptive signals from the external cuneate nucleus and the dorsal nucleus of Clarke. Input also comes from the vestibular nuclei and vestibular apparatus. Neurons make excitatory synapses in the deep cerebellar nuclei and the cerebellar cortex. Projects to UMNs in the motor cortex (via VA/VL complex), superior colliculus, reticular formation, and vestibular nuclei (directly from purkinje cells). Also projects to the inferior olive via the red nucleus. All functional divisions of the cerebellar cortex can influence brainstem sources UMNs, like the reticular formation via medial/lateral reticulospinal tracts (for balance), vestibular nuclei (bypassing the deep cerebellar nuclei) via vestibulospinal tracts (for VOR), superior colliculus via tectospinal tract (for head orientation and audiovisual reflexes) and saccades
Cerebrocerebellum: Uses the dentate nucleus and superior/middle peduncles, contains lateral areas of each hemisphere, gets input directly from the cerebellar cortex (pontine nuclei and inferior olive). Functionally associated with the dentate nuclei, functions in planning/execution of highly skilled movements (like speech), as well as in emotions and cognition. Damage can also show deficits in sequences of highly skilled movements like speech and playing instruments, or difficulty learning new motor skills
Spinocerebellum: Uses the interposed nuclei and the inferior peduncle, medial compared to the cerebrocerebellum, contains the paravermis (outputs to distal muscles) and vermis (outputs to proximal muscles and the eyes). Only part of the cerebellum with somatotopicity. Gets input from the somatosensory, motor, auditory, and visual cortices. Associated with the interposed (emboliform and globose) nuclei. Damage to the anterior vermis shows a wide-based gait and shuffling movements in place of walking, often as a result of long-term alcohol disuse disorder. Damage can also cause cerebellar motor syndrome
Vestibulocerebellum: Uses the fastigial nuclei and the interior peduncle, contains the flocculus and nodulus, gets input from vestibular nuclei. Associated with the fastigial nuclei, can directly project to the vestibular nuclei. Functions in the VOR and balance/posture. Damage causes nystagmus and interferes with muscle tone to result in difficulties standing upright
Nuclei of the cerebellum:
Fastigial (medial): Oldest
Interposed (usually fused): Inputs come through here and then into the cerebellum, fused in non-humans
Emboliform
Globose
Dentate (lateral): Newest
Cerebellar processing: Entering neurons make two excitatory synapses, on the deep cerebellar nuclei and the cerebellar cortex. Purkinje cells in the cerebellar cortex inhibit the deep cerebellar nuclei, the deep cerebellar nuclei is the source of most of the cerebellar projections with output based on balancing direct excitation of nuclei with inhibitory synapses from Purkinje cells after processing in the cerebellar cortex
Cerebellar circuits: Projection neurons carry signals to the cortex via excitatory connections using glutamate, for example mossy fibers with synapse on granule cells. This is used with all cerebellar input except those from the inferior olive. Granule cell axons form parallel fibers which synapse on Purkinje cells, along with climbing fibers from the contralateral inferior olive. Purkinje cells then carry information from the cortex and are inhibitory using GABA
Inhibitory local circuit neurons: Involve granule cells and parallel fibers. They have golgi cells that make reciprocal synapses with granule cells. Basket cells and stellate cells are excited by parallel fibers but inhibit Purkinje cells
Inferior olive: Contains projections from the red nucleus, projects to the cerebrocerebellar cortex. Axons from here form climbing fibers, which form synapses onto Purkinje cells in the cortex. They fire infrequently onto AMPA-like receptors (1-2 Hz) but produce strong and extended depolarizations by opening Ca2+ channels. Form multiple synapses with a single cell, and make a complex spike. These climbing fibers are necessary for both error correction and motor learning
Mossy fiber: Formed by axons projecting to the cerebellar cortex, synapse on granule cells
Granule cell: Axons are parallel fibers, carry glutamate (excitatory) and synapse on Purkinje cells in the cerebellar cortex, form single synapses onto multiple cells, making “simple” spikes at 30-100 Hz. Make reciprocal connections with Golgi cells
Purkinje cell: In the cerebellar cortex, receive input from parallel fibers. Fire frequently onto AMPA-like receptors and mGluR (Gq) to produce weak depolarizations and cause Ca2+ to be released from the ER. Also project to the vestibular nuclei and deep cerebellar nuclei. Synapses onto these cells are glutamatergic. Synapses created from these cells are GABAergic, and onto deep cerebellar nuclei. Only source of output for the cerebellar cortex
Purkinje module: Provides real-time corrections of errors and allows for motor learning. Purkinje cells and deep cerebellar nuclei compare patterns of motion (convergent activity), and recognize errors. These errors are corrected by deep cerebellar nuclei, which influence UMNs
Motor learning: Possible due to Purkinje modules, demonstrated by experiments where monkeys are trained to make saccades to a target. The lateral rectus of one eye is lesioned which disrupts ability to fixate on a target. Covering the intact eye shows adjustment of the lesioned eye, though lesions in the vermis erase this motor learning. Moving a visual image on the retina (after being altered by a lens) allows the VOR to adjust. After a few trials, activity in the deep cerebellar nuclei and Purkinje cells is altered, cerebellar lesions block the VOR
Ataxia: Characterized by difficulty producing smooth, well coordinated, precisely directed, and multi-jointed movements. Errors are ipsilateral to the side of cerebellar damage, specific deficits are related to the location of the damage, these deficits are similar for both incoming projections to and outgoing projections from the cerebellum
Nystagmus: Caused by damage to the vestibulocerebellum, characterized by impaired gaze maintenance
Cerebellar motor syndrome: Characterized by motor ataxia, dysmetria and intention tremors, wide-based gait/shuffling, and dysdiadochokinesia
Schmahmann’s/Cerebellar cognitive-affective syndrome: Caused by lesions of the lateral posterior lobes of the cerebellum. Motor coordination is in tact, but executive function is impaired. There are difficulties with visual-spatial processing, impaired linguistic skills, and disordered regulation of affect. May be related to connections between the prefrontal lobe and the posterolateral cerebellum.
Peduncles to/from the cerebellum: Only ways information gets to the cerebellum
Superior cerebellar peduncle: Contains projections from the cerebellum to the cortex via the VA/VL thalamic nuclei, superior colliculus, and red nucleus. Contains part of the ventral spinocerebellar tract, bringing information from GTOs of the lower body to the cerebellum (with double decussation)
Middle cerebellar peduncle: Contains cortical projections to the cerebellum via the deep pontine nuclei
Inferior cerebellar peduncle: Contains projections from the cortex via the inferior olive (or climbing fibers), from the vestibular nuclei and apparatus, and from the dorsal spinocerebellar and cuneocerebellar tracts (proprioceptive tracts). Projects to the vestibular nuclei and reticular formation (with UMNs)
