Basal Ganglia Circuits PDF

Basal Ganglia Circuits Dr Sam Merlin Basal: Forming or belonging to a bottom layer or base Ganglia: Neuronal cell bodies in the peripheral nervous system Learning Objectives By the end of the lecture you will be able to: Identify the location of basal ganglia nuclei Describe the connections...

Basal Ganglia Circuits Dr Sam Merlin Basal: Forming or belonging to a bottom layer or base Ganglia: Neuronal cell bodies in the peripheral nervous system Learning Objectives By the end of the lecture you will be able to: Identify the location of basal ganglia nuclei Describe the connections between basal ganglia nuclei and how they interact with the cortex to regulate movement (motor loop) Describe the outcomes of basal ganglia dysfunction (i.e., Parkinson’s disease, hemiballismus & Huntington’s disease) Explain experimental approaches to testing basal ganglia function in animal models Motor Control Prefrontal cortex Parieto-occipito- temporal association area Basal Ganglia Striatum (caudate/putamen) Telencephalon Globus pallidus (internal/external) Telencephalon Subthalamic nucleus Diencephalon Substantia nigra (reticulata) Mesencephalon Basal Ganglia Striatum (caudate/putamen) Globus pallidus (internal/external) Subthalamic nucleus Substantia nigra (reticulata) Subthalamic nucleus Substantia nigra Basal Ganglia Terminology Dorsal striatum (caudate/putamen) Ventral striatum (nucleus accumbens) Globus pallidus (internal/external) Ventral pallidum Subthalamic nucleus Substantia nigra (pars reticulata) Various names to various grouping of nuclei Striatum- appearance/origin – caudate & putamen (dorsal) /nucleus accumbens (ventral) Lentiform nucleus – adjacent/shape - putamen & globus pallidus Corpus striatum- caudate & putamen & globus pallidus Pallidum- globus pallidus & ventral pallidum Coronal Section Striatum (caudate/putamen)(accumbens) Globus pallidus (internal/external) Subthalamic nucleus Substantia nigra (reticulata) Corpus Callosum Lateral ventricle Dorsal striatum Internal capsule Head of caudate Putamen Ventral striatum Nucleus accumbens Striatum Dorsal striatum Caudate Corpus Callosum Lateral ventricle Internal capsule Putamen Ventral striatum Nucleus accumbens Striatum is latin for striped Striatum Dorsal striatum Caudate Corpus Callosum Lateral ventricle Internal capsule Putamen Ventral striatum Nucleus accumbens Striatum Medium spiny neurons‐ GABAergic neurons Dorsal striatum: caudate & putamen Ventral striatum: nucleus accumbens Anatomically similar Neurochemically similar Functionally similar Two separate populations of neurons Caudate Putamen Accumbens. 2011 Sep 6;5:58. doi: 10.3389/fnana.2011.00058. eCollection 2011. Coronal Section Striatum (caudate/putamen) Globus pallidus (internal/external) Subthalamic nucleus Substantia nigra (reticulata) Corpus Callosum Lateral ventricle Internal capsule External capsule Globus Body of Putamen Pallidus caudate External/internal parts  Globus Pallidus Striatum (caudate/putamen) Globus pallidus (internal/external) Subthalamic nucleus Substantia nigra (reticulata) Corpus Callosum Lateral ventricle Globus Internal capsule Pallidus External/internal External parts capsule Pallidus is latin for pale GPi and GPe have high tonic firing rates (spontaneously active) GABAergic neurons (inhibit downstream structures) Coronal Section Body of caudate Putamen Corpus Callosum Globus Lateral ventricle Pallidus Internal capsule External/internal parts External capsule Thalamus Not part of basal ganglia Lateral ventricle‐ Inferior horn Subthalamic nucleus Substantia nigra  Subthalamic Nucleus Thalamus Not part of basal ganglia Corpus Callosum Subthalamic Lateral ventricle nucleus Internal capsule Substantia External capsule nigra Lateral ventricle‐ Subthalamic nucleus Inferior Part of the subthalamus horn Produces glutamate (activates downstream structures) Subthalamic Nucleus Corpus Callosum Lateral ventricle External capsule VL Lateral ventricle‐ Inferior horn Coronal Section Striatum (caudate/putamen) Globus pallidus (internal/external) Subthalamic nucleus Corpus Callosum Lateral ventricle Substantia nigra (reticulata) Internal capsule Thalamus Not part of basal ganglia Body & tail Lateral ventricle‐ Inferior horn of caudate Substantia Putamen nigra Substantia Nigra Part of the midbrain (and subthalamus) Consists of pars compacta (SNc) - produces dopamine pars reticulata (SNr) - produces GABA, tonically Corpus Callosum active Lateral ventricle Ventral tegmental area (VTA) - homologue of SNc Internal capsule in reward loop SNc Lateral ventricle‐ SNr Inferior horn Substantia Nigra Corpus Callosum Lateral ventricle Internal capsule Lateral ventricle‐ Inferior horn Horizontal Section Corpus Callosum: genu Lateral ventricle Internal capsule – anterior limb genu Posterior limb Head & tail of Globus Thalamus Putamen caudate Pallidus Summary Striatum - Caudate, putamen, Body of accumbens (GABA) caudate Globus Pallidus - external/internal Putamen parts, ventral pallidum (GABA) Corpus Callosum Lateral ventricle Subthalamic nucleus (Glut) Globus Internal capsule Substantia nigra - reticulata (GABA), Pallidus External compacta (Dopamine), VTA External/internal parts capsule (Dopamine) Subthalamic Lateral ventricle‐ nucleus Inferior horn Substantia nigra Learning Objectives By the end of the lecture you will be able to: Identify the location of basal ganglia nuclei Describe the connections between basal ganglia nuclei and how they interact with the cortex to regulate movement (motor loop) Describe the outcomes of basal ganglia dysfunction (e.g., Parkinson’s disease & Huntington’s disease) Explain experimental approaches to testing basal ganglia function in animal models Functional Loops Basal ganglia regulate cortical activity through loops with the thalamus cortex → basal ganglia → thalamus → cortex Basal ganglia receives robust input from the cortex Basal Ganglia Basal ganglia projects back to the cortex via the thalamus Functional Loops Basal ganglia regulate cortical activity through loops with the thalamus cortex → basal ganglia → thalamus → cortex Input nuclei Input nuclei are the striatum (caudate, putamen, accumbens) Basal Ganglia Output nuclei are the GPi/SNr Output nuclei Globus pallidus, internus (GPi) Substantia nigra, reticulata (SNr) Functional Loops Parallel loops subserve different functions Cortex → basal ganglia → thalamus → cortex 4 functional loops: Motor loop: modulates the initiation, termination and amplitude of movement, as well as selection of a movement & ‘motor plans’ - “procedural learning” Oculomotor loop: voluntary eye saccades Executive/associative loop: cognitive functions: attention, planning, foresight, learning, self control, flexible thinking, reasoning, problem solving. Limbic loop: emotion, motivated behaviours, & reward Different parts of cortex, basal ganglia and thalamus contributing to the 4 different loops  Functional Loops Input nuclei: striatum Basal ganglia Output nuclei: GPi/SNr Functional Loops Motor Loop Modulates the initiation, termination and amplitude of movement, as well as selection of a movement & ‘motor plans’ Motor cortex → putamen → GPi → VL and VA thalamus → motor cortex Basal ganglia influences motor cortex (not motor neurons directly) Motor cortex → descending motor pathways, e.g., corticospinal Motor Loop Basal ganglia regulate cortical activity through loops with the thalamus cortex → basal ganglia → thalamus → cortex Signal for volitional movement is generated in the cortex The cortex needs to “check with” the basal ganglia. Input nuclei of BG is the striatum Basal ganglia projects back to cortex via the thalamus Output nuclei are the GPi/SNr GABA/inhibitory neuron Glutamate/excitatory neuron Motor Loop The thalamus needs to activate the cortex to allow for movement to occur. Thalamus targets the motor-associated areas of the cortex. Output nuclei (of BG) control thalamus The thalamus produces glutamate (excites cortex) Output nuclei of the basal ganglia are inhibitory (GABA) Output nuclei have high tonic firing rates → suppressing activity in target regions GABA/inhibitory neuron Glutamate/excitatory neuron Motor Loop Output nuclei have high tonic firing rates → prevents activation of neurons in the thalamus and in turn the cortex Thalamus is tonically inhibited Movement does not occur Inhibit the inhibitor in order for movement to occur BG modulates movement through disinhibition The thalamus becomes active when the inhibition on it is prevented GABA/inhibitory neuron Glutamate/excitatory neuron Motor Loop Inhibit the inhibitor in order for movement to occur BG modulates movement through disinhibition The thalamus becomes active when the inhibition on it is prevented Inhibit the activity in the GPi/SNr → movement GABA/inhibitory neuron Glutamate/excitatory neuron Intrinsic BG pathways Input nuclei are the striatum Output nuclei are the GPi/SNr Direct pathway: directly from input nuclei to output nuclei Indirect pathway: indirectly from input nuclei to output nuclei via globus pallidus externus (GPe) and subthalamic nucleus (STN) Direct pathway – “go” facilitates movement Indirect pathway – “stop” inhibits movement GABA/inhibitory neuron Glutamate/excitatory neuron Striatum Consists of caudate & putamen (or nucleus accumbens) Main input structure to basal ganglia: receives Indirect Direct inputs from cortex & brainstem pathway pathway 95% of neurons within the striatum are medium spiny neurons (MSNs)- GABA producing neurons (50% form direct pathway, 50% form indirect pathway GABA/inhibitory neuron Projects within the basal ganglia to: GPe (direct pathway) & GPi/SNr (indirect pathway) Direct pathway: express D1 receptors Indirect pathway: express D2 receptors Dopamine Dopamine receptors (G-protein coupled receptors) D1 - Gs Protein (excitatory) D2 - Gi Protein (inhibitory) D1 expressed exclusively on direct pathway MSNs D2 expressed exclusively on indirect pathway MSNs Dopamine promotes direct activation → therefore, movement Glutamate conductance Direct Pathway Movement requires inhibition of basal ganglia output nuclei i.e., Inhibit GPi/SNr Cortical excitation ( ) drives discharge in the striatum ( ) This causes a transient inhibition of GPi/SNr firing (due to the release of GABA by the striatum). Activation of the direct pathway promotes action GABA/inhibitory neuron Glutamate/excitatory neuron Direct Pathway Movement requires inhibition of basal ganglia output nuclei i.e., Inhibit GPi/SNr Cortical excitation ( ) drives discharge in the striatum ( ) This causes a transient inhibition of GPi/SNr firing (due to the release of GABA by the striatum). Activation of the direct pathway promotes action GABA/inhibitory neuron Glutamate/excitatory neuron Indirect Pathway Movement requires inhibition of basal ganglia (BG) output nuclei More active BG output nuclei will inhibit movement During movement, cortical excitation drives the striatum Note GPe & GPi are tonically active Indirect Pathway Cortical activation ( ) leads to activation of the striatum ( ) Indirect Pathway Cortical activation ( ) leads to activation of the striatum ( ) Transient activation of D2 striatal neurons ( ) Indirect Pathway Cortical activation ( ) leads to activation of the striatum ( ) Transient activation of D2 striatal neurons ( ) Disinhibition of STN ( ) Indirect Pathway Cortical activation ( ) leads to activation of the striatum ( ) Transient activation of D2 striatal neurons ( ) Disinhibition of STN ( ) Increase in firing of GPi Inhibition of thalamus Direct vs Indirect Direct pathway “go” promotes movement Indirect pathway “stop” suppresses movement Balance is what matters Dopamine signals the intention for movement Functional Loops Learning Objectives By the end of the lecture you will be able to: Identify the location of basal ganglia nuclei Describe the connections between basal ganglia nuclei and how they interact with the cortex to regulate movement (motor loop) Describe the outcomes of basal ganglia dysfunction (e.g., Parkinson’s disease, hemiballismus & Huntington’s disease) Explain experimental approaches to testing basal ganglia function in animal models Basal Ganglia Dysfunction Two types of dysfunctions: Erroneous or inappropriate motor loop (habit) formation Addiction Tourette Syndrome OCD Schizophrenia Pathological changes to basal ganglia Parkinson Disease Hemiballismus Huntington Disease Habit Formation Habits are beneficial Learning utilises reward, and associative (goal-directed) loops Cognitively demanding Well-learned behaviours form habits Reduced cognitive demand Once learned difficult to unlearn Addiction Same learning circuit Reward and goal-directed loops responsible early Motor (habit) loop forms after repeated use Inflexible Not goal-directed Stimulus driven Tourette Syndrome Gilles de la Tourette’s syndrome Verbal or physical ‘ticks’ are motor programs that have erroneously formed Stimulus driven - an automated response to an environmental cue OCD Obsessive-compulsive disorder Motor program Possibly influenced by abnormal reward loop to prefrontal cortex loops Dyskinesias Hypokinetic Disorders Hyperkinetic Disorders Imbalance- toward indirect Imbalance- toward direct pathway pathway Reduced movement Increased movement Parkinson’s disease Hemiballismus Huntington’s chorea Parkinson’s Disease Primary/cardinal symptoms: Bradykinesia: decreased amplitude and velocity of movement Akinesia: difficulty with movement initiation Rigidity (muscle resistance. No change to reflexes) Resting tremor (4-6 Hz, ‘pin-rolling’) Other motor symptoms: Flexed posture, postural instability, impaired gait (shuffling steps, no arm swing), ↓ facial expression, ↓ blinking, ↓automaticity of movement, vocal impairment, small handwriting, ↓ swallowing Parkinson’s Disease Degeneration of SNc, dopamine neurons → striatum 70-80% loss of dopamine → motor symptoms Degeneration not limited to SNc Reduced neuromelanin in SNc in PD olfactory bulb, DMNVX, raphe, locus Purves, Neuroscience, Fig 18.9 coeruleus, reticular nuclei cortex, thalamus, basal ganglia Lewy body formation in SNc alpha synuclein Lewy body in SN revealed by staining for alpha synuclein Parkinson’s Disease Direct pathway facilitates movement Indirect pathway suppresses movement indirect direct What happens when there is no dopamine? → reduced activity in direct pathway, and increased activity in the indirect pathway → increased BG output → reduced movement (bradykinesia & akinesia) Hemiballismus Hyperkinetic disorder Contralateral damage to subthalamic nucleus Uncontrollable ballistic movements of the arm or leg (on one side of the body). Hemiballismus Example of lesion of subthalamic nucleus (due to tumour) Also occurs as a result of a vascular lesion Hemiballismus Direct pathway facilitates movement Indirect pathway suppresses movement indirect direct What happens when there is no subthalamic nucleus? → STN no longer activating the GPi (indirect pathway) → less inhibition by GPi of thalamus, and un-opposed direct pathway → too much movement (involuntary flailing of limbs) Hemiballismus Chorea Huntington’s disease Control Hyperkinetic disorder Chorea means dance e.g. Huntington’s disease Involuntary, irregular, and purposeless movements of limbs, face, & tongue (chorea or athetosis) Genetic disorder → loss of striatal neurons (D2) projecting to GPe (impaired indirect pathway)  Chorea Direct pathway facilitates movement Indirect pathway suppresses movement indirect direct What happens when there is no indirect pathway from striatum? → Reduced inhibition by GPe → increased inhibition of STN → reduced activity in GPi (from indirect pathway/ STN no longer activating the GPi) and unopposed direct pathway → too much movement (chorea/athetosis ) Learning Objectives By the end of the lecture you will be able to: Identify the location of basal ganglia nuclei Describe the connections between basal ganglia nuclei and how they interact with the cortex to regulate movement (motor loop) Describe the outcomes of basal ganglia dysfunction (e.g., Parkinson’s disease, hemiballismus & Huntington’s disease) Explain experimental approaches to testing basal ganglia function in animal models Identifiable Circuits Animal Models Genetic models Induced models DJ1 6OHDA PRKN MPTP SNCA Rotenone (pesticides) PINK1 Virally-mediated LRRK2 Animal Models Motor Tests Open field Tapered Beam-crossing Grip strength Balance  Animal Models Cognitive Tests Operant chambers Goal-directed Habitual Fear-conditioning Pellet Sucrose Right Left lever lever  Animal Models Outcome devaluation task Devaluing one reward, should reduce lever pressing 30 Free-feed to satiety 25 Sucrose 20 Lever presses es Non- Devalued n 15 o yes noyes noyes noyes noyes devalued 10 * Devalue pellets  5 0 Non- Devalued Non- Devalued devalued lever devalued lever lever lever  Animal Models Stimulus-driven not outcome driven Devalued food does not affect lever pressing n es o yes noyes noyes noyes noyes 30 25 20 Lever presses 15 Pellet Sucrose 10 * 5 Left Right lever lever 0 Non- Devalued Non- Devalued devalued lever devalued lever lever lever Histology