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Lecture 5

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Rutsuko Ito

Lecture 05 Synaptic organization of the basal ganglia Lecture outline: 1. Anatomy and function of basal ganglia a. Multifaceted functions i. Basal ganglia is not only associated with motor function ii. it is one of the most oldest structures b. Neural circuitry 2. Afferent input to striatal principal neurons a. Medium spiny neurons (MSN) b. Intrinsic properties of MSN, interneurons c. Dopaminergic input d. Patch / matrix pathways 3. Output from the basal ganglia a. Direct / indirect pathways b. Dopamine action and function Basal ganglia anatomy Basal ganglia components 1. Four sets of nuclei a. Striatum i. Caudate ii. Putamen b. Globus pallidus i. Internal GP ii. External GP c. Subthalamic nucleus i. STN d. Substantia nigra (SN) i. Pars compacta (SNc) 1. Source of dopamine neurons ii. Pars reticulata (SNr) 1. Source of output of BG Striatum and subdivisions 1. Ventral striatum a. Nucleus accumbens i. AKA ventral striatum 2. Dorsal striatum a. Putamen b. Caudate Cross species homology 1. BG fundamentally important structure 2. Not directly connected to any motor / sensory structures in the brain What is the function of the basal ganglia? 1. Control over movement 2. Action selection 3. Procedural learning 4. Reward learning 5. Executive functions a. e.g. working memory, behavioral flexibility i. More associated with prefrontal areas 6. Sensorimotor integration a. Ability to integrate information from sensory and motor areas and convert them into meaningful behavior 7. Limbic motor integration a. Limbic i. Amygdala ii. Hippocampus b. Learning associated with limbic system c. Integrate and connect information regarding emotions into meaningful behaviors Multifaceted functions 1. Competing input selection a. Select and sequence internally generated motor programs for posture and voluntary movements 2. Limbic motor interface a. Select a goal; i. The actions to achieve the goal ii. The movement to achieve the actions 3. Learning a. Associating cues with actions and outcome of actions for optimising responses to changes in environment 4. Cognition a. Behavioral flexibility i. Changing behavior to different circumstances b. Working memory Functional cortico-striatal-thalamic loops 1. The basal ganglia is intimately linked to the sensory, motor, cognitive and motivational apparatus of the brain Somatotopic organization - motor circuit 1. Arrows indicate topographically organized pathways that link the respective 'arm' representations at different stages of the circuit 2. Thalamo-cortico-striatal circuit 1. Important in selecting what actions you will make 2. Cortex  basal ganglia  thalamus  behavioral output 3. Cortex  thalamus  basal ganglia thalamus  behavioral output 4. Basal ganglia  thalamus  cortex  thalamus  behavioral output 5. Basal ganglia a. Can intervene in selecting some motor plan to affect behavior i. E.g. inhibiting the thalamus Detailed connectivity Afferent input to striatal principal neurons Medium spiny neurons (MSN) 1. Cortical (glutamatergic) input terminates on dendrites of medium spiny neurons (MSN), which are principal neurons of the striatum (~90%) 2. Each MSN receives convergent input from many cortical neurons originating in functionally related (and interconnected) cortical areas 3. MSNs are GABAergic (unlike other principal neurons) with two types of peptide expression (peptides that co-localize with GABA) a. Substance P / Dynorphin b. Enkephalin i. Indirect pathway More facts about spiny neurons 1. A spiny neuron has approximately 25-30 dendritic terminal branches radiating from cell body 2. Spines first appear at about 20 um from the soma a. Peak in density at about 80 um (4-6 spines / um) b. Taper off in density at distal sites 3. Repeated administration of drugs of abuse such as amphetamine can increase the density of spines on striatal MSN at distal dendritic sites a. What does this mean? i. Distal dendritic sites receive cortico-thalamic input 1. Therefore there could be more innervation at cortico-thalamic structures ii. Learning is associated with increase in spines iii. Spines exist in areas that function in learning 1. How? -- still uncertain Distribution of synaptic inputs to MSN 1. Every MSN neuron receives about 11000 synaptic contacts from cortex and thalamus 2. Over 90% of cortical inputs end on spines a. Not dendritic shaft or cell bodies b. Source of a lot of dopaminergic input? 3. External inputs tend to terminate on more distal parts of the dendritic tree 4. Local inputs (other MSNs / interneurons) tend to terminate on proximal parts of the dendritic shaft / cell body (more inhibitory power) Intrinsic properties of MSN and interneurons Intrinsic properties of MSN 1. Resting membrane potential is close to E (-80Kto -90 mV in the striatum) a. Suggests high permeability / conductance to K+ ions at rest 2. High K+ conductance is mediated by K voltair sensitive inward rectifying channels that are permeable to K+ at hyperpolarized potentials a. BUT blocked by intracellular polyamines (e.g. spermine) and Mg2+ at depolarized potentials MSN excitability 1. MSN neurons are usually silent at resting state because they are highly hyperpolarized 2. MSN neurons require highly convergent and simultaneous input from the cortex (i.e. coactivation of many cortical neurons and lots of EPSPs) to depolarize Ramp-like depolarizing response 1. Depolarization of spiny neurons by current injection induces a long lasting plateau potential 2. The depolarization response is slow due to activation of a slow non-inactivating (persistent) Na+ channel and slow inactivation of K+ channel called I . Af a. Other non-inactivating K+ channels (I / I ) open with depolarization to stabilize As Kpersistent the membrane potential at around -60 mV 3. With TTX, rise of the plateau is significantly decreased 4. With TTX + 4-AP 5. Channels come together to generate currents to give rise to the slow depolarizing current Bi-stable membrane potential 1. Striatal spiny neurons have a bi-stable resting membrane potential 2. The 'down' hyperpolarized state is dominated by inwardly rectifying conductance (g ) irk 3. The 'up' depolarized state is dominated by slowly activating Na+ current, offset by outward K+ conductance a. The upstate is the excitable state b. MSN neurons can fire AP 'Up' state activity 1. Up states are associated with the following channel activations a. NMDAR activation (also AMPAR) yielding slower excitatory potentials that summate more readily b. Low voltage activated L-type Ca2+ channel activation i. Also mediates the slow rise 2. Electronic changes in dendritic tree during synaptic excitation 1. Down state a. Rm is low due to fast K+ conductance i. If Rm is low, its less excitable b. Electronic length of the dendrite is long c. Synaptic inputs at dendritic sites therefore have little or no impact on soma EPSP 2. Intermediate state a. Transition from down to up state b. As a larger number of synapses depolarize, the I beK+ns to turn off i. Increasing the Rm c. The electronic length of the dendrites will decrease i. Rendering the neuron more sensitive to subsequent inputs 1. Most likely to be excited by dendritic input 3. Up state a. As the Vm approaches spike threshold, the depolarization activated K+ currents turn on b. The electronic length increases c. Vm stabilizes at -60 mV d. Most excitable period; but it is also when Rm begins to decrease i.  Return to down state Striatal interneurons 1. Receive glutamatergic inputs from cortex / thalamus a. Targets MSNs and other interneurons 2. Cholinergic interneuron (less than 2%) a. Often mistaken for being principal cells because of its large size b. Few thick, aspiny dendrites c. Prominent axonal arborisation d. High spontaneous activity 3. Somatostatin / nitric oxide synthase - containing interneuron (less than 2%) a. 3-5 thick aspiny dendrites b. Least dense axonal arborisation i. Axonal branching vs dendritic branching c. Longest axon d. Spontaneous activity 4. GABA / parvalbumin - containing interneuron (3-5%) a. Heterogeneous group of interneurons b. Medium sized c. Few thick dendrites d. Little axonal arborisation e. Long axons f. Very sparse, spread apart g. 5-8 aspiny dendrites h. Form dendro-dendritic gap junctions with other PV+ dendrites for synchronous firing GABA interneurons 1. Most important regulator of MSN firing? a. Single MSN receives 4-27 inputs from GABA interneurons (main regulator) b. Its activity can delay onset of firing and reduce spiking activity in MSN 2. GABA interneurons a. Fast AP b. High rates of firing (200 spikes / s) c. Little spike frequency adaptation i. They just keep firing d. Linear I/V relationship e. Enriched in dorsolateral striatum - important for sensorimotor integration? Dopaminergic input Nigrostriatal input to MSN Distribution of dopaminergic synaptic contacts 1. Dopaminergic inputs end up on spines 2. Dopaminergic terminals can be identified immunihistochemically by using antibodies to tyrosine hydroxylase (TH - the first enzyme in catecholamine biosynthesis which catalyzes the conversion from L-tyrosine to L-DOPA) as a marker 3. Each MSN neuron receives ~300 DA synapses 4. Only just over half of synaptic inputs terminate on spines Synaptic convergence of afferents 1. MSN spines receive co-localized inputs from glutamate and dopamine terminals 2. a Dopamine / acetylcholine interaction 1. Due to spontaneous activity in cholinergic neurons, there is an ongoing Ach signal that is usually rapidly terminated by AChE (acetylcholinesterase) 2. M1R activation enhances NMDAR mediated currents a. M2/M3R activation of presynaptic Glu cell causes inhibition of Glu release b. Presynaptic nAChR activation enhances Glu release 3. Dopamine (acting via D2R) inhibits striatal ACh efflu
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