Lecture 5 Notes.docx

Lecture 5 Notes Synaptic organization of the basal ganglia Basal ganglia: A group of interconnected subcortical nuclei in the mammalian forebrain and midbrain. None of the nuclei are directly connected to the sensorimotor organs. However, the basal ganglia are commonly linked to the control of movement implicated in neurodegenerative diseases associated with the basal ganglia: 1. Parkinson's a. Rigidity b. Pausity of movement 2. Huntinton's a. Emission of unintended movements Basal ganglia has multifaceted functions: 1. Motor control 2. Reward learning 3. Executive functions a. Working memory b. Behavioral flexibility 4. Sensorimotor integration 5. Limbicmotor integration Common theme in basal ganglia: Involved in the selection of certain motor plans, strategies, goals, sensory and limbic information, while inhibiting others Basal ganglia components: 1. Striatum a. Caudate nucleus b. Putamen 2. Globus pallidus 3. Subthalamic nucleus 4. Substantia nigra Striatum: 1. Largest part of the basal ganglia 2. The main input nucleus receiving excitatory glutamatergic input from the cortex (corticostriatal inputs) and thalamus Nucleus accumbens: 1. Known as the ventral striatum 2. Plays an important role in learning and motivational processes (limbic-motor integration) Dorsal striatum: 1. Composed of a. Caudate b. Putamen 2. Implicated in certain types of learning a. Procedural learning b. Habit (stimulus-response) learning c. Sensorimotor integration Globus pallidus 1. Composed of a. Internal segment (GPi) i. One of two output nuclei that send inhibitory projections to the thalamus b. External segment (GPe) Basal ganglia projections 1. Striatum sends inhibitory (GABAergic) projections to both GPe and GPi Substantia nigra 1. Composed of two divisions a. Pars compacta (SNc) i. Projects to the striatum (except the nucleus accumbens) ii. Releases the neurotransmitter dopamine 1. Dopamine is vital for the functioning of the basal ganglia b. Pars reticulata (SNr) i. One of two output nuclei that send inhibitory projections to the thalamus Ventral tegmental area 1. Located near the SNc 2. It is a cluster of dopaminergic neurons that project to the nucleus accumbens (ventral striatum) Connections to other brain areas 1. Basal ganglia are not directly connected to sensory and motor organs 2. Basal ganglia are instead intimately linked to the sensory, motor, cognitive, and motivational apparatus of the brain through their cortico-thalamic connections 3. The mammalian brain is organized into parallel, segregated cortico-striatal-thalamic loops which mediate different functions a. The pathways connect topographically relevant regions at each stage of the loop Cortico-striatal-thalamic loop 1. Can be thought to provide a mechanism by which behavioral output can be inhibited 2. Thalamus and cortex are reciprocally connected and mutually excite one another via the thalamocortical loop a. Sensory / motor / motivational information gets relayed to the cortex via the thalamus b. Returns to the thalamus as 'plans of action' c. Cortex also sends an excitatory projection to the basal ganglia i. The basal ganglia serves as a relay station in transmitting inhibitory signals to the thalamus ii. This circuit serves as an inhibitory 'side loop' by which information represented in the thalamocortical loop ('plans') could be inhibited from being implemented via the basal ganglia Net effect of basal ganglia output 1. Dependent on the outcome of a complex series of information processing within the basal ganglia themselves (nuclei of the basal ganglia) Model of the cortical-striatal-thalamic loop 1. The cortex sends excitatory projections to the striatum 2. The striatum projects via two pathways a. Direct i. Projection to GPi and SNr ii. Send inhibitory axons to the thalamus b. Indirect i. Projection to GPe ii. Sends an inhibitory projection to the STN 1. The STN (subthalamic nucleus) sends excitatory projections to the GP a. GPe b. GPi + SNr c. The SNc projects to the striatum GPe and STN i. The SNc axons release dopamine 3. Both pathways are inhibitory Cortical inputs to the striatum Medium spiny neurons (MSN) 1. Principal neurons of the striatum 2. Large number of dendritic spines 3. Constitute around 90% of the cells in the striatum 4. Each MSN receives convergent input from thousands of cortical neurons (11000) originating in functionally related (interconnected) cortical areas 5. GABAergic (unlike other principal neurons) 6. Segregation of peptide expression (peptides that co-localize with GABA) a. Nigral projecting MSN neurons i. Substance P / Dynorphin 1. Co-expressed with D1 receptors in the direct pathway b. Pallidal projecting MSN neurons i. Enkephalin 1. Co-expressed with D2 receptors in the indirect pathway 7. An MSN typically has up to 30 dendritic branches radiating from the cell body a. Characteristic spines typically appear about 20 um from the soma b. Characteristic spines typically peak in density at about 80 um (4-6 spines / 1 um) c. Typically tapers off in density at distal sites d. Local inputs (i.e. other MSNs, interneurons) tend to terminate at more proximal dendritic sites Spine density and learning 1. Li et al (2003) a. Demonstrated that repeated administration of drugs of abuse such as amphetamine can induce increases in spine density on nucleus accumbens MSNs at distal dendritic sites i. Sites that cortical and thalamic glutamatergic inputs preferentially terminate ii. Establishing a direct functional link between spine changes and behavior is not easy Intrinsic membrane properties of MSN 1. Striatal spiny neurons a. Have a high resting K+ conductance i. Keeps the resting membrane potential close to E (-80Kto -90 mV in the striatum) ii. Difficult to depolarize iii. Maintained by K (irward rectifying channels) that activates with hyperpolarization 1. K irannels usually blocked by intracellular polyamines (e.g. spermine) and Mg2+ ions at depolarized potentials 2. IV relationship shows a characteristic inward rectifying shape a. Consists of i. A strong inward current at membrane potentials more negative to the reversal potential for K+ ii. A very small outward current at membrane potentials more positive to the reversal potential iii. Application of cesium chloride (blocking K chirnels) reduces the inward rectification 3. A channel that is inwardly rectifying generally a. Passes current more easily in the inward direction b. This current plays an important role in regulating neuronal activity by helping to establish the resting membrane potential of the cell c. K cirnnels also contribute a small outward current at hyperpolarized potentials to ensure a resistance to depolarization and stabilization of resting membrane potentials around E K The defining feature of MSN neuronal excitability 1. MSN neurons are usually quiescent (marked by inactivity) 2. Depolarization of MSNs require a highly convergent and simultaneous input from the cortex When spiny neurons are depolarized 1. They show a slow, long lasting plateau depolarization due to the activation of non-inactivating (persistent) Na+ channels 2. Depolarization is initially countered by a number of depolarization-activated K+ conductances 3. The rapidly inactivating I and I channels inactivate AT As 4. MSNs continue to depolarize until it reaches a plateau at -60 mV 5. The plateau occurs because of the activation of another K+ conductance non-inactivating K+ channels (IAsnd I Kpersistentat stabilizes the membrane at around -60 mV 6. End result a. Bi-stable resting potential i. Up state 1. Dominated by slowly activating Na+ current 2. Offset by outward K+ conductance 3. Associated with the activation of other channel types which provide slower EPSPs that allow temporal summation to occur more readily. a. NMDA receptors b. AMPA receptors 4. Associated with activation of low threshold L-type Ca2+ channels 5. Upstate is the excitable state ii. Down state 1. Dominated by inwardly rectifying K+ conductance (g ) irk 2. Downstate is the quiescent (inactive) state Electronic length changes in dendrites 1. The impact of synaptic input at different dendritic sites can change as a function of different states of MSN excitability a. The neuron is potentially most sensitive to synaptic inputs at different dendritic sites during the transition from down to up state when ionic conductances across the membrane are low i. Short electronic length of dendrites b. In the down state, the electronic length of dendrites is long i. The K irnductance makes the membrane 'leaky' 1. Rm is low ii. Inputs to distal dendrites are less likely to contribute to action potential generation Striatal interneurons 1. Play a role in regulating MSN activity 2. They receive glutamatergic inputs from the cortex and/or thalamus (input) 3. Remain local and innervate MSNs and other inteneurons (output) There are three major types of interneurons 1. Cholinergic neurons a. Large cells often mistaken for principal neurons b. Have few thick aspiny dendrites c. Highly arborized axons i. Axonal branching d. Show high spontaneous firing due to the expression of hyperpolarization activated cation (Ih) currents 2. Somatostatin / nitric oxide synthase containing interneurons a. 3-5 thick aspiny dendrites b. Have the least axonal arborization c. Very long axons (up to 1 mm) 3. GABA / parvalbumin containing interneurons a. Medium sized b. Aspiny neurons c. Intensely branching axonal arborizations that form 'baskets' on the soma of the spiny neurons d. Often spaced widely apart in the striatum e. Dendrites are connected together by gap junctions i. Forming a network of cells that can fire synchronously Importance of interneurons 1. Regulator of MSN activity 2. A single MSN receives 4-27 inputs from GABA interneurons 3. Serve to delay the onset of AP and reduce spiking activity 4. A single GABA interneuron can make contact with 150-500 MSNs 5. Do not show spontaneous activity at resting membrane potential a. But with stimuli above threshold, they show i. Fast spike activity with short duration AP ii. Short afterhyperpolarization iii. Ability to maintain firing at high rates (200 spikes / sec) without spike frequency adaptation 6. Seems to be particularly dense in the dorsolateral striatum a. An area implicated in sensorimotor integration Dopamine input to the striatum 1. Dopamine is vital to basal ganglia function a. Degeneration of nigrostriatal dopaminergic input to the striatum is responsible for parkinson's disease 2. Dopamine axon terminals in the striatum can be visualized readily by staining for tyrosine hydroxylase (essential for dopamine synthesis) 3. A single MSN neuron can receive around 300 dopaminergic inputs a. 59% terminate on dendritic spines i. Where there are dopaminergic inputs to the spine, there is co-localization with cortical / thalamic afferents b. 41% terminate on dendritic shafts and the soma Dopamine pathways in the brain 1. Nigrostriatal pathway a. Originates in the substantia nigra b. Innervates the caudate putamen i. Dorsal striatum 2. Mesocorticolimbic pathway a. Can be split into sub-pathways i. Mesolimbic ii. Mesocortical b. Originates in the ventral tegmental area (VTA) c. Innervates the frontal cortex, limbic areas, and nucleus accumbens (ventral striatum) Dopamine / Acetylcholine interaction 1. Striatal cholinergic interneurons are recipients of a prominent glutamatergic drive from a. Cortex and thalamic nuclei b. Dopaminergic innervations from the substantia nigra pars compacta c. Ongoing ACh signal that is usually rapidly terminated by AChE d. Cholinergic receptors regulate the activity of MSN both pre and post synaptically i. Post synaptic M1R (muscarinic) activation enhances NMDAR mediated currents 1. Promoting depolarization