THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Introduction to Neuronal NetworksChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/NeuronalNetworks.pptx

3. Aims At the end of this lecture students should be able to • explain how EEG traces arise; • recognise some cortical rhythms; • discuss the concept of cortical column and microcircuit; • illustrate how excitation is routed through microcircuit; • outline how inhibition endows microcircuit with richness; • identify how connectivity shapes processing of input signals; • recognise how excitation and inhibition can drive network patterns; and • illustrate how electrical stimulation can evoke locomotor activity in spinal patients.

4. Contents • Note of neocortical evolution • Basis of the EEG and cortical rhythms • Concept of cortical column and microcircuit • Flow of excitation in microcircuit • How inhibition is highly targeted and varied • Simple network topologies • Excitation & inhibition in a network response • Oscillations and central pattern generators • Electrical stimulation in spinal patients

5. Evolution of Neocortex • During evolution, human neocortex got increasingly larger compared to other hominoids. • Likely that ability of the human brain is based on neocortical size. • Scaling laws predict cortical size: • Input (thalamus) determines the size. • Increase in cortical volume is matched by that of thalamus. • However, neocortex is largely quite uniform despite functional specializations (V1, auditory, motor cortex, …). • How can neocortical networks be monitored? EEG. Stephens (2001), Nature 411:193-195

6. Basis of Electroencephalogram • EEG useful in about 50% of newly diagnosed epileptic patients. • Gold standard for diagnosis & therapy. • Tracks local electric fields caused by underlying currents. • A local depolarising (inward) current serves as sink to which currents from sources flow → negative polarisation in EEG. • A local hyperpolarising (outward) current represents the source from which these will find sinks → positive polarisation in EEG. • Currents are summed from activity of lots of neurons. • Currents mostly caused by synapses. • AP currents require large extent of synchronisation until visible (epilepsy): sharp waves.

7. Spatial Aspects of EEG • The underlying current flow is the determinant of the polarisation: • EPSP causes a current sink at the location of the synapses: • If synapses in layer IV, current is sourced from apical tufts → positive deflection in EEG. • If on apical tufts → negative deflection in EEG. • IPSP causes a current source at the location of synapses: • If synapses in layer IV, current is sunk from apical tufts → negative deflection in EEG. • If on apical tufts, then positive deflection in EEG. • EEG represents the spatial summation of all activity in time and space (population response). • Recordings from cortical surface: superficial layers more influential. • voltage drops off with 3rdpower…

8. Basic Properties • Electrodes placed onto defined points on scalp: • Allows for later localisation… • Rhythms identifiable • α: 8 – 12 Hz (relaxed; eyes closed). • β: 13 – 25 Hz (concentration, motor activity). • γ: 26 – 70 Hz (perception, consciousness). • δ: 0.5 – 3 Hz (slow wave sleep). • θ: 4 – 7 Hz (arousal, drowsiness). • Power of rhythms variable in different brain areas.

9. Signs of Synchronisation in EEG • Signs of synchronisation: high frequency spikes and spike and wave features. • Action potentials (cellular ‘spikes’ ~1 ms) are too brief to summate effectively and are usually not detectable on EEG. • EEG ‘spikes’ (~50 ms) correspond to highly synchronized synaptic activity and therefore follow volleys of APs.

10. The Conundrum • Mammalian neocortex has 6 layers. • Cellular composition ± uniform (modular): • Few excitatory cell types • Lots of inhibitory cell types • Santiago Ramón y Cajal(1852-1934): • Nobel price in 1906 • Cortical microcircuit is an “impenetrable jungle”. • How does a uniformly structured neocortex process sensory, cognitive and motor information? • “Multipotent” processing modules: microcircuit (µC).

11. Evidence for Microcircuit Concept

12. The Cortical Microcircuit: Excitation • “Recurrent amplifier” • Few excitatory cell types: • Pyramidal cells (PC) and • Spiny stellate cells (SSC). • Input into cortex largely from • thalamus → L4 (SSC, PC) • long-range L1 (PC) • local recurrents (SSC, PC) • Intracortical relay • from L4 → L2/3 (SSC/PC → PC) • massive recurrents (PC → PC) • L2/3 → L5 (PC → PC) • L5 → L6 (PC → PC) • Output from cortex • from L5 (PC) to BG, SC • from L6 (PC) to thalamus • locally to next column Modified from Dimitrijevicet al. (1998), Ann. N.Y. Acad. Sci. 860:360-376

13. The Cortical Microcircuit: Inhibition • As many as >36 types of interneurons – some shown • Specific in type, location and targets. • Some types electrically coupled (gap junctions). • Characterised by peptidergic co-transmitters. • BC: perisomatic inhibition • BP: basal dendrites in L2-4 • MC: inhibit apical tufts • CRC: inhibit apical tufts, in L1 • NGC: horizontal dendrites • DBC: dendritic inhibition • CHC: inhibition at initial segment • Interneurons endow MC with functional richness. Modified from Grillneret al. (2005), TIPS 28:525-533

14. Unresolved Questions • What constitutes a microcircuit (µC)? • How big is it? • Is a µC congruent with a cortical column? • Vertically oriented “module” • Smallest unit processing a single sensory modality (functional def.) • Might have a morphological correlate (blobs, barrels, etc.) • Cortical column made up of a single or several µC? • What is processed in a µC? • Feature extraction (recept. field) • Learning in network Szentágothai (1975), Brain Res 95: 475-496

15. Functional Consequences of Excitation & Inhibition Topologies: convergence, lateral inhibition. How small networks can produce rhythms. Spinal central pattern generators

16. Simple Networks • Most important in sensory afferent processing (hearing, vision, proprioception). • An excitatory PC receives ~ 10’000 synapses; number of release sites per axon is variable. • Divergence at 1st neuron; convergence at 2ndneuron. • Pro: Improve transmission of small signals requiring integration of several afferents. • Con: Loss of precision in localizing source.

17. Networks and Lateral Inhibition • Without inhibition, at each level, the frequency of discharge broadens over the whole network: summation (pro) and “smearing-out” (con). • “Fixed” with lateral inhibition, where at each level, sharpening of discharge strength to the centre occurs (strength of inhibition): emergence of centre-surround inhibition (receptive fields).

18. Networks and Oscillations Yuste et al. (2005), Nat. Rev. Neurosci. 6:477-483 • Scheme works to generate • pacemakers (~SA-node): self-autonomous (CPG, next); • excitation and inhibition (feed-back and -forward); • inhibition typically strategically located (perisomatic); and • requires AP adaptation: slowing of rate (self-limiting).

19. Examples of CPGs • At all levels of motor control (oscillators) • Spinal cord (whole program of transcription factors) • Locomotion generator • Brainstem (& high spinal cord) - incomplete • Breathing: phrenic activity • Swallowing • Chewing • Eye movements (saccades) • Basal ganglia (see Parkinson’s disease) • Cortex (fine control of movement) • Feature: • Quite autonomous • Typically require supraspinal/-brainstem command input • Modulation by cellular properties

20. Spinal Central Pattern Generator • Paraplegic patient • Stimuli of ~5 V intensity (0.2 - 0.5 ms width at 25 - 60 Hz) elicit knee movements (K.M.); alternating innerva-tion: agonists / antagonist. • A severed spinal cord can produce movement: seg-mental networks ± intact; command signals↓ from higher control centres. • Proof of concept for CPG. • Location of cells/networks currently unknown (peri-aqueductalcells?) Modified from Dimitrijevicet al. (1998), Ann. N.Y. Acad. Sci. 860:360-376

21. Take-Home Messages • EEG reflects current sources and sinks in three dimensions. • Several different rhythms can be identified in an EEG. • Cortical function likely related to processing in microcircuits. • Excitation is entering L4, relayed to L2/3, then L5 which projects outside the cortex. • A feedback loop from L6 projects to the thalamus (corticothalamic rhythms). • There is a large variety of inhibition within the microcircuit. • Oscillators emerge from interaction between excitatory and inhibitory transmission; details given by neuronal properties. • Locomotion is partly result of CGP activity. • Direct spinal stimulation can initiate locomotor activity in tetraplegicpatients.

22. MCQ Which of the following statements best describes the inability to provide excitation within a simple network (no presynaptic inhibition observed)? • Metabolic alkalosis • Na+ channel block • K+ channel activation • Hypochloraemia • AMPA receptor desensitisation

23. That’s it folks…

24. MCQ Which of the following statements best describes the inability to provide excitation within a simple network (no presynaptic inhibition observed)? • Metabolic alkalosis • Na+ channel block • K+ channel activation • Hypochloraemia • AMPA receptor desensitisation