1. 3-01-2014Neuromodualtors in CognitionVijaya Kumar 2. Overview • • • • • •What is Neuromodulation? How exactly the modulation is brought about? Brain regions involved in cognition Modulatory projections Cholinergic modulation Summary 3. Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neuronsNeuromodulators are the neurotransmitters, neuropeptides, hormones that have spatially distributed, temporally extended effects on the recipient neurons and circuits. 4. Neuromodulatory systems Ascending neuromodulatory systems • Cholinergic • Dopaminergic • Serotonergic • Adrenergic Co-transmitters as neuromodulators Neuropeptides as neuromodulators Circulating hormones as Modulators 5. Architecture of the neuromodulatory systems.Jeffrey L. Krichmar, Adaptive Behavior 2008; 16; 385 6. K. Doya / Neural Networks 15 (2002) 495–50 7. Commonalities among neuromodulatory systems 1.The origination of these systems is sub-cortical. 2. Each of these neuromodulatory systems is the locus of a particular chemical transmitter that is projected to broad areas of the brainstem, thalamus, and cortex. 3. All of these neuromodulatory systems are reciprocally connected with the frontal cortex and parts of the limbic system. 8. Modes of modulationE. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 9. E. Marder ;Neuron; 2012 10. Heterosynaptic facilitationPresynaptic inhibitionDiffusely delivered modulator Postsynaptic can act on presynaptic receptors release mechanismE. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 11. Crustacean models of neuromodulationE. Marder ;Neuron; 2012 12. Intrinsic properties of a model neuron with different balance of conductances.Activity patterns of pyloric neurons in the intact circuit and when isolated.E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 13. Alteration of intrinsic properties by neuromodulators • The same neuron can be thetarget of multiple modulatory Substances • Some modulators can produce qualitative changes in the intrinsic properties of neurons, e.g. transform a tonically firing neuron into a bursting neuron •modulators can influence the frequency of either tonic activity or bursting, and •Different cell types within a network can be influenced differentially by the same neuromodulatory substances. E. Marder ;Neuron76; 012 14. Effects of Modulatory Substances on a Membrane potential of NeuronE. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 15. Co-existance with other modulatorsE. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 16. Multiple Neuromodulators Can Activate Different Forms of the Pyloric RhythmE. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493 17. Principles of neuromodulation • Modulators co-ordinately act on opposing processes • Voltage dependence of modulator actions • Convergence of many modulators onto the Same voltage-dependent current • Saturation of postsynaptic action: Bigger synaptic inputs produce larger effects on target neuron activity • Modulators act co-ordinately on multiple targets to keep systems functionally ‘‘Matched’’ Eve Marder , Neuron 2012 18. Coexistence of some neuropeptides and neurotransmitters in brain areas associated with cognitive functions.S.O. Ögren et al. / European Journal of Pharmacology 626 (2010) 9–17 19. Role of Prefrontal cortex in Cognition • • • •Working memory Behavioral inhibition Attentional processing Future planning 20. L.A. Briand et al. / Progress in Neurobiology; 83 (2007) 21. coronal sections from the macaque monkey PFC illustrating the relative densities of tyrosine hydroxylase (DA),dopamine-b-hydroxylase (NE), choline acetyltransferase (ChAT), and serotoninL.A. Briand et al. / Progress in Neurobiology; 83 (2007) 22. Principles of Neural science, Kandle and Shwartz,4th edition 23. Neuromodulatory systems projecting to PFC • • • • • • •Cholinergic system Serotonergic system Adrenergic system Dopaminergic system Histaminergic system Volume transmission Neuropeptides 24. Basal Forebrain and brainstem cholinergic projectionsNewman et al; June 2012; Frontiers in Behavioral Neuroscience; 25. Newman et al; June 2012; Frontiers in Behavioral Neuroscience; 26. Cholinergic receptors • Muscarinic receptors M1 & M2 M1 subtypes: m1, m3, m5 (Layer I, II) M2 subtypes: m2, m4 (Layer III, V ) • Nicotinic receptors α subunits (α2-10 ) β subunits (β 2-4 ) 27. Principles of Neural science, Kandle and Shwartz,4th edition 28. Experimental evidences of modulation of cognitive functions • • • •Cholinotoxins: 192 IgG saporin Microdialysis studies Electrophysiological studies Pharmacological studies 29. Cued appetitive response taskME Hasselmo and M Sarter, NeuropsychopharmacologyREVIEWS(2011) 36, 52–73 30. • cholinergic system is required specifically for the detection of cues. • It increases the signal to noise ratio (Metherate & Ashe 1991) 31. Effect of Ach on LTPHigh Ach lowers the threshold for LTP induction. Heurta and Lisman 1993Newman et al 2012; Frontiers in Behavioral Neuroscience 32. The Gestalt law of Visual Grouping and Acetylcholine 33. Acetylcholine contributes to attentional modulation and orientation selectivity in the primary visual cortex through mAChR. • Acetylcholine can boost neural signals in response to low contrast stimuli, through presynaptic nAChR mediated upregulation of Glutamate release. • Acetylcholine can bias cortical processing in favour of sub or intracortical inputs. • 34. Noradrenergic modulation of prefrontal cholinergic function Source: Locus cereoleus Receptors: α 1 & α 2 α 1 agonists increases Ach release α 2 agonists decreases Ach release Atomoxetine : NE reuptake inhibitor enhances Ach release Effect on basal forebrain: Depolarise cholinergic neurons L.A. Briand et al. / Progress in Neurobiology; 83 (2007) 35. Serotonergic modulation of prefrontal function Source : Dorsal raphe nucleus Receptors: 5-HT (1-7) subtypes 5-HT 2 Agonists increase Ach release 5-HT 3 Agonists decrease Ach releaseL.A. Briand et al. / Progress in Neurobiology; 83 (2007) 36. Dopaminergic modulation of prefrontal function Source: Ventral tegmental mesocortical neurons Receptors: D1,D2,D3 D1 Agonists increase Ach release D2 Agonists has no effect D3 Agonists decreases Ach releaseL.A. Briand et al. / Progress in Neurobiology; 83 (2007)