Neuromodualtors in Cognition

Vijaya Kumar

3-01-2014

Overview

• What is Neuromodulation?• How exactly the modulation is brought about?• Brain regions involved in cognition• Modulatory projections• Cholinergic modulation• Summary

Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neurons

Neuromodulators are the neurotransmitters, neuropeptides, hormones that have spatially distributed, temporally extended effects on the recipient neurons and circuits.

Neuromodulatory systems

Ascending neuromodulatory systems• Cholinergic• Dopaminergic• Serotonergic• AdrenergicCo-transmitters as neuromodulatorsNeuropeptides as neuromodulatorsCirculating hormones as Modulators

Architecture of the neuromodulatory systems.

Jeffrey L. Krichmar, Adaptive Behavior 2008; 16; 385

K. Doya / Neural Networks 15 (2002) 495–50

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.

Modes of modulation

E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493

E. Marder ;Neuron; 2012

Heterosynaptic facilitation

Presynaptic inhibition

Diffusely delivered modulator can act on presynapticrelease mechanism

Postsynaptic receptors

E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493

Crustacean models of neuromodulation

E. Marder ;Neuron; 2012

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

Alteration of intrinsic properties by neuromodulators• The same neuron can be the target of multiple modulatorySubstances• 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 anetwork can be influenced differentially by the same neuromodulatory substances.

E. Marder ;Neuron76; 012

Effects of Modulatory Substances on a Membrane potential of Neuron

E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493

Co-existance with other modulators

E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493

Multiple Neuromodulators Can Activate Different Forms of the Pyloric Rhythm

E. Marder, V. Thirumalai / Neural Networks 15 (2002) 479–493

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

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

Role of Prefrontal cortex in Cognition

• Working memory• Behavioral inhibition• Attentional processing• Future planning

L.A. Briand et al. / Progress in Neurobiology; 83 (2007)

coronal sections from the macaque monkey PFC illustrating the relative densities of tyrosine hydroxylase (DA),dopamine-b-hydroxylase (NE), choline

acetyltransferase (ChAT), and serotonin

L.A. Briand et al. / Progress in Neurobiology; 83 (2007)

Principles of Neural science, Kandle and Shwartz,4th edition

Neuromodulatory systems projecting to PFC

• Cholinergic system• Serotonergic system• Adrenergic system• Dopaminergic system• Histaminergic system• Volume transmission• Neuropeptides

Basal Forebrain and brainstem cholinergic projections

Newman et al; June 2012; Frontiers in Behavioral Neuroscience;

Newman et al; June 2012; Frontiers in Behavioral Neuroscience;

Cholinergic receptors

• Muscarinic receptors M1 & M2M1 subtypes: m1, m3, m5 (Layer I, II)M2 subtypes: m2, m4 (Layer III, V )• Nicotinic receptorsα subunits (α2-10 )β subunits (β 2-4 )

Principles of Neural science, Kandle and Shwartz,4th edition

Experimental evidences of modulation of cognitive functions

• Cholinotoxins: 192 IgG saporin• Microdialysis studies• Electrophysiological studies• Pharmacological studies

Cued appetitive response task

ME Hasselmo and M Sarter, NeuropsychopharmacologyREVIEWS(2011) 36, 52–73

• cholinergic system is required specifically for the detection of cues.

• It increases the signal to noise ratio (Metherate & Ashe 1991)

Effect of Ach on LTP

High Ach lowers the threshold for LTP induction. Heurta and Lisman 1993

Newman et al 2012; Frontiers in Behavioral Neuroscience

The Gestalt law of Visual Grouping and Acetylcholine

• 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.

Noradrenergic modulation of prefrontal cholinergic function

Source: Locus cereoleusReceptors: α 1 & α 2

α 1 agonists increases Ach release

α 2 agonists decreases Ach releaseAtomoxetine : NE reuptake inhibitor enhances Ach

releaseEffect on basal forebrain: Depolarise cholinergic

neurons

L.A. Briand et al. / Progress in Neurobiology; 83 (2007)

Serotonergic modulation of prefrontal function

Source : Dorsal raphe nucleusReceptors: 5-HT (1-7) subtypes5-HT 2 Agonists increase Ach release5-HT 3 Agonists decrease Ach release

L.A. Briand et al. / Progress in Neurobiology; 83 (2007)

Dopaminergic modulation of prefrontal function

Source: Ventral tegmental mesocortical neuronsReceptors: D1,D2,D3

D1 Agonists increase Ach releaseD2 Agonists has no effectD3 Agonists decreases Ach release

L.A. Briand et al. / Progress in Neurobiology; 83 (2007)

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