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					      Computational Neuroscience:
Towards Neuropharmacological Applications


                       Péter Érdi
                 Henry R. Luce Professor

               Center for Complex Systems
                   Kalamazoo College
                      Kalamazoo, MI
                http://www.kzoo.edu/physics/ccss



 KFKI Research Institute for Particle and Nuclear Physics
         of the Hungarian Academy of Science
                  Budapest, Hungary
             http://www.rmki.kfki.hu/biofiz/cneuro
                          Contents




• Computational neuroscience: microscopic and macroscopic methods



• Modeling the pharmacological modulation of the septohippocampal
  system



• Dynamical approach to neurology/psychiatry
    Computational Neuroscience:
Microscopic and Macroscopic Methods
     Computational Neuroscience:
 Microscopic and Macroscopic Methods

                Brain / Behavior /
                   Organism


                                     Brain Regions
  Schemas        Neural                Layers /
 Functional                            Modules
           The bottom-up
               Networks
Decomposition   Structure              Structural
          modeling approach
                 meets               Decomposition
                Function


                  Neurons


                 Subneural
                Components               by Micheal A. Arbib
       Computational Neuroscience:
   Microscopic and Macroscopic Methods


                  Brain / Behavior /
                     Organism
                                       Brain Regions
  Schemas                                Layers /
 Functional            Neural            Modules
                      top-down
                  The Structure
Decomposition        Networks            Structural
                                       Decomposition
                modeling approach
                       meets
                      Function


                          Neurons


                         Subneural
                        Components          by Micheal A. Arbib
       Computational Neuroscience:
   Microscopic and Macroscopic Methods



           Describing morphology



  Reverse engineering the brain,
        Identifying ion channels


learning how its components work...
          Adding synaptic connections
  Single-cell models: the compartmental technique
           The Hodgkin-Huxley framework

            Cl-
                                Na+



       A-            K+


    Ionic movement                                                                   Equivalent electrical circuit
                                                           The HH equations
       dVm t  Vm t   Em                                                                 Modelled action potential
  Cm                             Vm t   Ek g k t  
         dt          Rm           k


  
    V t   V t   V t   V t   I t 
       '
       m         m
                           ''
                           m         m
                                                         k  Na, K, l
             '                               inj
           R a                 R a


I Na t   g Na t ENa  V t        g Na t   g Na m3 t ht 

I K t   g K t EK  V t           g K t   g K n 4 t 
                                          dst 
I l t   g l El  V t                        V t 1  st    V t st 
                                           dt
           Computational Neuroscience:
       Microscopic and Macroscopic Methods


     Incorporating knowledge on the
              microscopic
      into modeling the macroscopic

Measurement                             Theory

Unit & intracellular recording   Hodgkin-Huxley formalism

EEG & brain imaging techniques   Budapest Group: statistical
                                 neurodynamical approach to activity
                                 propagation in neural populations
    Computational Neuroscience:
Microscopic and Macroscopic Methods

Activity propagation in the feline cortex




        Adaptation of the database by Scannel et. al.
                Computational Neuroscience:
            Microscopic and Macroscopic Methods
           Activity propagation in the feline cortex


                                              Dorsomedial prefrontal cortex
               Control                         inhibition induced epilepsy




                                                                                 low
                                                                         population
                                                                          activity

From http://www.rmki.kfki.hu/biofiz/cneuro/tutorials/duke/
 Modeling the pharmacological
           modulation
of the septohippocampal system
               Modeling the pharmacological modulation
                  of the septohippocampal system

                 Effects of reboxetine on theta activity
                                       Control
                                                                                   20
                                   3




                                                                     Events (Hz)
                                                                                   15
1 mV




                               Power
                                   2

                                                                                   10


                                   1
                                                                                    5



                                   0                                                0

       3 sec                       Frequency (Hz)
                                       0               5   10                           -2.5     -2.0   -1.5    -1.0    -0.5    0.0    0.5    1.0    1.5    2.0
                                           Frequency            Hz                          Time
                                                                                                               Time (sec)                                    seconds




                      After treatment with reboxetine
                                                                                   20
                                   3




                                                                     Events (Hz)
                                                                                   15
                                   2
                               Power
1 mV




                                                                                   10

                                   1

                                                                                    5


                                   0


       3 sec
                                       0               5   10                       0
                                   Frequency (Hz)
                                           Frequency            Hz                      -2.5     -2.0   -1.5    -1.0   -0.5    0.0    0.5    1.0    1.5    2.0
                                                                                            Time
                                                                                                               Time (sec)                                   seconds




       Hippocampal EEG          Fourier tr.                             Cross corr.
               Modeling the pharmacological modulation
                  of the septohippocampal system

                Effects of desipramine on theta activity
                                       Control
                                  0.8




                                                                          Events (Hz)
                                                                                    60

                                  0.6
1 mV




                              Power
                                                                                    40
                                  0.4



                                                                                    20
                                  0.2



                                  0.0                                                   0
                                            0               5   10

                                      Frequency (Hz)
                                                                                            -2.5           -2.0   -1.5    -1.0   -0.5   0.0   0.5   1.0   1.5    2.0
       3 sec                                    Frequency            Hz                            Time
                                                                                                                         Time (sec)                               seconds




                     After treatment with reboxetine
                                      0.8

                                                                                        60




                                                                          Events (Hz)
                                      0.6
                              Power
1 mV




                                                                                        40
                                      0.4



                                      0.2                                               20



                                      0.0

       3 sec                          Frequency (Hz)
                                            0               5   10                       0
                                                Frequency            Hz                      -2.5          -2.0   -1.5    -1.0   -0.5   0.0   0.5   1.0    1.5    2.0
                                                                                                    Time
                                                                                                                         Time (sec)                                seconds




       Hippocampal EEG         Fourier tr.                                   Cross corr.
               Modeling the pharmacological modulation
                  of the septohippocampal system

                Effects of fluvoxamine on theta activity
                                      Control
                                                                                    60
                                  0.8




                                                                      Events (Hz)
                                  0.6
1 mV




                                                                                    40




                              Power
                                  0.4

                                                                                    20
                                  0.2



                                  0.0                                                0
                                        0               5   10                           -2.5           -2.0    -1.5    -1.0    -0.5    0.0    0.5    1.0    1.5    2.0

       3 sec                      Frequency (Hz)
                                            Frequency            Hz                             Time
                                                                                                                       Time (sec)
                                                                                                                                                                     seconds




                     After treatment with reboxetine
                                                                                    60
                                  0.8




                                                                      Events (Hz)
                                  0.6
                              Power




                                                                                    40
1 mV




                                  0.4

                                                                                    20
                                  0.2



                                  0.0
                                                                                     0

       3 sec                      Frequency (Hz)
                                        0
                                            Frequency
                                                        5   10
                                                                 Hz
                                                                                          -2.5           -2.0    -1.5    -1.0    -0.5    0.0    0.5    1.0    1.5    2.0

                                                                                                                       Time (sec)
                                                                                                 Time                                                                 seconds




       Hippocampal EEG         Fourier tr.                               Cross corr.
       Towards a computational/physiological
      molecular screening (and drug discovery)




                       Desired temporal pattern
                       Nontrivial

                              enhanced cognition
                   e.g. Θ:
                              anxiogenics




Septohippocampal
                             Temporal pattern          Comp.
     system


           computational & pharmaceutical modulation      interface to
                                                          further testing
    Modeling the pharmacological modulation
       of the septohippocampal system

           The septohippocampal system



                                 Location of the hippocampus in
                                 rodents




Location of the hippocampus in
human
Modeling the pharmacological modulation
   of the septohippocampal system

     The septohippocampal system

                    Hippocampus




    Septum
                       Modeling the pharmacological modulation
                          of the septohippocampal system
                            The septohippocampal system
                                                                            C: convergence, D: divergence




                            Dentate Gyrus              C: 50 - 100
                                                       D: 15
                            granule cells
   Entorhinal Cortex




                            rat: 600 - 1000 x 103
                                                                          C, D: 5 - 10 x 103
                            human: 9000 x 103             CA3
                                                    pyramidal cells
                                                    rat: 160 x 103            C, D: 103
                                                    human: 2300 x 103
                                                                               CA1
                                                                        pyramidal cells
                                                                        rat: 250 x 103
                                                                        human: 4600 x 103
                                                     Subiculum
hippocampus proper: CA3 + CA1

hippocampus: DG + CA3 + CA1

hippocampal formation: EC + DG + CA3 + CA1 + Sub
         Modeling the pharmacological modulation
            of the septohippocampal system

NE re-uptake inhibition                           Inverse benzodiazepine agonist
    (reboxetine,                                              (FG-7142)
     desipramine)

                             NE
Locus Coeruleus                                                  GABA

                                             Septohippocampal
                                                  system
 Raphe Nucleus
                             5HT

                                                  treatment         induce/enhance θ

                                                   NE re-uptake inhibition    +
  5HT2C           5HT2C               5HT2C
                                                   5HT re-uptake inhibition   –
 agonist        antagonist          re-uptake
                                                   5HT2C antagonist           +
(m-cPP,                             inhibition
              (SB-206553,                          5HT2C agonist              –
 Ro60-0175)    SB-242084)         (fluvoxamine)    inverse benzodiazepine     +
                                                            agonist
 Message from Mihaly Hajos‟ works
      Modeling the pharmacological modulation
         of the septohippocampal system
              Simulation versus planning


    Knowledge from
                                  Building mathematical
•   Anatomy                               models
                                      using their results
•   Pharmacology

•   Physiology                    Conduction computer
•   Behavioral neuroscience           experiments
                                      understanding the
•   Physics                              phenomena

•   Mathematics
                                   Designing biological
•   Computer Science                  experiments
                 Modeling the pharmacological modulation
                    of the septohippocampal system
                            Simulation versus planning


                Reversible and irreversible transition between modes
Potential (V)




                                                 Potential (V)
                                        KA
                                      blockade
                      time (sec)                                 time (sec)
         Firing pattern of control               Firing pattern of KA current blocked
     hippocampal CA1 pyramidal cell                hippocampal CA1 pyramidal cell
          Modeling the pharmacological modulation
             of the septohippocampal system
                                  Computer Experiment
The experiment to be shown was                                  A modified Traub‟94 type pyramidal
done using the GENESIS simulation                               neuron was examined.
environment.


                                    Current injection (10 nA)               The model consists of 66
                                                                            compartments for dendrites,
      Membrane potential vs. time                                           the soma and the axon.
      curve measured in the axon.      apical
                                       dendrites
                                                                            Current types implemented
                                                                            are: Ca2+, KDR, KAHP, KA, KC
                                                                            and Na currents.
                                  Recording site
                                                                            The model also accounts for
                                                                     soma   intracellular Ca2+ concent-
                                                                            ration.
                  Time (sec)
                                                   axon
   +50 mV                -60 mV
                                          basal dendrites

  color code for membrane potential
Modeling the pharmacological modulation
   of the septohippocampal system
          Computer Experiment




       Control hippocampal CA1 pyramidal neuron
Modeling the pharmacological modulation
   of the septohippocampal system
          Computer Experiment




        Hippocampal CA1 pyramidal neuron
       after selective blockade of KA channels
Dynamical approach to
 neurology/psychiatry
     Dynamical approach to neurology/psychiatry
                                  Schizophrenia

                            positive and negative symptoms


                  hallucination          uncomplicated actions and speech
                                         decreased motivation
               state




                                                state
                          time
                                                            time
                       „waving‟                          „steady‟

                                                              storage and recall
Models:                                                       of memory traces
• „lesion models‟: does not explain waving
• neurotransmitter model (DOPA)
                                                        “E”




                                                                                   “E”
• disconnection hypothesis           Friston
• NMDA: delayed maturation of NMDA receptors                      state                  state
• cortical pruning (synaptic depression)
                                                          changes in attractor structure
                                                             „pathological attractors‟
     Dynamical approach to neurology/psychiatry
The NMDA Receptor Delayed Maturation Hypothesis
              Spontaneously occurring NMDA receptor hypofunction         E. Ruppin


                                 SCHIZOPHRENIA


                          increase in the expression of the
                       “immaturate” NR2D receptor subtype

 Reactive
anomalous
 sprouting




                                          Excessive growth of synapses




             Frontal cortex, basal view
   Dynamical approach to neurology/psychiatry
The NMDA Receptor Delayed Maturation Hypothesis


                      Pathological attractors appear


        recall of learned                          recall of never
         memory traces                             learned items
  “E”




                                           “E”
           state                                        state

                                                         “delusion”
                                                       “hallucination”
Dynamical approach to neurology/psychiatry
        Introduction to Attractors
                        Closing Words


One of the main intention of computational neuroscience is to
integrate anatomical, physiological, neurochemical/pharmacological
and behavioural data by coherent concepts and models.


[A basic structure for which such integration is particularly
important is the hippocampal formation. Hippocampus has a crucial
role in cognitive processes, such as learning, memory formation and
spatial navigation. Many neurological disorders, such as epilepsy,
Alzheimer diseases, depression, anxiety, partially schizophrenia are
hippocampus-dependent diseases.]


Computational models of normal and pathological processes may
help to develop more efficient therapeutic strategies.

				
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posted:8/15/2010
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