Introduction to Neuroscience: The Basal Ganglia

Michal Rivlin

Basal  Ganglia  anatomy  –  a  short  introduc4on  

•  Striatum:  caudate  &  putamen  •  Globus  pallidus  (external  &  

internal  segments)  •  Subthalamic  nucleus  •  Substan4a  nigra  (pars  compacta  

&  pars  re4culata)  

Basal ganglia-thalamo-cortical loop

•  Basal  Ganglia  receives  robust  input  from  the  cortex  

     

•  Principal  projec4on  of  the  BG  –  via  the  thalamus  back  to  cor4cal  targets  

 

Overview of BG organization •  Input:    

–  Caudate  and  putamen  (together,  the  striatum)  

•  Intrinsic:    –  Subthalamic  nucleus  (STN)  –  External  segment  of  globus  pallidus  

(GPe)  

Output:    Substan4a  nigra  pars  re4culata  (SNr)  Internal  segment  of  globus  pallidus  (GPi)    

Neuromodulator:    Substan4a  nigra  pars  compacta  (SNc)  

SNc

Striatum: Medium spiny neurons

•  Caudate  and  putamen  

•  Medium  spiny  neurons  –  95%  of  neurons;  primary  projec4on  neurons  

– GABAergic;  inhibitory    –  Very  liQle  spontaneous  ac4vity  

Striatum: Intrinsic interneurons

2  principle  types    – 3  GABAergic  interneurons  

– Tonically  ac4ve  neurons  (TANs)  • Cholinergic    • Large  cell  bodies  

Globus pallidus

Two segments Internal (GPi): Principle output nucleus External (GPe): intrinsic circuitry

GABAergic; inhibitory

high tonic firing rates

Globus pallidus

Elias et al. J. Neurosci. 2007

Subthalamic nucleus

Glutamatergic; excitatory

Substan4a  nigra

•  Midbrain  

•  SN  pars  re4culata  (SNr)  – GABAergic  –  high  tonic  firing  rates    – Output  of  BG  

•  SN  pars  compacta  (SNc)  – Neuromelanin-­‐containing  cells  

– Dopaminergic  –  Tonic/phasic  firing  

SNc

Direct  and  indirect  pathways  

Direct  pathway  promotes  ac4on  

+  

−  

−  

+  

Indirect  pathway  suppresses  ac4on  

+  

−  

+  

−  

+  −  

Hyperdirect  pathway  

+  

−  

+  

+  

Role  of  Basal  Ganglia  BG  dysfunc4on  has  been  associated  with  numerous  condi4ons  including  Parkinson's  disease,  Hun4ngton's  disease,  ToureQe's  syndrome,  schizophrenia,  aQen4on-­‐deficit  disorder,  obsessive-­‐compulsive  disorder,  and  many  of  the  addic4ons.  •  Motor  control  •  Learning  •  Mo4va4on  and  reward  •  Cogni4ve  tasks  

Reinforcement  learning  

•  Supervised  learning  –    All  knowing  teacher,  detailed  feedback    

•  Reinforcement  learning  –    Learn  and  relearn  based  on  ac4ons  and  their  effects  (rewards)    

•  Unsupervised  learning  –    Self  organiza4on  

Rescorla-­‐Wagner  rule  (1972)  

•  The  idea:  error-­‐driven  learning  •  Change  in  value  is  propor4onal  to  the  difference  between  actual  and  predicted  outcome  

Outcome:  Reward  value  

Reward  predicted  Learning  rate  

TD  learning  

Vt  =  Es4mated  value  of  current  state  based  on  predicted  future  reward  

η  =  Learning  rate  

rt  =  reward  given  at  4me  t  

‘truer’  value  of  current  state:  Reward  at  present  state  +  Es4mated  value  of  next  state  

Es4mated  value    of  current  state  

The  computa4onal  machinery  of  the  Basal  Ganglia  

The basal ganglia networks are built as Actor-Critic network and employ temporal difference algorithms. Dopamine provides the pleasure prediction error

Environment STATE

ACTION

REWARD

Ctx

SNc

Dop

amin

e ST

N, S

tr

GP

Fron

t ct

x

Environment STATE

ACTION

REWARD

ACTOR

CRITIC

TD

err

or

The  computa4onal  machinery  of  the  Basal  Ganglia  

The basal ganglia networks are built as Actor-Critic network and employ temporal difference algorithms. Dopamine provides the pleasure prediction error

Environment STATE

ACTION

REWARD

Ctx

SNc

Dop

amin

e ST

N, S

tr

GP

Fron

t ct

x

Environment STATE

ACTION

REWARD

TD

err

or

Dopamine  match  surprise  signal  

Schultz  et  al.,  1997    

Dopamine  match  surprise  signal  

Dopamine  signal  =  reward  occurred  –  reward  predicted  

Dopamine  neurons  encode  the  (posi4ve)  mismatch  between  predic4ons  and  reality  

Cue Reward NoReward

Rwr

DA

Cue No-Rwr Cue D

A P=1.00

P=0.75 P=0.50 P=0.25

Genela  Morris  et  al.,  Neuron,  2004  

Effects  of  dopamine  

•  Learning  =  plas4city  •  Teaching  =  modula4ng  synap4c  plas4city  •  Cor4co-­‐striatal  synapses  are  known  to  undergo  long-­‐term  changes  in  synap4c  efficacy.  – Long-­‐term  poten4a4on  (LTP)  is  mediated  by  ac4va4on  of  dopamine  D1  receptors  

– Long-­‐term  depression  (LTD)  is  mediated  by  ac4va4on  of  dopamine  D2  receptors  

D1  D2  

The  strive  for  the  dopaminergic  reward  

•  Cocaine  and  amphetamines  increase  amount  of  dopamine  by  inhibi4ng  its  reuptake  into  the  synap4c  terminals.  

•  Opiate  narco4cs  increase  dopamine  release  by  disinhibi4ng  dopaminergic  neurons.  

•  Nico4ne  increases  striatal  dopamine.  •  A  prolonged  increase  in  dopamine  levels  may  affect  synap4c  plas4city  and  

provide  the  neural  basis  for  drug  addic4on.  

•  Treatment  of  major  emo4onal  disorders  (Schizophrenia,  ADHD  and  major  depression)  is  done  by  manipula4on  of  dopamine  transmission.  

Electrical  self-­‐s4mula4on  in  neuronal  pathways  associated  with  dopamine.  Olds  and  Milner,  1954  

It’s  not  all  about  dopamine:  balance  between  neurotransmiQers  

Parkinson’s  disease:  deple4on  of  dopamine  

Parkinson   Normal  

Substan4a  nigra  

Striatum  

D1 D2

Effects  of  dopamine  deple4on  on    direct  and  indirect  pathways    

Direct  pathway  promotes  ac4on  Indirect  pathway  suppresses  ac4on  

Parkinson’s  disease  (PD)  

Clinical  symptoms  •  Akinesia/bradykinesia,    •  Tremor,    •  Muscular  rigidity,    •  Postural  deficits  •  Emo4onal  and  cogni4ve  deficits    Epidemiology  •  3/1000  of  total  popula4on  •  Mean  age  of  onset  –  60  years  •  1/100  of  >60  years  

James  Parkinson,  1817  

Dopamine  replacement  therapy  of  Parkinson’s  disease  

1967-9, George C. Cotzias: L-DOPA (a precursor of dopamine that cross the blood brain barrier) is established as the gold-standard therapeutic agent for Parkinson's disease. 1970 – today: Dopamine replacement therapy (L-DOPA, post synaptic agonists, MAO-B and COMT inhibitors, etc)

The  limits  of  dopamine  replacement  therapy  

Time

Bra

in D

A le

vel Best  

Typical  

S  

Levodopa-­‐induced  dyskinesia  Dystonia  

The  MPTP  model  of  Parkinson’s  disease  

From: Understanding Parkinson's Disease, Youdim and Riederer, Sci. American 276: 38 (1997)

MPPP (1-methyl-4-propionoxypiperidine)- a reverse ester of meperidine and a potent narcotic- easy to synthesize- synthesis typically results in MPTP as byproduct.

1976: A college student synthesized and abused MPPP for 6 months. - made a 'sloppy batch', and became severely Parkinsonian. - Pathology: severe cell loss limited to the SN (Davis et al. 1979).

1982: MPPP was distributed en-mass in California as 'synthetic heroin'- young drug abusers arriving in ER with advanced Parkinsonism.

- typical Parkinsonian rest tremor in about half (3-4/7) of MPTP patients (Langston et al. 1983, 1987, 1995).

MPTP: 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The  MPTP  model  of  Parkinson’s  disease  

D1 D2

Inac4va4on  of  the  subthalamic  nucleus  ameliorates  Parkinson  symptoms  of  the  MPTP  monkey  

Norm  

MPTP  

-­‐STN

 

-­‐STN

 

-­‐STN

 

MPTP  

MPTP  

Norm  

Norm  0

4 0 0

N o r m a lM P T P

Tre

mo

r T

ime

(s

)

S T N l e s i o n0

8

N o r m a lM P T PS T N l e s i o n0

6 0 0

N o r m a lM P T P

Mo

v.

Tim

e (

s)

Dis

pla

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me

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S T N l e s i o n

A.  Mo vem e nt B.  Rig id ity C .  Tre m o r

Bergman,  Wichmann  and  DeLong,  1990  

Appearance  of  neuronal  oscilla4ons  

•  The  parkinsonian  brain  demonstrates  oscillatory  ac4vity:  –  PD  pa4ents  during  brain  

surgery  –  MPTP  primates  

Nor

mal

GP

park

inso

nian

GP

o  Neural  oscilla4ons  (5-­‐15  Hz)  

Spontaneous  ac4vity  

•  Neuronal  oscilla4ons  appear  in  the  GP  as  well  as  in  MI  

¨  Tremor  frequency  differ  from  cor4cal  frequency  

Deep  brain  s4mula4on  (DBS)  

•  Deep  brain  s4mula4on  (DBS)  is  used  as  a  treatment  for  advanced  PD.  

•  An  electrode  is  located  in  the  STN/GPi  and  high  frequency  s4mula4on  (~130  Hz)  is  given  through  the  electrode.  

BG  hyperkine4c  disorders  

•  Hun4ngton’s  disease    –  striatal  projec4on  neurons  become  dysfunc4onal  and  degenerate  

–  causes  defects  in  behavior  and  uncontrolled  movements.  

–  hereditary  disease  •  Hemiballismus  

–  Reduced  ac4vity  in  the  subthalamic  nucleus  –  Repe44ve,  large  amplitude  involuntary  movements  of  the  limbs  

BG  non-­‐motor  disorders  

•  ToureQe  syndrome  •  Obsessive-­‐compulsive  disorder  •  AQen4on-­‐deficit  hyperac4vity  disorder  (ADHD)  •  Addic4on