Functional Anatomy of the Basal Ganglia

1. Functional Anatomy of the Basal Ganglia Sharif Taha, Ph.D. s.taha@utah.edu Department of Neurobiology and Anatomy

2. Outline • Anatomy a. BG components b. Anatomical connectivity • Function: Modulation through disinhibition • Action Selection • Neuromodulators: dopamine

3. What do the basal ganglia do? • Modulate the initiation, termination, amplitude, and selection of movement - Initiation and selection 2. Learning -Response-outcome associations - Stimulus-response associations

4. Basal ganglia: a modulatory cortical loop • Basal Ganglia receives robust input from the cortex - Almost all parts of cortex; excludes primary sensory cortices • Principal projection of the BG - back to cortical targets - Motor associated areas - Via ventral thalamic relay (Other targets: superior colliculus)

5. Overview of BG organization • Output: • Substantia nigra pars reticulata (SNr) • Internal segment of globus pallidus (GPi) • Neuromodulator: • Substantia nigra pars compacta (SNc) • Input: • Caudate and putamen (together, the striatum) • Intrinsic: • Subthalamic nucleus (STN) • External segment of globus pallidus (GPe) SNc

6. Striatum: Medium spiny neurons • Caudate and putamen • Medium spiny neurons • ~90% of neurons; primary projection neurons • GABAergic; inhibitory • Very little spontaneous activity; dependent on excitatory input for discharge

7. Up and down states • Inwardly rectifying potassium channels keep striatal neurons (very) hyperpolarized • Membrane potential shifts from hyperpolarized potentials (−80 mV) to more depolarized potentials (−50mV) • Transitions to the up state are correlated among nearby striatal neurons • Selection mechanism – requires concerted cortical activation to move to upstate Wilson 1998 Science

8. Striatum: Intrinsic interneurons 2 principle types • 3 GABAergic interneurons • Tonically active neurons (TANs) • Cholinergic • Large cell bodies

9. Globus pallidus Two segments → Internal: Principle output nucleus →External: intrinsic circuitry Neurons in both areas - high tonic firing rates GABAergic, inhibitory

10. Subthalamic nucleus Alone among the BG circuit elements –glutamatergic Target for deep brain stimulation (DBS)

11. Nigral Complex • Midbrain • Substantia nigra pars reticulata (SNpr) • GABAergic • Output of BG • Developmentally, related to Gpi • Substantia Nigra pars Compacta (SNpc) • Neuromelanin-containing cells • Dopaminergic (A9) SNc

12. Basal ganglia connectivity Cortical input Thalamus  Cortex Subthalamic nucleus

13. Three organizing principles of basal ganglia connectivity Cortical input • Anatomically parallel loops with distinct function • Finer-grain topographic organization within loops • Patch/matrix Thalamus  Cortex Subthalamic nucleus

14. Functional topography: Parallel loops w/in the BG subserve distinct functions

15. Functional topography: Parallel loops w/in the BG subserve distinct functions • 4 pathways: • Skeletomotor • Oculomotor channel • Association • Behavior, learning, cognition • Limbic • Addiction, emotional behavior • J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996

16. Topography is also maintained within loops: Somatotopy • J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996

17. Oculomotor topography • J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996

18. Patch/matrix compartments: neurochemical organization • Neurochemically distinct areas (patch, mu opioid receptor; matrix, calbindin) • Dendrites observe boundaries • Afferents/efferents are distinct • Functional roles – • Patch: limbic • Matrix: sensorimotor

19. Outline • Anatomy a. BG components b. Anatomical connectivity • Modulating action through disinhibition • Direct and Indirect Pathways • Action Selection • Neuromodulators • Pathology

20. Movement modulation through disinhibition

21. Movement modulation through disinhibition

22. Output nuclei of the basal ganglia are inhibitory

23. Output nuclei maintain a high tonic level of discharge, suppressing activity in target regions

24. Firing under quiescent conditions (in the absence of movement)

25. Movement modulation occurs through disinhibition of thalamocortical target regions

26. What advantages does modulation through inhibition confer? • Strong tonic inhibition allows basal ganglia to serve as a master regulator – arbitrating between multiple excitatory inputs • Initiating and • Discriminating Cortical regions Saccade generator

27. Basal ganglia: movement modulation through disinhibition • Output nuclei of the basal ganglia are inhibitory • Output nuclei maintain a high tonic level of discharge, suppressing activity in target regions • Phasic decrease in firing rate transiently releases target regions from inhibition. • Disinhibited thalamocortical circuit discharges, promoting movement.

28. Outline • Anatomy a. BG components b. Anatomical connectivity • Modulating action through disinhibition • Direct and Indirect Pathways • Action Selection • Neuromodulators • Pathology

29. Direct and Indirect Pathways

30. Direct Pathway

31. Basal firing rates in the striatum are very low,and dependent upon strong cortical excitation.

32. Under these conditions, striatal firing has little impact on GPi/SNr discharge

33. Phasic cortical excitation drives excitatory discharge in the striatum.

34. Activation of the direct pathway promotes action. This causes a transient inhibition of GPi/SNr firing.

35. Indirect pathway

36. Striatal neurons have low tonic firing rates; again, dependent upon strong cortical inputs

37. GPe neurons are similar to those in GPi; they have high tonic firing rates

39. Firing under quiescent conditions (in the absence of movement)

40. What happens with strong, phasic cortical excitation?

41. Transient inhibition of GPe firing…

42. Followed by phasic excitation of the STN (through disinhibition)…

43. And finally, a increased rate of discharge in the output nuclei - Activation of the indirect pathway suppresses action.

44. Rate model & basal ganglia pathology http://www.youtube.com/watch?feature=player_detailpage&v=fCL7RWaC3RA http://www.youtube.com/watch?feature=player_detailpage&v=AvBrP4yRTRA

45. Indirect pathway suppresses action. Direct pathway facilitates action. How do they cooperatively regulate motor output?

46. Outline • Anatomy a. BG components b. Anatomical connectivity • Modulating action through disinhibition • Direct and Indirect Pathways • Action Selection • Neuromodulators • Pathology

47. Action selection

48. Action encoding in output nuclei of the BG

49. Action encoding in the output nuclei of the BG

50. Direct pathway inputs are focused and robust