biol125-lectures/2016-11-18-lecture16.md

## What does the basal ganglia do?

* Modulate the initiation, termination, amplitude, and selection of movement
* Initiation and selection
* Learning
* Response-outcome associations
* Stimulus-response associations
* Used in dopamine circuits

Note:

[http://www.youtube.com/watch?v=Td4QGHNJ8Q0](http://www.youtube.com/watch?v=Td4QGHNJ8Q0)

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## Overall organization of neural structures that control movement

<figure><img src="figs/Neuroscience5e-Fig-16.01-0_copy_c8e6e7d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.1</figcaption></figure>


Note:

Today we will begin our examination of the pathways in the nervous system that modulate and give rise to volitional control of our skeletal muscles.

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## Basal ganglia and the control of movement

* Anatomy
* Basal Ganglia components
* Anatomical connectivity
* Function– modulation through disinhibition
* Neuromodulators– dopamine
* Diseases of the basal ganglia
* Other disinhibition loops

Note:

We will discuss…

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## Modulation of movement by the basal ganglia

* Basal ganglia do not project directly to the spinal cord, instead they influence movements by regulating the activity of upper motor neurons
* The basal ganglia are a large set of nuclei that lie deep within the cerebral hemispheres
* Three main nuclei– caudate, putamen, and the globus pallidus
* Together with the substantia nigra and the subthalamic nucleus make a loop that links most areas of the cortex with upper motor neurons
* These neurons are required for the normal course of voluntary movements. Supervise motor movements

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## Corpus striatum

* Corpus striatum (striped body)– contains two main nuclei, the caudate and putamen. These two areas are the input zone of the basal ganglia
* Most all areas of the cortex project here. Prominent innervation from the associational cortical areas of the frontal and parietal lobes. Collectively called the corticostriatal pathway. The receiving neurons are called medium spiny neurons. Large dendritic trees, integrate information form a variety of structures

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## Most cortical areas project to striatum

* Most cortical areas (except A1 and V1) project to the corpus striatum

Neuroscience 2001e

<div><img src="tmp/PN18040_650f7d6.jpg" height="100px"><figcaption></figcaption></div>

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## Anatomical location of the basal ganglia

Neuroscience 2001e

<div><img src="tmp/PN01163_78bf2e0.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/PN01161_c6af626.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/PN01162_4765168.jpg" height="100px"><figcaption></figcaption></div>

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## Anatomical location of the basal ganglia

Neuroscience 5e Fig. 18.1

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## Anatomy of the basal ganglia:caudate and putamen

Neuroscience 5e Fig. 18.1

<div><img src="tmp/HMS_7561_d233b5b.jpeg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/Neuroscience5e-Fig-18.01-0_51e5f90.jpg" height="100px"><figcaption></figcaption></div>

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Striatum: caudate and putamen

Make up what type of nuclei? (input)

Globus Pallidus interna and substantia nigra pars reticulata

Make up what type of nuclei? (output)

Globus pallidus externa, STN, and substantia nigra pars compacta 

make up what nuclei? (intermediate)

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## Striatum: medium spiny neurons

* Medium spiny neurons (MSNs) located in caudate and putamen
* ~90% of neurons in striatum; primary projection neurons
* GABAergic; inhibitory
* Very little spontaneous activity; dependent on excitatory input for discharge
* Large dendritic trees
* Inputs from cortical, thalamic, and brainstem structures

<div><img src="tmp/Closeupofthedendriteofastriatalmediumspinyneuron_98d5cb8.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/Kreitzer-f01-clr_12da371.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/Kreitzer-f01-clr1_3db2803.jpg" height="100px"><figcaption></figcaption></div>

Note:

[lower spine image: http://en.wikipedia.org/wiki/Image:Spines.jpg](http://en.wikipedia.org/wiki/Image:Spines.jpg)

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## Medium spiny neuron in the corpus striatum

<div><img src="tmp/image_6dc4725.png" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/image1_45332b6.png" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/image2_0adcfc5.png" height="100px"><figcaption></figcaption></div>

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## Cortical inputs to the caudate and putamen

* Caudate receives cortical projections primarily from multimodal association cortices and motor areas from frontal lobe that control eye movements
* Putamen receives input from the primary and secondary somatic sensory cortex and extrastriate visual cortex in occipital and temporal lobes, premotor and motor cortex, and auditory association areas in temporal lobe
* These inputs are excitatory, glutamatergic synapses
* Each spiny neuron can get synapses from lots of different cortical neurons. Each cortical neuron synapses onto a few MSNs

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## Organization of inputs to basal ganglia

Neuroscience 5e Fig. 18.2



<div><img src="tmp/Neuroscience5e-Fig-18_1edf85b.jpg" height="100px"><figcaption></figcaption></div>

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## More inputs to MSNs

* MSNs also get non-cortical input. From interneurons within striatum, from thalamic neurons, and from brainstem dopaminergic nuclei
* Dopaminergic inputs come from the substantia nigra pars compacta
* Interneurons and thalamic neurons synapse near the dendritic shaft (inhibitory) while dopaminergic neurons synapse onto the distal dendrite
* MSNs need lots of simultaneous inputs in order to go above threshold. Therefore they are usually silent
* Neurons tend to fire in anticipation of a movement. Putamen for body movements, caudate for eye-movements

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## Projections from MSNs

* MSNs of caudate and putamen give rise to inhibitory GABAergic projections that terminate in a pair of nuclei within the basal ganglia called the globus pallidus (external and internal segments) and a region of the substantia nigra called the pars reticulata which in turn contain the major output neurons of the basal ganglia
* On average more than 100 MSNs converge onto each neuron in the globus pallidus
* Globus pallidus (GP) internal neurons then convey information back to the cortex via the thalamus (ventral lateral and ventral anterior nuclei) to make a loop

Note:



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## MSNs send projections to the globus pallidus and pars reticulata

Neuroscience 5e Fig. 18.3



<div><img src="tmp/Neuroscience5e-Fig-18.03-0_41f7b30.jpg" height="100px"><figcaption></figcaption></div>

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## The direct pathway 

* Substantia nigra (SN) pars reticulata neurons project to upper motor neurons in the Superior colliculus that command eye movements without going to the thalamus
* Globus pallidus (GP) and pars reticulata neurons are GABAergic. Unlike MSNs they have high levels of spontaneous activity that normally are used to prevent unwanted movementsThus the output from the basal ganglia is normally inhibitory
* When MSNs fire (in anticipation of movement) this inhibits the inhibition (disinhibition) and allows upper motor neurons to send commands to local circuit and lower motor neurons that initiate movement
* Called the direct pathway

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## Direct pathway of outputs from the basal ganglia

Neuroscience 5e Fig. 18.4



<div><img src="tmp/Neuroscience5e-Fig-18.04-2R_fb419a1.jpg" height="100px"><figcaption></figcaption></div>

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## Example of a disinhibitory circuit…

Neuroscience 5e Fig. 18.5



<div><img src="tmp/Neuroscience5e-Fig-181_96db57b.jpg" height="100px"><figcaption></figcaption></div>

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## Disinhibitory interaction in basal ganglia regulates downstream activity in downstream motor centers

[http://www.youtube.com/watch?v=P6uTlnyNaTs](http://www.youtube.com/watch?v=P6uTlnyNaTs)

Neuroscience 5e Fig. 18.6



<div><img src="tmp/Neuroscience5e-Fig-18.06-1R_87ffd00.jpg" height="100px"><figcaption></figcaption></div>

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## Direct excitatory pathway via disinhibition

* Turns up motor activity









<div><img src="tmp/pasted-image_cb55c4b.pdf" height="100px"><figcaption></figcaption></div>

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Overall excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement)

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## Direct and indirect pathways through the basal ganglia

Dopamine excites the direct and inhibits the indirect pathway



Neuroscience 5e Fig. 18.7



<div><img src="tmp/Neuroscience5e-Fig-18.07-2R_c6497a9.jpg" height="100px"><figcaption></figcaption></div>

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## Indirect pathway circuits

* Provides a second route of influence via a loop back to the direct pathway.
* MSN project also to the globus pallidus external nuclei which then project to the subthalamic nucleus of the ventral thalamus.
* Subthalamic nucleus projects to globus pallidus internal which then projects out of basal ganglia to the VA/VL complex of the thalamus.
* Subthalamic projections are excitatory which increases the inhibition of Globus pallidus. Opposite of the direct pathway.  Acts as a brake to prevent too much disinhibition of upper motor neurons.
* Turns down motor activity.

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## Indirect pathway 













<div><img src="tmp/pasted-image1_c3ab683.pdf" height="100px"><figcaption></figcaption></div>

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Overall inhibitory. Serves to modulate the disinihibitory actions of the direct pathway

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## Center–surround functional organization of the direct and indirect pathways

Neuroscience 5e Fig. 18.\8



<div><img src="tmp/Neuroscience5e-Fig-182_0799e82.jpg" height="100px"><figcaption></figcaption></div>

Note:

think center-surround receptive fields for luminance contrast in retinal ganglion cells mediated by synaptic interactions between photoreceptors, bipolar cells, and horizontal cells in the outer plexiform layer.







-difference of Gaussians is a feature enhancement algorithm

-mexican hat distribution (shaped like a sombrero)

-multidimensional generalization of this wavelet is called the Laplacian of Gaussian function

-frequently used as a blob detector

[-automatic scale selection in computer vision applications; see Laplacian of Gaussian https://en.wikipedia.org/wiki/Mexican_hat_wavelet](https://en.wikipedia.org/wiki/Mexican_hat_wavelet)



Attentional field has a Mexican hat distribution

http://www.sciencedirect.com/science/article/pii/S0042698904005735



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## Hemiballismus: violent involuntary movements of the limbs

* Defects in the subthalamic nucleus of the contralateral side of the movements

















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## Dopaminergic neurons modulate direct and indirect pathways 

* Medium spiny neurons in striatum project to the substantia nigra pars compacta, which in turn projects back to sets of medium spiny neurons.
* Both spiny neurons that project to internal and external globus pallidus receive these inputs.
* Those that project to internal globus pallidus have type D1 receptors (coupled to a Gαs, excitatory) and those that project to external globus pallidus use type D2 receptors (Gαi, inhibitory). 
* Dopamine excites the direct and inhibits the indirect pathway

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## Effector pathways associated with G-protein-coupled receptors

specificity at the level of the α subunit

Like D1 receptors

Neuroscience 2001



D2 receptors

<div><img src="tmp/PN08060_9ef2a4d.jpg" height="100px"><figcaption></figcaption></div>

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## Dopamine used by the direct pathway to excite medium spiny neurons









SN

pars

compacta

dopamine (+)

<div><img src="tmp/HMS_2008_2f7aee4.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="tmp/pasted-image2_816b777.pdf" height="100px"><figcaption></figcaption></div>

Note:

Overall excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement)



Predominantly D1-receptors

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## Dopamine in the indirect pathway used to inhibit medium spiny neurons













SN

pars

compacta

dopamine (-)

<div><img src="tmp/pasted-image3_ed7ad3c.pdf" height="100px"><figcaption></figcaption></div>

Note:

Overall inhibitory. Serves to modulate the disinihibitory actions of the direct pathway





Predominantly D2-Receptors

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## Synaptic input to and output from striatal medium spiny neurons

## 









Smith and Bolam, 1990



<div><img src="tmp/image_df8a81c.tif" height="100px"><figcaption></figcaption></div>

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## Disinhibition in direct and indirect pathways through the basal ganglia

Neuroscience 5e Fig. 18.7



<div><img src="tmp/Neuroscience5e-Fig-18.07-1R_b2fc699.jpg" height="100px"><figcaption></figcaption></div>

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## Disinhibition in direct and indirect pathway through the basal ganglia

Dopamine excites the direct and inhibits the indirect pathway



Neuroscience 5e Fig. 18.7



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## Motor behavior is determined by the balance between direct/indirect striatal outputs

* Hypokinetic disorders (decreased movement)
* insufficient direct pathway output
* excess indirect pathway output
*     Hyperkinetic disorders (excess movement)
* excess direct pathway output
* insufficient indirect pathway output

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## Parkinson’s disease

* Pathophysiology is the loss of nigrostriatal dopaminergic projections

SNc



Striatum

Michael J. Fox

Muhammad Ali

Pope John Paul II 

Janet Reno

Katherine Hepburn

<div><img src="tmp/humanheadandnigra_3646779.jpeg" height="100px"><figcaption></figcaption></div>

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<div><img src="tmp/Ali_100354f.jpg" height="100px"><figcaption></figcaption></div>

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<div><img src="tmp/KatharineHepburn_458d7ac.jpg" height="100px"><figcaption></figcaption></div>

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## Parkinson’s disease

* Due to the degeneration of dopaminergic neurons of the substantia nigra pars compacta.
* Leads to tremors, slowness of movements, rigidity of extremities and neck, minimal facial expressions.
* Slowly progressing disease.
* Some success in slowing the progression comes from the use of Levadopa (L-DOPA)– gets converted to dopamine and gets to dopamine receptors in basal ganglia.

<div><img src="tmp/Neuroscience5e-Fig-18.09-1R_bb039f3.jpg" height="100px"><figcaption></figcaption></div>

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[from https://en.wikipedia.org/wiki/Substantia_nigra](https://en.wikipedia.org/wiki/Substantia_nigra)

>Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons.

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## Summary explanation of hypokinetic and hyperkinetic disorders

<div><img src="tmp/Neuroscience5e-Fig-18.10-1R_598692d.jpg" height="100px"><figcaption></figcaption></div>

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## What causes dopaminergic neurons to die?

* Most cases are late-adult onset without a clear inheritance pattern.
* Small fraction are familial.  
* α− Synuclein a synaptic protein that when mutated can lead to aggregation and cause the formation of Lewy bodies. Autosomal dominant mutations.
* Aggregates may spread from neuron to neuron.
* Two other autosomal recessive mutations Pink1 and Parkin block mitochondria function in dopaminergic neurons-conserved from fly to humans.

Note:



[from https://en.wikipedia.org/wiki/Parkinson%27s_disease](https://en.wikipedia.org/wiki/Parkinson%27s_disease)

-mostly idiopathic, having no known cause

>These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[7][37] In most cases, people with these mutations will develop PD.





Models:  mptp, insecticide rotenone, herbicide paraquat and the fungicide maneb.



>proportion in a population at a given time is about 0.3% in industrialized countries. PD is more common in the elderly and rates rises from 1% in those over 60 years of age to 4% of the population over 80



alzheimers:

[http://www.alz.org/facts/](http://www.alz.org/facts/)

2/3 women

6.4% dementia over 60 & 4.4% with AD over 60



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## Parkinson’s like pathology in mouse after injection of α-synuclein protein aggregates into striatum

<div><img src="tmp/ScreenShot2015-05-13at3_6e2f649.png" height="100px"><figcaption></figcaption></div>

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(A) Serial coronal brain maps of a wild-type mouse 180 days after injection of preformed α-synuclein fibrils (PFF) into the dorsal striatum revealed the development of α-synuclein pathology across the brain. Cells with α-synuclein aggregates are shown in red; the injection site is marked by a light red circle in the 2nd map from left. (B) A high-magnification image of the substantia nigra, showing two dopamine neurons with aggregated α-synuclein in Lewy body-like inclusions (arrows). Dopamine neurons are visualized in green by immunostaining against tyrosine hydroxylase, a marker for dopamine neurons. α-Synuclein is visualized in red using an antibody that preferentially stains aggregated α-synuclein. (C) Substantia nigra pars compacta (SNc) cells that exhibited α-synuclein pathology were located primarily on the ispilateral side of the injection. Injecting phosphate-buffered saline (PBS) into wild-type (wt) or injecting PFF into α-synuclein knockout (Snca−/−) mice did not cause α-synuclein pathology. 

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## Genes linked to Parkinson’s disease regulate mitochondria function

<div><img src="tmp/ScreenShot2015-05-13at4_4d1c25b.png" height="100px"><figcaption></figcaption></div>

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## Treatments for Parkinson’s

* Dopamine can’t cross the blood brain barrier but L-dopa can. Stops working after a few years.
* Deep brain stimulation– bypass the circuit by inhibiting the the STN output.
* Cell replacement therapy– implant dopamine making neurons into the striatum.

[http://www.youtube.com/watch?v=mO3C6iTpSGo](http://www.youtube.com/watch?v=mO3C6iTpSGo)

[http://www.laskerfoundation.org/awards/2014_c_description.htm](http://www.laskerfoundation.org/awards/2014_c_description.htm)

[https://www.youtube.com/watch?v=JAz-prw_W2A](https://www.youtube.com/watch?v=JAz-prw_W2A)

<div><img src="tmp/ScreenShot2015-05-13at6_44d26db.png" height="100px"><figcaption></figcaption></div>

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[from: http://www.ncbi.nlm.nih.gov/books/NBK28180/](http://www.ncbi.nlm.nih.gov/books/NBK28180/)

>Neutral l-amino acids have various rates of movement into the brain [13,14]. Phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine, histidine and l-dihydroxy- phenylalanine (l-DOPA) may enter as rapidly as glucose. These essential amino acids cannot be synthesized by the brain and, therefore, must be supplied from protein breakdown and diet (see Chap. 33)





L-DOPA is transported across the blood brain barrier by  LAT-1 (L or Large amino acid transporter). Dopamine is too polar to be lipid soluble and has no specific transporter



non-polar: symmetric distribution of charge. 





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## Huntington’s disease

One of the most common inherited neurological disease.

Progressive deterioration of the caudate and putamen that project to the GP external, the head of the indirect pathway.

Leads to a movement disorder consisting of rapid jerky motions with no clear purpose.

<div><img src="tmp/Neuroscience5e-Fig-18.09-2R_7f6abfd.jpg" height="100px"><figcaption></figcaption></div>

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## Huntington’s Disease





















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## Summary explanation of hypokinetic and hyperkinetic disorders

<div><img src="tmp/Neuroscience5e-Fig-18.10-2R_2f1fc16.jpg" height="100px"><figcaption></figcaption></div>

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## Huntington’s disease

* Dominantly inherited– strikes around midlife.
* Patients develop depression, mood swings, and abnormal movements (striatum).
* Caused by alterations in a single gene that encodes the huntingtin protein. 
* Huntingtin protein has an expansion of a CAG trinucleotide repeat, resulting in an extended polyglutamine (poly Q) repeat. Leads to aggregation of proteins and cell death.

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## The huntingtin protein has expanded glutamine repeats in the diseased state

<div><img src="tmp/image3_40b3e0b.png" height="100px"><figcaption></figcaption></div>

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## Non-motor loops of the basal ganglia

* Basal ganglia are also involved in loops that modulate non-motor behaviors.
* Maybe work the same way to suppress outputs.
* A limbic loop that may regulate emotional behavior and motivation.
* Tourette’s may be a problem with limbic loop (no longer have inhibitions about language?)
* Drugs of abuse affect dopamine release.
* Schizophrenia, may be due to aberrant activity in multiple loops resulting in hallucinations etc.  

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## Types of corticostriatal loops

[http://www.youtube.com/watch?v=jYRa-fpNonY](http://www.youtube.com/watch?v=jYRa-fpNonY)

Neuroscience 5e Box 18D



<div><img src="tmp/Neuroscience5e-Box-18D-0_6118915.jpg" height="100px"><figcaption></figcaption></div>

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Tourettes may be a disruption to non-motor corticostriatal loops. 

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