* Basal ganglia are a large set of nuclei that lie deep within the cerebral hemispheres
* Consists of striatum (**caudate**, **putamen**) and the **globus pallidus**
* Together with the **substantia nigra** and the **subthalamic nucleus** comprises the **basal ganglia system** which links most areas of the cortex with upper motor neurons of the frontal cortex
* Basal ganglia influence movements by regulating the activity of upper motor neurons
* Modulate the **initiation** and **termination** of movement
* Proper basal ganglia function required for normal voluntary movements
* Disorders of basal ganglia or associated structures result in upper motor neurons not switching smoothly between movement initation and termination commands
* Corpus striatum ('striped body') contains two nuclei– the caudate and putamen
* Function as the input zones for the basal ganglia
* Most regions of the cortex project to the striatum. Prominent innervation from the associational cortical areas of the frontal and parietal lobes. Collectively called the corticostriatal pathway
* Neurons in striatum that receive corticostriatal input are called medium spiny neurons. Large dendritic trees, integrate information form a variety of structures
<figure><img src="figs/Neuroscience-2e-cortical-areas-striatum-proj_copy_ba7049e.jpg" height="400px"><figcaption>Neuroscience 2e 2001</figcaption></figure>
Main outputs of basal ganglia system include: Globus pallidus interna (thalamus) and substantia nigra pars reticulata (superior colliculus, eye movements)
* 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
* 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 (GP) and a region of the substantia nigra called the pars reticulata (SNr)
* Approximately 100 MSNs converge onto each neuron in the globus pallidus
* Globus pallidus contains two nuclei– GP externa (GPe) and GP interna (GPi)
* The GPi and the SNr contain the main output neurons of the basal ganglia
* Globus pallidus interna (GPi) neurons then convey information back to the cortex via the thalamus (ventral lateral and ventral anterior nuclei, VA/VL) to make a loop
* Substantia nigra pars reticulata (SNr) neurons project to upper motor neurons in the superior colliculus that command eye movements without going to the thalamus
* **Globus pallidus and pars reticulata neurons are GABAergic**. Unlike MSNs they have high levels of spontaneous activity– they are tonically active
* Thus the output from the basal ganglia is normally inhibitory-- tonic inhibition
* 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
* Provides a second route of influence via a loop back to the direct pathway
* MSN neurons also project to the globus pallidus external (GPe) nuclei which then project to the subthalamic nucleus (STN) of the ventral thalamus
* STN neurons project back to GPi which then projects out of basal ganglia to the VA/VL complex of the thalamus
* **Subthalamic projections are excitatory which increases the inhibition of GPi**. Opposite/antagonistic of the direct pathway. Acts as a brake to prevent too much disinhibition of upper motor neurons
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)
* Medium spiny neurons (MSNs) in striatum project to the substantia nigra pars compacta (SNc), which in turn projects back to MSNs
* Both MSNs that project to GPe and GPi receive these inputs
* Those that project to GPi have type D1 receptors (coupled to a Gαs, excitatory) and those that project to GPe use type D2 receptors (Gαi, inhibitory)
* 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
>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.
<div><img src="figs/coronal7b_21f2276.svg" height="300px"><figcaption>B. Crawford and K. McBurney, Univ. of Victoria</figcaption></div>
Note:
substantia nigra pars compacta, a nucleus containing neurons making the neurotransmitter dopamine that are important for regulating motor movements via their connections with the basal ganglia and which are devastated in parkinson’s disease.
*dark appearance due to high levels of dark pigment neuromelanin in dopaminergic neurons*
*Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH)*
>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
(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.
## Genes linked to Parkinson’s disease regulate mitochondria function
>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
* 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 repeat. Leads to aggregation of proteins and cell death
* antipsychotic drugs that act on dopaminergic receptors support hypothesis that schizophrenia involves disruption of basal ganglia non-motor loops
* drugs of abuse that affect dopamine neurotransmission
* methylphenidate, amphetamine, meth, cocaine as well as those of nicotine [#Volkow-2000]
from [#Volkow-2000]:
>drug abusers have marked decreases in dopamine D2 receptors and in dopamine release. This decrease in dopamine function is associated with reduced regional activity in orbitofrontal cortex (involved in salience attribution; its disruption results in compulsive behaviors), cingulate gyrus (involved in inhibitory control; its disruption results in impulsivity) and dorsolateral prefrontal cortex (involved in executive function; its disruption results in impaired regulation of intentional actions)
* obsessive-compulsive disorder, depression, chronic anxiety all could involve dysfunctions of the limbic loop
* nucleus accumbens is a component of the limbic loop in ventral division of striatum and implicated in addiction to drugs of abuse expression of addictive reward-seeking behavior
[#Volkow-2000]: Volkow, N. D., Fowler, J. S., Wang, G. J., Baler, R., & Telang, F. (2009). Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology, 56(Suppl 1), 3–8. http://doi.org/10.1016/j.neuropharm.2008.05.022
