Neuroscience essay title:

1. Describe the functional organization of the basal ganglia and state how this is
altered in Parkinson's disease.
Essay:
Parkinsons disease (PD) is a neurodegenerative movement disorder characterised by
hypokinesia, tremor and rigidity. Affecting about 120,000 people in the UK alone, this
chronic disorder has variable motor and non-motor symptoms. The aetiology of this
complex disorder is not completely comprehended. However, scientists have proposed
many theories surrounding the degeneration of dopaminergic neurons in the basal
ganglia. It is crucial to understand the function of the basal ganglia to gain an insight into
how its dysfunction could contribute to some of the symptoms experienced in PD.
The basal ganglia are a cluster of brain cells found at the base of the forebrain consisting
of
the substantia nigra, caudate, putamen, globus pallidus and subthalamus. The caudate
and putamen are anatomically separated by the internal capsule, but are functionally
grouped together as the striatum. The putamen and globus pallidus are anatomically
grouped as the lentiform nucleus. However, they are distinct functionally.
The complex basal ganglia circuit runs in two pathways: direct and indirect. The direct
pathway, as the name suggests, is a more straightforward circuit, while the indirect
pathway takes a long-winded route through the subthalamic nucleus.
To commence the direct pathway, an excitatory signal arrives from the motor cortex to
the striatum. The striatum then projects inhibitory neurons to the internal part of globus
pallidus (GPi). GPi in turn sends inhibitory signals to the thalamus. The thalamus projects
excitatory neurons back to the motor cortex. The excitatory and inhibitory signals are
transmitted by glutamate and GABA respectively. In this combination of excitatory and
inhibitory signalling, the double inhibitory signals between the striatum, GPi and
thalamus, result in a final excitatory transmission from the thalamus to the motor cortex.
Therefore, the direct pathway has a POSITIVE modulation of movement on the motor
cortex; if the direct pathway is stimulated, motor activity is increased.
On the other hand, the indirect pathway achieves the opposite effect in the following
manner. After an excitatory signal reaches the striatum from the motor cortex, the
striatum sends inhibitory signals to the external part of Globus pallidus (GPe). GPe sends
inhibitory signals to the subthalamic nucleus (STN). STN then projects excitatory fibres to
GPi. The circuit then follows the same route as the direct pathway from the GPi, to the
thalamus, back to the motor cortex. However, in this pathway, the final effect is a
decrease in motor activity due to the positive signal that augments the negative effect in
the STN.
Two neurotransmitters engage in these pathways to influence these modulations further:
Dopamine and Acetylcholine.
Dopamine, a monoamine neurotransmitter, participates in the mesolimbic, mesocortical
and nigostriatal pathways in the CNS. It is its participation in the nigostriatal pathway
that influences movement control. Dopamine is produced by the cells of the PARS
COMPACTA in the substantia nigra (SNc). Axons from the SNc project into the striatum to
release dopamine. The striatum has two metabotropic dopamine receptors: D1 and D2.
D1 is a Gq G-protein coupled receptor, and when bound to dopamine, it potentiates the
effects of the DIRECT pathway. D2 is a Gi G-protein coupled receptor, and downgrades
the effects of the INDIRECT pathway. The resulting effect achieved by dopamine is a
positive influence in motor activity along the basal ganglia circuitry.

Acetylcholine is transmitted along inter-neurons within the striatum, and these

interneurons synapse onto the neurons leaving from the striatum along the direct and
indirect pathways. Acetylcholine INHIBIT the direct pathway and EXCITES the indirect
pathway, hence countering the effects of dopamine. The balance between these 2
neurotransmitters is crucial in regulating motor activity.
A diagram summarises the direct and indirect pathway:
Research shows that the reduction of dopamine results in hypokinesia, a characteristic
motor symptom of Parkinsons disease (PD). This reduced neurotransmission, coupled
with normal cholinergic signals, depress the direct pathway and elevates the indirect
pathway. The reduction of dopamine is attributed to the loss of dopaminergic neurons in
the SNc resulting in degeneration along the nigrostriatal tract. This is observed in
neuropathological studies highlighting the loss of pigmentation in PD brains due to
decreased neuromelanin in the substantia nigra (MANN and YATES, 1983).
The underlying mechanisms are vastly conjectural, and each mechanism proposes a
biochemical reasoning for the destruction of the dopaminergic neurons in the substantia
nigra. The first theory proposed is oxidative stress. This oxidative stress in PD is a
result of the imbalance in free radical production and antioxidant defences in the SNc.
Free radicals are normally produced in SNc through dopamine metabolism and autooxidation. Both reactions, which produce hydrogen peroxide, are converted to hydroxyl
free radicals through the Fenton reaction. Usually, these free radicals are countered by
antioxidant defences such as glutathione in SNc. However, in PD, the glutathione levels
drop by about 30%. Furthermore, there is increased production of free radicals which
potentiate this effect. Fe2+ is a reactant along with hydrogen peroxide in the Fenton
reaction, and elevated Fe2+ levels have been observed, which drive the reaction further
to produce increased OH- free radicals. The cause of this elevation of Fe2+ is unknown,
but it has been speculated that infiltration of microglia could play a role. Activation of
microglial cells have shown to contribute to oxidative stress further by releasing nitric
oxide and superoxide free radicals (Hwang, 2013). Another reason for increased free
radical production is attributed to mitrochondrial dysfunction. There is an impairment in
the mitochondrial complex I activity in the SNc, and this leads to a leaky electron
transport chain that elevates hydrogen peroxide levels. H2O2 is fed into the fenton
reaction, hence driving the production of increased OH-. Oxidative stress is detrimental
to the SNc because it modifies essential macromolecules and destroys it, which in turn
damages the SNc.
The second proposed mechanism is excitotoxicity. Due to the mitochondrial
dysfunction described previously, the amount of ATP produced is decreased. ATP is
necessary to maintain the Na+/K+ATPase pump in the neuronal cell membrane. When
the pump is not maintained, the resulting membrane depolarization removes the Mg2+
that inactivates the NMDA glutamate receptor. This increases the chances of activating
the NMDA receptor, which would drive the influx of calcium ions into the cell. Excess
calcium is toxic and would lead to SNc degeneration following the death of vital proteins.
The ventral tier of SNc is more prone to damage due to the decreased presence of
calbindin compared to the dorsal tier of SNc. Glutamate has a secondary role in this
excitotoxicity, whereby the stimulation of STN leads to increased extracellular glutamate
surrounding the GP and SNc, which would amplify the effects of excitotoxicity by
increasing the activation of the NMDA receptors.
Finally, the accumulation of mutated a-synuclein and faulty protein degradation have
been attributed to the formation of Lewy bodies, a pathological finding behind
neurodegeneration. These mutations in various signaling molecules are more common to
the familial form of parkinsons disease, which is present in about 1% of cases. The
formation of Lewy bodies could be an underlying cause of hyposmia in Parkinsons
disease.

All these mechanisms reiterate the importance of the basal ganglia in mediating
movement control in the brain. Understanding the role of these mechanisms could be
advantageous in discovering therapies to manipulate these pathways. This could
potential delay or even reverse the degenerative pathways in the basal ganglia.
Hypokinesia could be explained using the loss of dopaminergic neurons, but there are
other motor and non-motor symptoms whose mechanisms are still being discovered. A
very recent publication has shown promising evidence where consistent and progressive
micrographia, another PD symptom could be attributed to a dysfunction in the basal
ganglia motor circuit ((Wu et al., 2015). This shows a promising potential towards research
and therapeutics of this multi-faced disorder.