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Functions of Basal Ganglia

BASIAL GANGLIA Objectives: Define basal ganglia and describe the parts, describe the main connections and functions, describe the function and the disorders of basal ganglia The main function of the basal ganglia is to provide a feedback mechanism for the selection and initiation of voluntary movement. They way it does that is it provides an input to the thalamus which acts as an inhibitory input to the lateral ventricle of the thalamus which then projects an excitaroty input to the motor cortex. Its motor input loop is essentially how voluntary movement is selected and initiated.

So if anything affects this loop with either dampen or enhance voluntary movement (Parkinsons/Huntingson diseases). The basal ganglia is a series of interconnected nuclei that composes of the caudate nuclei, putamen, globus pallidus and as well as the substantia nigra. These nuclei essentially form a feedback loop that connects to the cerebral cortex that allows for the selection of inhibitory and stimulating movements that may lead to a generation of purposeful movement. Caudate is an egg-like structure and located laterally from the lateral ventricle.

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Putamen is next to the caudate which is separated by the internal capsule. The caudate is responsible for telling the brain that there is something wrong and something should be done to fix it. Caudate can be used in many ways but if its is overused you have conditions like Obsessive Compulsive Disorder. Putamen is involved with learning abilities such as playing the piano or riding a bike. Behind the putamen lays the globus pallidus which essentially acts as the output structure of the basal ganglia. CAUDATE PUTAMEN (CPu)/Striatum Early anatomist have subdivided these two structures by the presence of the internal capsule * More recently with neurochemical and microscopical studies have shown that these structures are essentially similar in many regards based on their neurotransmitters as well as the receptors that are present * Therefore they made a recent subdivision that impinges on both the caudate and the putamen. It is subdivided rather than from the internal capsule, you have patches that are described as striosomes which are predominately D1 receptors abundant and the bulk of the matrix has D2 receptors.

Essentially these receptors are different as D1 receptors are involved in direct pathways, pro-movement pathways and the D2 receptors are involved in inhibitory or anti-movement pathways * The bulk of the neurons are at least 95% of the neurons in the striatum (collectively known as the caudate putamen) GLOBIS PALLIDUS They are separated again into the external and internal segment. It sits in a close proximity to the thalamus and this is ideal because the globis pallidus sends its outputs greatly onto the thalamus to essentially summarise the information derived from the striatum.

It is essentially the external globis pallidus that acts as the output. The basal ganglia is made up direct and indirect pathways. Direct pathway being ‘pro-movement’ and this receives a direct movement from the striatum into the globis pallidus internal whereas the indirect pathway goes from the striatum to the globis pallidus external which then projects on the subthalamic nucleus and then projecting back to the globis pallidus internal. So essentially the GPi has the final say of the information that sends to the thalamus. SUBTHALAMIC NUCLEUS (STM)

The subthalamic nucleus is an egg-like structure that is located just above the substantia nigra. It is considered the ‘engine’ of the basal ganglia. The reason why it is known as the ‘pacemaker’/’engine’ of the basal ganglia is because it is the only substructure that has glutamatergic neurons. The significance is because the neurons are excitatory, therefore it is able to cause an increase in action potential. These neurons are capable of exerting or stimulating on the GPi which balances out the negative influence that the strital neurons may have on the GPi by the direct pathway.

So essentially were getting a balance between the negative effect of the striatum on the GPi as oppose to the subthalamic nucleus which has a positive influence. The STM has a pacemaker role and can be isolated from the brain into a medium container and its action potential can be recorded even though its input has been depleted. Therefore it is able to generate its own rhythm and essentially the basal ganglia follows what the input of the STM says. It is also a key target for surgery in Parkinson’s disease because it is know that this particular structure becomes over active.

People in late stage Parkinson’s disease have found a lot of benefit from implanting these de-brain stimulating electrodes in the STM. SUBSTANTIA NIGRA (SN) This structure is part of the midbrain(dark-stained area that is located in the mesencephalon). The SN is essentially divided into two structures. i. Substantia nigra pars compacta (SNpc) * Serves mainly as an input to striatum(that is the main structure that receives input in the basal ganglia) * SNpc has dopamine neurons(serves to inhibit or excite neurons – semi dual role.

It does this by activating Dopamine D1 receptor or D2 receptor) D1 has a stimulating action on the nerve cells whereas the D2 has an inhibitory role * MAIN ROLE OF THE SNpc IS TO MODULATE MOTOR CONTROL – it does this through the D1/D2 receptors = direct or indirect pathways * it can be said that the Dopamine neurons have the ‘brake’ and ‘accelerator’ switch for stimulating or inhibiting movements * ANOTHER ROLE OF SNpc is learned responses to stimuli (reward/addiction) ~ New stimulus : Everytime a new toy is rewarded for a child or the anticipation of a ciggarette you get an activation of the SNpc activity ~ Following repetition : the child gets the toy, plays with it and gets bored – the activity gets dampened and SNpc activity declines ii. Substantia nigra pars reticulate (SNr) * Serves mainly as an output of the basal ganglia * Similar in structure and function to GPi * Inhibit targets of the BG * Inhibits dopaminergic activity in the SNpc via axon collaterals * Saccadic eye movement (Parkinson’s, Epilepsy) PARKINSON’S DISEASE (PD) PD is a progressive degenerative disorder.

Characterised by symptoms of treamour, rigidity, reduction in movement and postural instability. It is due to the loss of the dopamine cells in the substantia nigra pars compacta. The reason why these neurons degenerate is relatively unknown but what is considered as risk factors are age, environmental factors: working with various pestasites or drugs abuse as well as males. Normal PD DIAGRAM TO ILLUSTRATE THE DIRECT AND INDIRECT PATHWAYS IN THE BASAL GANGLIA The striatum neurons projects the D2 receptors that contain neurons into the globis pallidus external (which is highlighted in blue). These neurons project onto the inhibitory neurons which is then projected into the subthalamic nucleus.

The STN are the only nucleus that contains the excitatory glutamatergic neurons which goes on to project onto the GPi. Also in the striatum neurons, it projects D1 receptors which goes straight to the GPi, therefore direct. The GPi has the final say on telling the thalamus what type of movement and how much movement to generate. After the information being fed to the thalamus, it is then projected back to the cortex. The cortex information is then projected back to the striatum to form the ‘motor loop’. Having said all that, you have lastly the dopamine neuron is really there almost like an outsider because it doesn’t give precise instruction. It sends these dopermergic neurons onto the D1 / D2 containing receptors.

So depending on how much dopamine is released onto the D2 or D1 receptor pathway, it tells the neuron is it going to inhibit or facilitate movement. PARKINSON’S DISEASE PATHWAY In the case of PD, it is an overactivation of the D2 pathway. So what that means is that because of the lack of dopamine going to the substantial nigra there is an overactivation of the inhibitory pathway going from the striatum neurons to the GPe which causes a massive inhibition therefore causing a DISinhibition of the GABAretic neuron (remember: massive inhibition of a inhibition will cause a reduction of inhibition) thereby causing a massive excitation because of the lack of inhibitory input.

As a result of massive excitation to the GPi, it tells the thalamus it needs to inhibit the movement. Therefore overall has output of impaired movement. PARKINSON’S DISEASE: DRUG TREATMENT In order to target ot treat PD, the gold standard therapy is with a drug called Levodopa. Levodopa is essentially a substrate for making dopamine. Because we have a loss in dopamine containing cells we are trying to bypass that pathway by providing the brain with exogenous L-DOPA. Thankfully L-DOPA itself is able to cross the blood brain barrier thereby you can take it orally and this has been the hallmark therapy for PD. Very effective and has an amazing reverse motor deficits observed for about 3 – 5 years.

Unfortunately you get side affects known as L-DOPA induced carnassials and also seems to lead to unwanted behaviours ie some PD patients want to gamble, sex? (reward cycle) Here is a PET scan from a normal and PD patient. In the normal patient, the red area is a scan of F-DOPA update. Fluro DOPA is a radioactive tracer that is able to be taken up by the dopamine terminals. In the normal scan it indicates that the dark stained areas is the putamen that has taken up the tracer normally. Looking at the PD patient, Pre (baseline) you have severely reduced activity uptake of Fluro DOPA therefore means reduced dopamine terminals. In the Post is when patient is given L-DOPA and it can be seen it was able to rescue the dopamine terminals.

After 3 – 5 years of using L-DOPA, you start to get an overactivation of the direct pathway (pathway on the bottom). This is where we have a stimulation of the dopamine D1 receptor which provides a massive inhibition from the Striatum to the GPi thereby telling the thalamus it can do whatever it pleases (L-DOPA Induced Dyskinesia/Huntington’s disease). PARKINSON’S DISESE – SURGICAL TREATMENT There are surgical treatment for PD. 1/ Pallidotomy * Turn off the GPi. So in PD we have this massive inhibition coming from the GABAretic neurons therefore we have a massive overactivity of the GPi neurons. Therefore the pallidotomy aims to switch it off 2/ Deep brain stimulation The thalamus, able to implant a stimulating electrode into the different substructures, in this case the subthalamic nucleus and its becoming a more popular option in advanced PD patients * Expensive * Side effects – leading to suicide Here you have a massive inhibitory coming in on the striatum in the GPe leading to the overactivity of the STN that is an excitatory input to the GPi leading to the thalamus reading impaired movement. DBA dampens the STN and therefore facilitates movements. HUNTINGTON’S DISEASE Neurodegenerative disease * Hereditary disease with a dominate gene (Huntington) * Degeneration of the MSNs in the caudate putamen ~ reduced inhibition of the GPi * Symptoms ~ continuous dance-like movements of the face and limbs ~ small brain


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