notes - NPB12 Lecture 7 T here are two major...

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Unformatted text preview: NPB12 Lecture 7 T here are two major neurotransmitters that open ligandgated channels. Glutamate opens ligand-gated Na+ channels:so these synapses are considered excitatory The other major neurotransmitter is gamma-aminobutyric acid (GABA). GABA binds to a ligand- gated Cl- channel, which allows Cl- to cross the membrane:so it can be considered inhibitory Asynergia: Loss of coordinated movement Choreas Symptoms: arrhythmic involuntary movements Usually termed writhing . Can involve only a few body parts or progress to the entire body. Huntington s Chorea is an autosomal dominant. It will progress from no symptoms to full writhing and death. There are also cognitive symptoms, where you become irritable, violent, incoherent, etc. George Huntington Ballismus: When these movements are of high amplitude and involve the proximal muscles Presented in 1872. Thought it was exclusive to the east end of Long Island Dystonias An abnormal hyperkinetic movement distinct from chorea. It is generally a twisting motion and repetitive. Over time the body part affected may develop a fixed posture. Three types, depending on how many body parts are affected: Focal Dystonia one or two body parts affected - writer s cramp -  musicians Segmented Dystonia Several body parts affected - frozen shoulder General Dystonia multiple body parts affected Tics: Brief, sudden stereotyped movements. Commonly in the face, neck, and eyelids. Most famous is probably Tourette s Syndrome: Inherited disease that starts with a tic of the face or neck. Can progress to arms, chest, legs, etc. Often get vocalizations (grunts, barks) Most famous for eventually leading to coprolalia =saying obseen things Dr. Gilles de la Tourette Dr. Gilles de la Tourettee writes; Marquise de Dampierre at the age of 7 was afflicted by convulsive movements of the hand and arms! After each spasm, the movements of the hand became more regular and better controlled until a convulsive movement would again interrupt her work. She was felt to be suffering form over excitement and mischief, and because the movements became more and more frequent, she was subjected to reprimand and punishment. It soon became clear that these movements were indeed involuntary. They involved the shoulders, the neck, and the face, and resulted in contortions and extraordinary grimaces. As the disease progressed, and the spasms spread to involver her voice and speech, the young lady made strange screams and said words that made no sense. However, during all this, she was clearly alert, and showed no signs of delirium or other mental problems. Months and years passed with no real change in her symptoms. It was hoped that with puberty these might naturally abate, but this did not occur. In the midst of an interesting conversation, all of a sudden, without being able to prevent it, she interrupts what she is saying or what she is listening to with horrible screams and with words that are even more extraordinary than her screams. All of this contrasts deplorable with her distinguished manners and background. These words are, for the most part, offensive curse words and obscene saying. These are no less embarrassing for her than for those who have to listen, the expressions being so crude that an unfavorable opinion of the woman is almost inevitable. Tremor at rest: Uncontrollable motion before the initiation of a voluntary movement. Once the movement is started, the motion is essentially normal. "brain surgeon analogy" Most commonly occurs in the hands, but also the mouth and neck. Tremor in motion: No tremor before movement initiation, but then one the trajectory is off, it appear that there is over-compensation. So you go a bit too far to the right, then too far to the left, then too far to the right again, etc. Parkinson s Disease Four Cardinal Symptoms: Patient can have two or more of varying severity 1) Tremor at rest: Pill-rolling tremor 2) Rigidity: cogwheeling ( ratchet-like ) from upper motor neuron lesions a tremor of motion between the index finger and thumb like you are rolling a pill. 4) Postural Deficits this is easily demonstrated by pulling the patient back by the shoulders. A normal person will take only one step to recover, but the Parkinson's patient will continue to make small, shuffling steps backward and usually never regain balance. in which the rigidity is relaxed, but it soon becomes very rigid again. This is called cogwheeling, and is very ratchet-like. 3) Bradykinesia (progresses to akinesia) is a slowness of movement, or an inability to initiate movement Sending signals from the brain down the spinal cord: Corticospinal tract distal muscles fine motor movements Cortico-Spinal Tract: These are the axons from neurons with the cell body in the cerebral cortex that synapse onto the ventral horn neurons. The vast majority of these neurons are in either the motor cortex or the somatosensory cortex. In the most simple world, these axons control movement of the small distal muscles, for example of the fingers and hands. Rubrospinal tract proximal muscles gross motor movements posture Rubro-Spinal Tract: These are the axons from neurons with the cell body in the Red Nucleus that synapse onto the ventral horn neurons. these neurons control the larger proximal muscles that control posture, and large scale movements. Six areas in the brain involved in motor control (1) Cerebral Cortex Fine motor control forms the corticospinal tracts T his "map" of the movements created by stimulation of the motor cortex has been called a "homunculus". This means that if you have a very small lesion in the cerebral cortex, you can lose the function of a restricted body part, and if the lesion is only on one side, you lose the ability to move that restricted body part only on the contralateral side from the lesion. (2) Cerebellum: coordination of fine motor movements, particularly maintaining posture, speech, and eye movements influences the coordination of movements, and makes the difference between smooth and clumsy movements. This region of the brain is particularly affected by alcohol, which is why inebriation causes clumsy walking, slurred speech, and most deficits revealed by law enforcement officers using a field sobriety test (3) Basal Ganglia Movement Initiation accurately described as a set of nuclei located near the center of the brain. (4) Motor thalamus Integrates information and sends to the cerebral cortex function as an integrator, and "gateway" for the interactions between the cerebral cortex and the cerebellum and basal ganglion. cell bodies get inputs from cerebral cortex. (5) Substantia Nigra Provides key input to the basal ganglion T his is also a structure of the midbrain that is the primary non-cortical input to the basal ganglion. For this reason it is mostly involved in the initiation of movements. Many of the cells of this area use dopamine as their neurotransmitter. It is located ventral to the basal ganglion. T his is a structure of the midbrain that sends axons directly down the spinal cord. Is primarily involved in movement of the proximal muscles of the limbs (6) Red nucleus Input to the ventral horn of the spinal cord for control of proximal muscles, gross limb and trunk movements cerebral cortex thalamus substantia nigra basal ganglia red nucleus cerebellum brainstem spinal cord cerebral cortex thalamus substantia nigra basal ganglia red nucleus cerebellum brainstem spinal cord cerebral cortex thalamus substantia nigra basal ganglia red nucleus cerebellum brainstem spinal cord cerebral cortex thalamus substantia nigra basal ganglia red nucleus cerebellum brainstem spinal cord A close look at Parkinson s Disease 1817 James Parkinson noted shaking palsy due to >80% of dopamine neurons in substantia nigra dying 4 primary ways that you can get it: 1) paralysis agitans: don t know why (most common) 2) encephalitis lethargica: infection from a virus 3) artheriosclerotic 'parkinsonism : due to stroke in the substantia nigra 4) toxin-induced. (MPTP) Locus ceruleus: This is a small nucleus that is made up of neurons that release norepinephrine as the neurotransmitter. Norepinephrine is a slowsynapse neurotransmitter, but can be considered in general terms as excitatory. Raphe nucleus: This is another small nucleus in the brainstem that is made up primarily of neurons that release serotonin, another slowsynapse transmitter. Substantia Nigra: The substantia nigra is located in the midbrain, and is characterized, and thus named, by dark pigmentation. in fresh brain tissue without staining it. This area is more appropriately divided into two parts. One part projects to both the caudate and putamen. These neurons contain and release dopamine, a slow neurotransmitter. What does dopamine do? It is a neuromodulator A B C membrane potenti al (mV) s ti m A time s tim B stim A stim B How does it do that? The neurotransmitter binds to a receptor, but doesn t have to open a channel (in some cases it does). The receptor then activates a G-protein. The G-protein then activates another molecule, which is an enzyme. This enzyme causes a chemical reaction, which increases the amount of a particular molecule called the second messenger. This second messenger then activates yet another molecule that can then affect the receptors at other synapses, for example the ligand-gated Na+ channels. The net effect of this is absolutely determined by which receptors are activated, and in what ways. Adenylate cyclase: Converts ATP to cAMP. Guanyl cyclase: Converts GTP to cGMP. Phospholipid Hydrolysis: Makes IP3 (inositoltriphospate) and/or (several different enzymes): DAG (diacylglycerol) How can the second messenger change the response of the cell to a different synapse? (e.g. how does stimulation at A change the response at B?) Make the glutamate-receptor Na+ channel open more easily (excitatory) Make the glutamate-receptor Na+ channel more difficult to open (inhibitory) Make the glutamate-receptor Na+ channel stay open longer (excitatory) Make the glutamate-receptor Na+ channel close sooner (inhibitory) Tell the cell to make more glutamate-receptor Na+ channels (excitatory) Tell the cell to make fewer glutamate-receptor Na+ channels (inhibitory) Tell the cell to make more K+ pores that are always open (inhibitory) Tell the cell to make fewer K+ pores that are always open (excitatory) You could also do the same things with the GABA channels Make the GABA-receptor Cl- channel open more easily (inhibitory) Make the GABA-receptor Cl- channel more difficult to open (excitatory) Make the GABA-receptor Cl- channel stay open longer (inhibitory) Make the GABA-receptor Cl- channel close sooner (excitatory) Tell the cell to make more GABA-receptor Cl- channels (inhibitory) Tell the cell to make fewer GABA-receptor Cl- channels (excitatory) Globus Pallidus: There are two subdivisions of the globus pallidus, called either the internal and external or the medial and lateral. Each nucleus of the striatum projects to both nuclei of the globus pallidus, and the striatum neurons release GABA, which inhibits the post synaptic cell by opening a Cl- channel. The opened Cl- channel drives the membrane potential to a voltage below the activation threshold, and therefore it is inhibitory. Many neurons also release protein neurotransmitters such as enkephalin, dynorphin, and substance P. These proteins are the "endogenous opiates" which bind to the same receptors and act just like morphine. It is actually more accurate to say that morphine acts like these proteins. Two mechanisms also regulate dopamine action (1)  specific re-uptake autoreceptors (2) enzymes that break it down: monoamine oxidase These enzymes work not only on (MAO) dopamine, but also on other modulatory neurotransmitters such as norepinephrine and serotonin. MAO is also found inside the presynaptic neuron. This is important because many drugs used for mental illness work on these enzymes to effectively increase or decrease the amount of dopamine, serotonin, and/ or norepinephrine in the synaptic cleft. Substantia Nigra: The outputs from the caudate and putamen also project to the same cells in the substantia nigra that release dopamine, again these neurons are inhibitory and release GABA. The accumbens and caudate nuclei also project onto a second part of the substantia nigra, on cells that do not contain dopamine, but contain and release GABA. These cells project their axons to the thalamus, superior colliculus, and the brainstem. These outputs are inhibitory and release GABA Other neuromodulators use similar mechanisms, and the same enzymes. Serotonin (5HT) and norepinephrine (noradrenaline) also use specific reuptake autoreceptors Monoamine oxidase (MAO) catechol-o-methyl transferase (COMT). glutamate cerebral cortex Raphe nucleus (serotonin) + + glutamate striatum (caudate & putamen) Locus coreleus (norepinephrine) GABA - globus palladus GABA Substantia Nigra (dopamine) minus = inhibitory plus= excitatory thalamus + cerebral cortex Raphe nucleus (serotonin) glutamate less excitatory input means less output less excitatory input glutamate means less output + striatum (caudate & putamen) Locus coreleus (norepinephrine) less excitatory input means less output GABA - globus palladus Substantia Nigra (dopamine) less inhibitory input means more output - thalamus more inhibitory input GABA means less output + + cerebral cortex Raphe nucleus (serotonin) glutamate less excitatory input means less output less excitatory input glutamate means less output + + striatum (caudate & putamen) Locus coreleus (norepinephrine) less excitatory input means less output GABA - globus palladus Substantia Nigra (dopamine) less inhibitory input means more output - thalamus more inhibitory input GABA means less output Treatments: In principle you can either replace the dopamine, keep the substantia nigra cells from dying, or replace the substantia nigra cells. Replace the dopamine: dopamine doesn t cross the blood-brain barrier, so use L-Dopa Side effects include choreas, ballismus, psychosis, depression Keep substantia nigra cells alive: Difficult to do when you don t know why they are dying in the first place. Diet, vitamins, etc. have been touted, but little direct evidence that they work. Replace the dead/dying cells: Much promise with stem cells, although research is difficult to conduct. Transplant of other cells tends to lead to those cells dying as well. Could be due to the difficulty in transplantation techniques, or whatever killed the original dopamine cells kills the transplanted cells as well. Deep Brain Stimulation + cerebral cortex Raphe nucleus (serotonin) glutamate less excitatory input means less output less excitatory input glutamate means less output + striatum (caudate & putamen) Locus coreleus (norepinephrine) less excitatory input means less output GABA - globus palladus Substantia Nigra (dopamine) less inhibitory input means more output - thalamus more inhibitory input GABA means less output + + cerebral cortex Raphe nucleus (serotonin) glutamate mess excitatory input l ore means more output means less mlore excitatory input glutamate ess excitatory input mmeans less output + eans more output + striatum (caudate & putamen) Locus coreleus (norepinephrine) more excitatory input means less excitatory input means more output less output GABA - globus palladus Substantia Nigra (dopamine) more inhibitory input less inhibitory input means less output means more output electrically stimulate - GABA thalamus more inhibitory input means less output Added electrical pulses increases activity A second treatment is to make lesions in the globus palladus, where the neurons are more active than usual. + cerebral cortex Raphe nucleus (serotonin) glutamate + more excitatory input glutamate less excitatory input means more output means less output + + striatum (caudate & putamen) Locus coreleus (norepinephrine) lmore excitatory input means ess excitatory input means lmore output ess output GABA - - globus palladus Substantia Nigra (dopamine) more inhibitory input lesioninhibitory input less of active cells means less output means more output - thalamus less inhibitory input more inhibitory input more output GABA means less output Huntington s Chorea: Loss of GABAergic cells in the striatum, leading to overactivity of the dopaminergic cells. It also causes atrophy of the caudate nucleus and degeneration of the cerebral cortex. Sources of the problems associated with different motor disorders: Choreas: Basal Ganglia Dystonias: Probably the cerebral cortex Tremors: Basal Ganglia (at rest) or Cerebellum (in motion) Tics: Usually Basal Ganglia ...
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This note was uploaded on 12/01/2011 for the course NPB 72965 taught by Professor Recanzone during the Fall '11 term at UC Davis.

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