TA questions

The autonomic nervous system is often summarized as fight of flight response. Is this really accurate?

"fight-or-flight" response is a critical sympathetic function. Two important ideas underlie this insight. First, the sympathetic and parasympathetic systems play complementary, even antagonistic, roles; the sympathetic system promotes arousal, defense, and escape, whereas the parasympathetic system promotes eating and procreation. Second, actions of the sympathetic system are diffuse; they influence all parts of the body and once turned on can persist for some time. These ideas are behind the popular notion of the "adrenaline rush" produced by excitement, as by a roller coaster ride. Because the fight-or-flight model assumes antagonistic roles for the sympathetic and parasympathetic systems, Cannon's model led to an overemphasis on the extremes of autonomic behavior. Actually during everyday life the different divisions of the autonomic system are tightly integrated. In addition, we now know that the sympathetic system is less diffusely organized than first envisioned by Cannon. Subsets of neurons even within the sympathetic division control specific targets, and these pathways can be activated independently. As in the somatic motor system, reflexes in the autonomic motor system are elicited through sensory pathways and are hierarchically organized. The simplest feedback loops are confined to the periphery and spinal cord, whereas more complex loops extend to higher centers. An important feature of this organization is that it allows for coordination between the different divisions of the autonomic system. The interplay between different systems in simple autonomic behaviors is analogous to the role of antagonist muscles in locomotion. To walk, one must alternately contract antagonist muscles that flex and extend a joint. Similarly, the sympathetic and parasympathetic systems are often partners in the regulation of end-organs. In most cases, ranging from the simplest reflexes to more complex behaviors, all three peripheral divisions of the autonomic system work together.

Describe the activity of the basal ganglia neurons in an awake, resting, non-human primate.

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Describe the series of lesion experiments done in the 1960s by Lawrence and Kuypers that decipher the roles of the descending pathways. 1. CST lesion 2. CST and lateral brainstem (red nucleus) lesion 3. CST and medial brainstem lesion

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How were electrical stimulation experiments used to validate Penfield's motor map?

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Know some examples of experiments that demonstrate how inhibition of SNr leads to motor movement.

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Know the canonical circuit of the Basal Ganglia. Distinguish the direct from the indirect pathway.

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Know the spino-cerebellar system - how are the pathways divided?

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What is the cause of Parkinson's disease and how does it affect the basal ganglia pathways?

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What is the purpose of the indirect pathway?

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What is the role of gabaergic interneurons in the basal ganglia? What is the role of cholinergic interneurons?

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Be familiar with the anatomy of the ocular motor system: nuclei, cranial nerves, and the muscles they innervate.

...The lateral rectus is innervated by the abducens nerve (cranial nerve VI), ventricle. The superior oblique muscle is innervated by the trochlear nerve (cranial nerve IV), whose nucleus is located in the midbrain at the level of the inferior colliculus. (The trochlear nerve gets its name from the trochlea, the bony pulley through which the superior oblique muscle travels.) All the other extraocular muscles—the medial, inferior, and superior recti and the inferior oblique— are innervated by the oculomotor nerve (cranial nerve III), whose nucleus lies in the midbrain at the level of the superior colliculus. The oculomotor nerve also contains fibers that innervate the levator muscle of the upper eyelid.

Saccades: How long is the latency of the saccade after target movement? Be familiar with these traces

200ms saccade (/sᵻˈkɑːd/ sə-kahd, French for jerk) is a quick, simultaneous movement of both eyes between two phases offixation in the same direction.[1] The phenomenon can be associated with a shift in frequency of an emitted signal or a movement of a body part or device. Controlled cortically by thefrontal eye fields (FEF), or subcortically by the superior colliculus, saccades serve as a mechanism for fixation, rapid eye movement, and the fast phase of optokinetic nystagmus As saccade velocity increase you get bigger movements The peak angular speed of the eye during a saccade reaches up to 900°/s in humans. Saccades to an unexpected stimulus normally take about 200 milliseconds (ms) to initiate, and then last from about 20-200 ms, depending on their amplitude (20-30 ms is typical in language reading). Under certain laboratory circumstances, the latency of, or reaction time to, saccade production can be cut nearly in half (express saccades). The amplitude of a saccade is the angular distance the eye travels during the movement. For amplitudes up to 15 or 20°, the velocity of a saccade linearly depends on the amplitude (the so-called saccadic main sequence,[9] a term borrowed fromastrophysics; see Figure). For amplitudes larger than 20°, the peak velocity starts to plateau[9] (nonlinearly) toward the maximum velocity attainable by the eye at around 60°. For instance, a 10° amplitude is associated with a velocity of 300°/s, and 30° is associated with 500°/s.[4] Therefore, for larger amplitude ranges, the main sequence can best be modeled by an inverse power law function.[10] The high peak velocities and the main sequence relationship can also be used to distinguish micro-/saccades from other eye movements like (ocular tremor,ocular drift and smooth pursuit). Velocity-based algorithms are a common approach for saccade detection in eye tracking

Kalaska set out to resolve these disparate conclusions. What was his experimental design? What were his findings? What does this lead him to conclude about M1 neurons and load sensitivity?

A monkey made arm movements exactly as in the task used by Georgopoulos (Figure 37-10), but additional external loads pulled the arm in different directions. To continue to move the arm along the same path, the monkey had to change the activity of its arm muscles to counteract the external loads. The level of activity of many motor cortex neurons changed systematically with the direction of the external load even though the movement path did not change. When the load opposed the direction of reach, the single-cell and total population activity increased. When the load assisted the reaching direction, the neural activity decreased At least over part of the tested range these responses vary linearly with the level of static force. When a monkey uses its whole arm to exert isometric force in different directions, the activity of many motor cortex neurons varies systematically with force direction, and the directional tuning curves resemble those for activity associated with reaching movements (Figure 37-14B). Because no movement is intended or produced in isometric tasks, this strongly suggests that the primary motor cortex contributes to the control of static and dynamic output forces during many motor actions

What is the function of gamma motorneurons? Why is alpha gamma co-activation important?

Alpha (α) motor neurons are large, multipolar lower motor neurons they innervate extrafusal muscle fibers and are directly responsible for initiating their contraction. Alpha motor neurons are distinct from gamma motor neurons, which innervate intrafusal muscle fibers of muscle spindles. When the central nervous system sends out signals to alpha neurons to fire, signals are also sent to gamma motor neurons to do the same. This process is called alpha gamma co-activation, which is what maintains tautness of the muscle spindles. It is important to note that nuclei of spindle muscle cells are located in the middle of these spindles and intrafusal muscle fibers do not have myofibrils, the contractile elements of muscles. Without gamma motor neurons, muscle spindles would be very loose as the muscle contracts more. This does not allow for muscle spindles to detect a precise amount of stretch since it is so limp. However, with alpha gamma co-activation where both alpha neurons and gamma neurons are present, muscle fibers with the muscle spindles are pulled parallel to the extrafusal contraction causing the muscle movement. The firing of gamma motor neurons in sync with alpha motor neurons pulls muscle spindles from polar ends of the fibers as this is where gamma motor neurons innervate the muscle. This part of the spindle is innervated by type Ia sensory fiber that go on to synapse with alpha motor neurons, completing the gamma-loop. The parallel pulling keeps muscle spindles taut and readily able to detect minute changes in stretch.

What do neurons in the parietal reach region encode?

Andersen and his associates propose that the reach-related region of parietal cortex is particularly important for specifying the goal or target of reaching but not how the action should be performed. The activity of many neurons in this area varies with the location of the target relative to the hand. Remarkably, however, this motor error signal is not centered on the current location of the hand or target but rather on the current direction of gaze. Each time the monkey looks in a different direction the reach related activity in the neurons changes (Figure 38-6). In contrast, the reach related activity of many neurons in area PEip is less gaze-centered and more related to the current hand position and arm posture. Another important property of neurons in the parietal reach region is that they respond not only to passive sensory inputs but also before the onset of movements and during the planning period of delayed-reaching tasks. This behavior indicates that these neurons receive centrally generated signals about motor intentions prior to movement onset, likely through their reciprocal connections with precentral motor areas.

Know the baro-reflex pathway anatomy and function. What is its purpose?

Arterial blood pressure is sensed by baroreceptors, a type of stretch receptor neuron, in the carotid sinus near the base of the brain. After integration in the medulla this information provides negative feedback control of the cardiovascular system. The sympathetic component of the circuit includes outputs that stimulate the heart's pumping capacity (cardiac output) by increasing heart rate and the strength of contractions. In addition, sympathetic stimulation causes arteries to contract, which raises the hydraulic resistance to blood flow. Together the effects of increased cardiac output and increased vascular resistance raise mean arterial blood pressure. Importantly, inhibitory projections from the caudal to the rostral ventral lateral medulla create negative feedback so that an increase in blood pressure inhibits sympathetic activity, whereas a decrease raises sympathetic activity. Although omitted for simplicity, parasympathetic neurons in the cardiac ganglion also contribute to the reflex by creating an inhibitory cardiac input that is functionally antagonistic to the sympathetic pathway (see Figure 49-9B). During baroreceptor reflexes parasympathetic activity within the heart is therefore increased by hypertension and reduced by hypotension the firing of sensory neurons conveys information about arterial pressure that medullary circuits use as feedback to control descending commands and thereby regulate preganglionic sympathetic neurons. This feedback is said to be negative because of the inverse relation between sensory input and functional motor output: An increase in blood pressure increases sensory activity that decreases sympathetic motor tone, which then reduces pressure. Set point and gain are critical components of this type of control, as they are in regulating motivational state. The set point is the target for regulation and is analogous to thermostat settings on home heating systems. Gain is the amplification generated by the feedback loop.

How does peak velocity of the eye movement relate to saccade amplitude?

As saccade velocity increase you get bigger movements The peak angular speed of the eye during a saccade reaches up to 900°/s in humans. The amplitude of a saccade is the angular distance the eye travels during the movement. For amplitudes up to 15 or 20°, the velocity of a saccade linearly depends on the amplitude (the so-callled main sequence). For amplitudes larger than 20°, the peak velocity starts to plateau (nonlinearly) toward the maximum velocity attainable by the eye at around 60°. The high peak velocities and the main sequence relationship can also be used to distinguish micro-/saccades from other eye movements like (ocular tremor,ocular drift and smooth pursuit).

What is the general gradient as you go from the premotor areas to the primary motor cortex?

As you move from the central sulcus in the most caudal part of primary motor cortex we move from areas that represent movement execution onto signals that represent more of where you want to go. As they moved from motor to premotor the movement related cells gradually decreased and the cognitive set gradually increased So intrinsic to extrinsic.

What is BMI? What is spike-sorting? How is Dr. Miller using Georgopoulos' models in his own research?

BMI is brain machine interface and spike sorting is the distinguishing of individual recorded action potentials in an array.

What happens when you stimulate the Rostral Ventral Lateral Medulla? Inactivate the RVLM? What does this imply about the function of the RVLM?

Baroreceptors are present in the auricles of the heart and vena cavae, but the most sensitive baroreceptors are in the carotid sinuses and aortic arch. While the carotid sinus baroreceptor axons travel within the glossopharyngeal nerve (CN IX), the aortic arch baroreceptor axons travel within the vagus nerve (CN X). Baroreceptor activity travels along these nerves directly into the central nervous system to contact neurons within the nucleus of the solitary tract (NTS) in the brainstem. Baroreceptor information flows from these NTS neurons to both parasympathetic and sympathetic neurons within the brainstem. The NTS neurons send excitatory fibers (glutamatergic) to the caudal ventrolateral medulla (CVLM), activating the CVLM. The activated CVLM then sends inhibitory fibers (GABAergic) to the rostral ventrolateral medulla (RVLM), thus inhibiting the RVLM. The RVLM is the primary regulator of the sympathetic nervous system, sending excitatory fibers (glutamatergic) to the sympathetic preganglionic neurons located in the intermediolateral nucleus of the spinal cord. Hence, when the baroreceptors are activated (by an increased blood pressure), the NTS activates the CVLM, which in turn inhibits the RVLM, thus decreasing the activity of the sympathetic branch of the autonomic nervous system, leading to a relative decrease in blood pressure. Likewise, low blood pressure activates baroreceptors less and causes an increase in sympathetic tone via "disinhibition" (less inhibition, hence activation) of the RVLM. Cardiovascular targets of the sympathetic nervous system includes both blood vessels and the heart.

Describe a motor learning experiment that reveals evidence for internal models for limb movement.

Bizzi recorded the activity of the same primary motor cortex neurons over several hours in monkeys as the animals first made arm movements without an external force field, then while they made many movements to adapt to a viscous curl field, and finally while they readapted to the baseline condition (the "washout" period). As the monkeys adapted to the force field the directional tuning of many neurons gradually changed from what it was before exposure to the viscous curl field as the movement paths became incrementally straighter. If the force field is then unexpectedly turned off, the path of movement curves strongly in the opposite direction. This after-effect demonstrates that the subject has changed the motor command required to produce the desired straight movement in anticipation of the perturbing effect of the force field. Eventually the limb movement rotated back to the baseline during the washout period. Arm muscles showed similar changes during adaptation and washout, implicating those neurons in the incremental adaptation of the motor command to the external curl field. As a subject adapts to the force field, motor behavior changes from feedback correction for actual perturbations to predictive feed-forward compensation for expected perturbation. Motor-learning theory suggests that this adaptive process may involve at least two distinct learning mechanisms, known as feedbackerror learning and supervised learning. In supervised learning the motor system gradually adapts internal models, neural circuits that learn the relationship between desired movements and required motor commands in that environment. An internal forward model estimates the state of the limb in the near future based on an efference copy of the motor command and sensory feedback of the ongoing movement, and uses this estimate to generate an error signal proportional to the deviation of the estimated movement from its desired kinematics. An internal inverse model uses this and other error signals to learn how to generate the motor command that will produce a desired movement by compensating in a predictive manner for the anticipated perturbation BIzzi found two other groups of neurons showed special properties. The directional tuning of one group changed when the monkeys switched from the null field to the curl field but did not return to baseline during washout. The other group did not change during the original adaptation from null field to curl field but changed during washout. Bizzi proposed that these two groups of neurons retain the memory of one or the other of the successive learning episodes—adaptation and washout—suggesting that the motor map of the primary motor cortex is not static.

What are some of the behavioral deficits we can observe with a cerebellar lesion? What is ataxia?

Cerebellar disorders are manifested in four symptoms. The first is hypotonia, a diminished resistance to passive limb displacements. Hypotonia is also thought to be related to so-called "pendular reflexes." In patients who have cerebellar disease, the leg may oscillate like a pendulum as many as eight times before coming to rest. The second symptom is astasia-abasia, an inability to stand or walk. Astasia is loss of the ability to maintain a steady limb or body posture across multiple joints. The third symptom is ataxia, the abnormal execution of multi-jointed voluntary movements, characterized by lack of coordination. Patients have problems initiating responses with the affected limb and controlling the size of a movement (dysmetria) and the rate and regularity of repeated movements (Figure 42-1). This last deficit is most readily demonstrated when a patient attempts to perform rapid alternating movements, such as alternately touching the back and the palm of one hand with the palm of the other. Patients cannot sustain a regular rhythm or produce an even amount of force, a sign referred to as dysdiadochokinesia (Greek, impaired alternating movement). Holmes also noted that patients made errors in the timing of the components of complex multi-joint movements (decomposition of movement) and frequently failed to brace proximal joints against the forces generated by the movement of more distal joints. The fourth symptom of cerebellar disease is a form of tremor at the end of a movement, when the patient attempts to stop the movement by using antagonist muscles. This action (or intention) tremor is the result of a series of erroneous corrections of the movement. Once a movement is clearly headed in the wrong direction, attempts to make corrections fail repeatedly and the hand oscillates irregularly around the target in a characteristic terminal tremor.

What is a mirror neuron?

Compelling evidence in support of the directmatching hypothesis was provided when Rizzolatti and colleagues discovered a remarkable population of neurons in area F5 of the ventral premotor cortex. These so-called mirror neurons discharge both when the monkey performs a motor act and when it observes a similar act performed by another monkey or by the experimenter (Figure 38-16). Mirror neurons do not respond when a monkey simply observes an object or when it observes mimed arm and hand actions without a target object. Because each of us understands the causes and outcomes of our own motor acts, the direct-matching hypothesis proposes that the activity of mirror neurons during observation of the actions of others provides a mechanism of transforming complex visual inputs into a high-level understanding of the observed actions. Other experiments with monkeys have provided further evidence that mirror neurons become active whenever an individual recognizes and understands the motor acts of others. Some F5 neurons selectively discharge when the monkey observes the act of grasping an object with the hand. When the target object is obscured by a screen, some of those mirror neurons discharge as the hand approaches the hidden object and continue to respond while the hand is behind the screen. If the monkey is first shown that there is no object behind the screen, however, those same neurons remain silent when the hand disappears behind the screen. This result suggests that mirror neurons generate an internal representation of the action even when it is not visible. Although area F5 receives no direct input from visual areas, the rostral intraparietal cortex that projects to it receives visual input from the superior temporal sulcus, a region that encodes high-level visual information but is devoid of motor signals.

What is the role of cholinergic interneurons in associative learning?

Conditioned stimuli produce a pause in tonic activity (3-5 Hz) lasting 100-200 ms, which may or may not be flanked by briefer periods of enhanced activity this signals the stratum that something is happening and we should be paying attention. It is necessary for the formation of new associations because without this phenomenon we dont see a conditioning of the stimuli

How does D1 and D2 receptor activation change the L-type inward current?

D1 are excitatory and increase L-type current because it activates the adenlycyclase that phosphorylates CAV1 increasing its activity D2 are inhibitory and decrease L-type Current via activation of phospholipase that eventually inactivate Cav1

Describe the basic steps involved in transformation of motor intent into motor execution. What is the difference between extrinsic and intrinsic kinematics?

Divided into three sequential stages. First, perceptual mechanisms generate a unified sensory representation of the external world and the individual within it. Next, cognitive processes use this internal replica of the world to decide on a course of action. Finally, the selected motor plan is relayed to action systems for implementation The final stage, execution of the chosen motor plan. The "action" stage that converts an intention into a physical movement is often presumed to involve a hierarchy of operations that transform a general plan into progressively more detailed instructions about its implementation. The model suggests that the brain plans a chosen reaching movement by first calculating the extrinsic kinematics of the movement (eg, target location, trajectory of hand displacement from the starting location to the target location), then calculating the required intrinsic kinematics (eg, joint rotations) and finally the causal kinetics or dynamics of movement (eg, forces, torques, and muscle activity).

Know the roles of SNc dopamine neurons in learning. What properties of reward do these neurons encode?

Dopamine neurons not only record unexpected reward response but also reward probability What this means is that the less probable the reward the lower the level of activity when presented the cue but the more the neuron will fire when it actually receives the reward. The increased concentration of dopamine could be particularly important for activation of D1-like dopamine receptors because they have much lower affinity for dopamine than D2-like receptors. Stimulated the nigre striatal pathway and first he stimulated at 4hz and saw these little peaks of activity which represents tonic activity Then he stimulated the same cells more frequently and saw an increase in dopamine activity, so we believe that LTP requires D1 receptors (D1 and D5) D1 is a low affinity receptor and that is why we need a burst of dopamine activity to activate learning.

Be comfortable demonstrating how the visual map corresponds to motor error map of the superior colliculus. Explain how the motor error map differs from a hypothetical goal-directed motor map.

Each line with an arrow is an eye movement, what we are suppose to get is that they are all the same, this is because we are stimulating the same part of the colliculi. But in each trial the eye was looking somewhere else, the point is that wherever you are looking the eye will jump in the same direction at the same amplitude, so it is a motor error or incremental command this is good because this is what we expect if we have a retinotopic map driving it i.e. So in reality what matters is how far off it is from the retina not where you are looking to begin with. Robinson knew this an so he added this figure about what people thought was happening i.e if you stimulate a spot in the colliculus then focus should go to this spot, that is a goal directed behavior but in reality this is a motor error or incremental system. The goal directed map doesn't make sense because it would imply that when you look at a different direction that the areas would need to encode for a different command even if the retinal displacement was the same.

What is the mechanism of this cerebellar learning? (Think about LTD in relation to the parallel fiber stimulation).

Ed - Climbing fiber (a.k.a inferior olivary neurons) activity produces long-lasting effects on the synaptic efficacy of parallel fibers. Climbing fiber input to Purkinje neurons modifies the response of the neurons to mossy fiber inputs and does so for a prolonged period of time. Climbing fibers can selectively induce LTD in the synapses between Purkinje neurons and parallel fibers that are activated concurrently with the climbing fibers. Concurrent stimulation of climbing fibers and parallel fibers depresses the Purkinje cell responses to subsequent stimulation of the same parallel fibers but not to stimulation of parallel fibers that had not been stimulated earlier along with climbing fibers. During inaccurate movements the climbing fibers respond to specific movement errors and depress the synaptic strength of parallel fibers involved with those errors.

Dr. Miller describes an experiment related to saccade gain. What happens when you remove the cerebellum?

Experimenters surgically weakened one eye in cat and covered this eve with a blind fold, upon observing the saccades they concluded that the cat was able to make normal saccades. They then switched the blindfold from the damaged eye to the normal eye and saw that the saccades were often too small. Cats were allowed to adjust to vision in the weakened eye, they then retested and saw that the cats were able to make close to normal saccades with the damaged eye. when they uncovered the normal eye they saw that while the damaged eye made normal saccades, the undamaged eye made saccades that were much too big. After a while the normal eye returned to normal. They then repeated the experiment but this time they removed the cerebellum, they saw that the cats could not get the normal eye to readjust their saccades and the eye movements were too large. Which lead investigators to believe that the gain of the system was affected. Mossy fibers can project to the deep nuclei which sends to the thalamus which projects to the motor cortex that send input to the pontine that supply input to the mossy fibers, Since this loop is excitatory it creates a positive feedback that results in gain. It is believed that the purkinji cells throttle this gain activity which can be used to readjust saccadic movements

Describe how the visual system interacts with our motor control.

Experiments showed that the neurons fall into three major categories: visually dominant, visuomotor, and motor-dominant neurons. Together these three classes of neurons contribute to neural operations that use visual input to encode the affordances of observed objects and associate them with appropriate motor acts. Visual-dominant neurons discharge when the monkey fixates an object or grasps it in the light, but not when the monkey grasps an object in the dark (Figure 38-8). In contrast, motor-dominant neurons are active during grasping both in the light and in darkness. They are not active, however, during object fixation, indicating that they signal primarily the motor act of grasping, independent of visual input. Many visual-dominant and motor-dominant neurons respond selectively to objects of particular shapes such as spheres, rings, and flat disks, each of which requires a different type of grip. Visuomotor neurons discharge when the monkey grasps objects, whether in the dark or in the light, but also during visual fixation. Individual visuomotor neurons additionally respond preferentially to shape: A neuron that becomes active when the monkey looks at a small disk also discharges when the monkey grasps the disk, but not when it grasps a sphere. This specificity to the shape of viewed objects indicates that these neurons link the affordances of an object to particular motor actions

What is the pulse-step model? Be able to explain changes in firing of an abducens motor neuron, tonic neuron, burst neuron, and omnipause neuron as the eye moves along the horizontal axis. What is the order in which these neurons act?

Figure explained: The record is from an abducens neuron of a monkey. When the eye is positioned in the medial side of the orbit the cell is silent (position θ0). As the monkey makes a lateral saccade there is a burst of firing (D1), but in the new position (θ1) the eye is still too far medial for the cell to discharge continually. During the next saccade there is a burst (D2), and at the new position (θ2) there is a tonic position-related discharge. Before and during the next saccade (D3) there is again a pulse of activity and a higher tonic discharge when the eye is at the new position (θ4). When the eye makes a medial movement there is a period of silence during the saccade (D4) even though the eye ends up at a position associated with a tonic discharge Medium-lead burst neurons in the paramedian pontine reticular formation and neurons of the medial vestibular nucleus and nucleus prepositus hypoglossi project to the ipsilateral abducens nucleus and deliver respectively the pulse and step components of the motor signal. Two populations of neurons in the abducens nucleus receive this signal. One is a group of motor neurons that innervate the ipsilateral lateral rectus muscle. The second group consists of interneurons whose axons cross the midline and ascend in the medial longitudinal fasciculus to the motor neurons for the contralateral medial rectus, which lie in the oculomotor nucleus (Figure 39-9A). Thus, medial rectus motor neurons do not receive the pulse and step signals directly. This arrangement allows for precise coordination of corresponding movements of both eyes during horizontal saccades and other conjugate eye movements. The length of the medial longitudinal fasciculus and its vulnerability to demyelination and ischemia make it clinically important

What is the pathway between the main brain regions involved in generating saccades?

Frontal eye field -> superior colliculus -> paramedic pontine reticular formation

How does the cerebellum signal and respond to unexpected input?

Gellman used cats that were standing on a platform, they would then puff or tap on the paw and the inferior olive would react to this stimuli. Inferior olive activity is synonymous with climbing fiber activity. They then found a somatic receptor in the paw that would reliably stimulate the inferior olive to touch, histograms showed the likelihood of olive cell firing to the tap was roughly 90%. But when the cat made movements of its own and the receptive field of the same somatic receptor was stimulated, there was no activity in the olive, this lead the experimenters to believe that the olive was firing in response to an unexpected stimuli in the environment. So an error signal or sorts.

What might be some of the reasons why dopamine neurons are vulnerable to degeneration?

Genetics. < 10% of PD has a monogenic basis; < 10% of monozygotic twins show concordant expression of PD. aberrant proteostasis and intracellular trafficking (a-synuclein, glucocerebrosidase, MAPT, LRRK2) impaired mitochondrial function (Parkin, PINK1, DJ-1, LRRK2). 2. Dopamine metabolites lead to production of ROS impair mitochondrial function, homeostasis and VMAT2. 3. Inflammation Glial cell activation and production of cytokines, ROS and lipid metabolites. Very sensitive to infections 4. Environmental factors Pesticides like paraquat, rotenone and maneb disrupt mitochondrial and proteosome function 5. Ca2+ Cav1 channels, energy demand for Ca homeostasis, ROS production Calbindin expressing neurons and VTA neurons less vulnerable Cav channel blockers reduce incidence of PD. by 30-40%

What is the population vector hypothesis?

Georgopoulos found that the global pattern of activity of the entire population provided a clear signal for each movement. He represented each cell's activity by a vector pointing in the cell's preferred direction. This vectorial representation implied that an increase of activity of a given cell is a signal that the arm should move in the cell's preferred direction, and that the strength of this directional influence varies continuously for different reach directions as a function of the neuron's directional tuning. Vectorial addition of all of the single-cell contributions to each output command produces a population vector that corresponds closely to the actual movement direction. That is, an unambiguous signal about the desired motor output is encoded by the summed activity of a large population of active neurons throughout the arm motor map in the primary motor cortex. As a result, neurons in all parts of the arm motor map contribute to the motor command for each reaching movement, and the pattern of activity across the motor map changes continuously as a function of the intended direction of the reaching movement.

What do Kalaska's experiments suggest about the cells in the posterior parietal cortex?

He saw that neurons in area 5 (posterior parietal) were only selective towards preferred direction independent of the loads. all they are doing is signalling the directions that the limb is going. there were groups of neurons here that lead the movement like premotor cortex that suggest that they initiate the movement but there are also neurons that lag from the movement. i.e. arm moves and then they become active

Know the OHDA model for PD.

He used optigenetics and channel rhodopsin of the D1 receptors which we think are hypoactive in this disease He stimulate the D1 striatal projection neurons tonically and you see a fairly rapid improvement in motor activity in this animal, so what he did was just switch the light on and so there is no real pattern stimulation kind of a surrogate to depolarizing the cells to make up for the lack of dopamine.

Eye-head gaze shift: What two components constitute the gaze shift? Why is it important to minimize the time course of the gaze shift?

Head and eye movements make up the gaze shift and must be coordinated to direct the fovea to a target. Because the head has a much greater inertia than the eyes, a small shift in gaze drives the fovea to its target before the head begins to move. The rapid movement of the eye is the saccade and since the head continues to move once the fovea is on its target the VOR keeps focus on the target as the head slowly reaches the target as well. • A small gaze shift usually consists of a saccade followed by a small head movement during which the vestibulo-ocular reflex moves the eyes to the center of the orbit of the new head position. • For larger gaze shifts, the eyes and the head move simultaneously in the same direction. o Because the vestibulo-ocular reflex ordinarily moves the eyes in the direction opposite that of the head, the reflex must be temporarily suppressed for the eyes and head to move simultaneously. o Many of the neural centers that control simple saccades also control gaze shift. Electrical stimulation of the superior colliculus in a monkey with its head fixed evokes saccades, but stimulation of an animal whose head can move freely results in saccades combined with head movement. Neurons in the superior colliculus that carry eye-movement signals also project to neurons in the reticular formation that drive the neck muscles, presumably enabling a combined head and eye movement to position the fovea on an object of interest We want to minimize the gaze shift time because the added velocities send the eyes flying in a direction which temporarily impairs our vision

Be able to recognize the firing pattern of different muscle afferents during motion. How do these firing patterns align with EMG and muscle length?

Ia afferents signal velocity of movement II afferents signal position Ib afferents signal muscle force Firing patterns of Ib align with muscle EMG Firing patterns of II align with muscle length

Vestibular nystagmus: What processes underlie the fast and quick phases? Review the vestibulocular reflex pathways.

Ideally, eye velocity is matched to head velocity, minimizing retinal motion. This compensatory eye rotation is called the vestibular slow phase, although it is not necessarily slow: The eyes may reach speeds of more than 200 degrees per second if the head's rotation is fast. With continued head rotation the eyes would eventually reach the limit of their orbital range and stop moving. To prevent this, a rapid saccade-like movement called a quick phase displaces the eyes to a new point of fixation in the direction of head rotation. If rotation is prolonged, the eyes execute alternating slow and quick phases called nystagmus. Although the slow phase is the primary response of the rotational vestibulo-ocular reflex, the direction of nystagmus is defined in clinical practice by the direction of its quick phase. Thus, rightward rotation excites the right horizontal canal and inhibits the left horizontal canal. This leads to leftward slow phases and a right-beating nystagmus If the angular velocity of the head remains constant, the inertia of the endolymph is eventually overcome, as in the coffee cup example earlier: The cupula relaxes and vestibular nerve discharge returns to its baseline rate. As a consequence, slow-phase velocity decays and the nystagmus stops, although the head is still rotating. In fact, the nystagmus lasts longer than would be expected based on cupular deflection. By a process called velocity storage, a brain stem network provides a velocity signal to the oculomotor system, although the vestibular nerve no longer signals head movement. Eventually, however, the nystagmus does decay and the sense of motion vanishes. If head rotation stops abruptly, the endolymph continues to move in the same direction that the head had formerly rotated. With rightward rotation this inhibits the right horizontal canal and excites the left horizontal canal, resulting in a sensation of leftward rotation and a corresponding left-beating nystagmus. However, this occurs only in darkness. In the light, optokinetic reflexes maintain nystagmus as vestibular input diminishes, as long as the head continues to rotate. Correspondingly, optokinetic reflexes suppress post-rotatory nystagmus in the light.

Although not necessary, it is good to know how cocaine abuse affects the direct and indirect pathways.

If you give cocaine to a rodent what we get is an elevated locomotion response, the basal ganglion becomes very sensitive. What he did was high frequency stimulation of the corticle striatal input causes LTP in the D1 and D2 receptors expressing medium spinal neurons. If we record from rats that were given cocaine for a few days then we only get LTP in the D2 receptors expressing spiny neurons. The inference is that D1 have already been strengthened by cocaine, D1 is necessary for LTP. The next experiment was to record postsynaptic currents in D1 receptors and if you do that you get that there is a larger deflection in D1 neurons or cocaine treated rodents. Ventral striatum coming from medial prefrontal cortex, he stimulated the medial prefrontal at low frequency which induced LTD. So he used cocaine to create LTP then stimulated prefrontal to make LTD, he saw that cocaine animals had more of a LTD effect So the next experiment is lets record these neurons and if you do that we see the deflection much longer in cocaine animals

What are some clinical implications of lesions in the parietal cortex? (Think about proprioception and hemi-spatial neglect).

In summary, when disks were presented on the illusion background, maximum grip aperture corresponded to the physical size of the disks, whether the disks appeared to be the same or different in size. Manual estimations of disk size showed exactly the opposite pattern; they were clearly influenced by the illusion. Importantly, this dissociation was seen despite the fact that the same effector, the hand, was used to produce the response for both tasks: in one case to reach out and grasp the disk and in the other case to "match" the size of the disk to the distance between the thumb and index finger. Reaches were made without vision of the objects, to avoid the subjects being able to adjust aperture size as they approached the target. Patients have been identified who are completely unable to process visual information perceptually (as in the ability to identify the orientation of the slot by drawing an oriented line, or rotating a second slot) but can use the same visual information to complete a motor task (in this case, inserting a card into the same slot). Another patient with optic ataxia due to a right parietal tumor has the opposite deficit. He was unable to place or orient his left hand correctly with respect to a rectangular slot Presented in his left visual field. The right visual field was unaffected.

What is a central pattern generator (CPG)? Interneurons are generally considered inhibitory. But there are glutamatergic interneurons in lamprey CPGs which control swimming

In the lamprey spinal cord, the intrinsic firing pattern of a set of interconnected sensory neurons, intemeurons and motor neurons, establishes the pattern of undulating muscle contractions that underlie swimming (Figure D). The patterns of connectivity between neurons, the neurotransmitters used by each class of cell, and the physiological properties of the elements in the lamprey pattern generator, are now known. One set of interneurons-known as excitatory premotor interneurons release glutamate as their neurotransmitter and thereby excite one another, as well as nearby inhibitory intemeurons. A local pool of these excitatory premotor interneurons provides the burst generating kernel for segmental motor output. One class of inhibitory intemeurons (neurons labeled I in Figure D) makes reciprocal connections across the midline that coordinate the pattern generating circuitry on each side of the spinal cord. This circuitry in the lamprey thus provides a basis for understanding the circuits that control locomotion in more complex vertebrates. Central pattern generators (CPGs) are biological neural networks that produce rhythmic patterned outputs without sensory feedback. CPGs have been shown to produce rhythmic outputs resembling normal "rhythmic motor pattern production" even in isolation from motor and sensory feedback from limbs and other muscle targets. To be classified as a rhythmic generator, a CPG requires: 1. "two or more processes that interact such that each process sequentially increases and decreases, and 2. that, as a result of this interaction, the system repeatedly returns to its starting condition

Dr. Miller describes a few experiments, including one about visually guided versus internally guided cues. Understand the details of these experiments. What can these patterns tell us about the function of primary motor cortex, supplementary motor cortex and premotor cortex?

In this case Mushi recored from three areas, the monkey was trained to press a buttons in front of him, there were visually cued action. In the second condition a pattern was learned (intrinsically guided) for the monkey to complete. When he recorded from primary motor he saw that each time the monkey made a movement the neurons fired equally in the two conditions, however the supplementary motor cortex was only active during the sequence task which represented the intrinsic condition. Interestingly, the premotor cortex was not active during the sequence and only showed activity during the visual condition. He concluded that the primary motor cortex contained both intrinsic and extrinsic cells The supplementary cortex only contained intrinsically guided cells Premotor cortex contained visually guided. In the premotor we see that the movement did not activate neurons.

How do serotonin levels fluctuate depending on behavioral state? Why might these fluctuations be advantageous?

Increased seasoning levels allow a greater degree of force to be generated in the muscles, decreasing staining levels allow for more refined control of muscle movements. Both conditions are advantageous because they allow us a greater range of motion and actions Ed - Serotonin level is low during sleep, moderate during quiet waking, and high during sustained motor output, such as locomotion. This is advantageous because serotonin helps modulating motor neuron excitability and during sleep, low serotonin level assists preventing from making movements.

What kind of information do Mossy fibers encode? Purkinje cells?

Inputs (Mossy fibers): Related to limb position rather than movement Related to limb end-point Outputs (Purkinje cells): Generally bi-directional rather than reciprocal Generally phasic, rather than position-related Encode speed of movement

What are intrafusal and extrafusal fibers? What innervations do they receive?

Intrafusal muscle fibers are skeletal muscle fibers that serve as specialized sensory organs that detect the amount and rate of change in length of a muscle. They constitute the muscle spindle and are innervated by two axons, one sensory and one motor. Intrafusal muscle fibers are walled off from the rest of the muscle by a collagen sheath. This sheath has a spindle or "fusiform" shape, hence the name "intrafusal." There are two types of intrafusal muscle fibers: nuclear bag and nuclear chain fibers. They are innervated by gamma motor neurons and beta motor neurons. It is by the sensory information from these two intrafusal fiber types that one is able to judge the position of one's muscle, and the rate at which it is changing. Extrafusal muscle fibers are the skeletal standard muscle fibers that are innervated by alpha motor neurons and generate tension by contracting, thereby allowing for skeletal movement. Each alpha motor neuron and the extrafusal muscle fibers innervated by it make up a motor unit. The connection between the alpha motor neuron and the extrafusal muscle fiber is a neuromuscular junction, where the neuron's signal, the action potential, is transduced to the muscle fiber by the neurotransmitter acetylcholine.

What would you expect the discharge pattern to be in intrinsically motivated cells versus extrinsically motivated cells in M1? What kind of cell responses are in ventral pre-motor cortex?

Intrinsically motivated cells would vary in the discharge rate depending on the application of force relative to the preferred direction, if the the force is opposite the preferred then we would expect there to be greater discharge and if the force is applied towards the preferred we would see a decrease in activity. Extrinsically motivated cells discharge rates are only modulated with respect to their preferred direction, the closer they are to preferred the more they will discharge. While M1 has a mix of extrinsic and intrinsically motivated cells the ventral pre-motor cortex is surprisingly only extrinsically motivated.

Why is the adrenal gland the exception?

It is innervated directly by the preganglionic there is no postganglion cell Adrenal medulla release adrenaline when stimulated and is a rare case where the preganglionic directly innervates the tissue, however in this case the cells are really a very specialized form of a sympathetic ganglion cell.

What is the difference between kinematics and kinetics?

Kinematics refers to the parameters that describe the spatiotemporal form of movement, such as direction, amplitude, speed, and path. Kinetics concerns the causal forces and muscle activity. It is also useful to distinguish the dynamic forces that cause movements from the static forces required to maintain a given posture against constant external forces such as gravity.

What are the most common treatments for PD?

L-DOPA (most common) Deep brain stimulation Gene therapy Stem cell transplantation

How do cortico-striatal synapses exhibit LTP and LTD?

LTP is NMDAR-dependent and due to an increase postsynaptic AMPAR expression LTD is CB1R-dependent and due to a reduction in presynaptic release probability Protocols that are associated with strong NMDAR activation and/or firing in response to excitation lead to LTP. Protocols that are associated with weak NMDAR activation and/or activity prior to excitation lead to LTD

How is the autonomic nervous system hierarchical? How is the hypothalamus functionally divided?

Langley divided the autonomic system into three divisions: sympathetic, parasympathetic, and enteric. All neurons in sympathetic and parasympathetic ganglia are controlled by preganglionic neurons whose cell bodies lie in the spinal cord and brain stem. The pre-ganglionic neurons synthesize and release the neurotransmitter acetylcholine (ACh), which acts on nicotinic ACh receptors in postganglionic neurons, producing fast excitatory postsynaptic potentials and initiating action potentials that propagate to synapses with effector cells in end-organs (Figure 47-1). The sympathetic and parasympathetic systems are distinguished by five criteria: 1. The segmental organization of their preganglionic neurons in the spinal cord and brain stem 2. The peripheral locations of their ganglia 3. The types and locations of end-organs they innervate 4. The effects they produce on end-organs 5. The neurotransmitters employed by their postganglionic neurons Organization of the hypothalamus into functionally different types of networks or zones. interpreted in the context of hypothalamic functions. Pattern generating network is for things like thermoregulation that require a fairly extensive network to maintain regulation, basal contraction of the skin to prevent loss of heat on a cold day. Shivering, a purposeless motor activity and increasing metabolism of the autonomic activity of fat Behavior control is a little more complicates, it is the means by which there is somatomotor, autonomic and endocrine outflow inorder to generate motivated behavior i.e. drinking water, maternal behaviors and aggressive reactions that need more complicated processing because they involve a lot of actions. The nuclei belonging to the respective network or zone are indicated in black. neuroendocrine motor zone. This zone is centered in the periventricular zone of the hypothalamus and contains the endocrine motor neurons related to the posterior pituitary or the anterior pituitary gland. The circadian timing network consisting of the suprachiasmatic nucleus (SCN) and the subparaventricular zone (SBPV), which organizes the temporal structure of hypothalamic functions. The hypothalamic visceral motor pattern generator network coordinating neuroendocrine and autonomic response patterns. The behavior control column representing regulation of defensive behavior, ingestive behavior (nutrition, fluid balance), reproductive behavior and thermoregulatory behavior.

Describe some of the functions of the paraventricular nucleus of the hypothalamus

Large neurons in the paraventricular and supraoptic nuclei (and a few neurons scattered in between) form the magnocellular component of the neuroendocrine motor system of the hypothalamus The magnocellular neurons send their axons through the hypothalamo-hypophysial tract to the posterior pituitary or neurohypophysis. Under normal conditions approximately one-half of the magnocellular neuroendocrine neurons synthesize and secrete vasopressin (the antidiuretic hormone) into the general circulation, whereas the other half synthesize and secrete the structurally similar hormone oxytocin. These hormones circulate to organs that control blood pressure, water balance, uterine smooth muscle, and milk release Paraventricular is also involved in parvicellular neuroendocrine neurons which are exceptionally important for the regulation of metabolism. CRH neurons in the paraventricular nucleus controls the release of anterior pituitary adrenocorticotropic hormone (ACTH), which in turn controls the release of cortisol (glucocorticoids) from the adrenal cortex. Thus this pool of CRH neurons is the "final common pathway" for all centrally mediated stress responses

Know the main types of interneurons and their sensory input.

Main types of interneurons and theirsensory input • Ia interneurons: main input, the large diameter musclespindle Ia afferents • Ib interneurons: Ib afferents from Golgi tendon organs(also get significant Ia input) • II interneurons: group II afferents from muscle spindles• Renshaw cells: collateral from motor axon • Flexion reflex/crossed extension interneurons: smaller diameter axons of a variety of types: cutaneous, muscular,joint. In muscle free nerve endings make an importantcontribution: these have no distinct sensory apparatus andsense temp, pain, pH.

Know some of the treatments for HD.

Memantine (NMDAR antagonist) poorly rationale Tetrabenazine (VMAT inhibitor), serious side effects reduces the level of dopmine in the striatum Deep brain stimulation RNA interference We need huntington to survive so we cant just inhibit huntington Stem cell transplantation

Why is correlated burst activity of M1 neurons in PD model surprising? What is this activity better known as?

Motor cortex should be shut down due to suppressed activity in the direct vs indirect pathway but its very active. These rhythms at rest are synchronous

What are the functions of muscle spindle and golgi tendon organ?

Muscle spindles are sensory receptors that primarily detect changes in the length of this muscle. They convey length information to the central nervous system via sensory fibers. The responses of muscle spindles to changes in length also play an important role in regulating the contraction of muscles, by activating motor neurons via the stretch reflex to resist muscle stretch. Because they are innervated by Ia fibers they also convey information about velocity of movement. The Golgi organ senses changes in muscle tension (force). When the muscle generates force, the sensory terminals are compressed. This stretching deforms the Ib afferent axon. As a result, the Ib axon is depolarized and fires nerve impulses. The Ib sensory feedback generates spinal reflexes and supraspinal responses which control muscle contraction. Ib afferents synapse with interneurons that are within the spinal cord that also project to the brain cerebellum and cerebral cortex. During locomotion, Ib input excites rather than inhibits motoneurons of the receptor-bearing muscles, and it affects the timing of the transitions between the stance and swing phases of locomotion. The switch to autogenic excitation is a form of positive feedback.

How does the "micro-circuit" of the cerebellum interact with the lateral and medial descending systems?

Neurons in the vermis of both the anterior and pos-terior lobes send axons to the fastigial nucleus. The fastigial nucleus projects bilaterally to the brain stem reticular formation and lateral vestibular nuclei, which in turn project directly to the spinal cord (Figure 42-7).The spinocerebellum therefore provides important inputs to the brain stem components of the medial descending systems. Its outputs are important for movements of the neck, trunk, and proximal parts of the arm, rather than the wrist and digits, for balance and postural control during voluntary motor tasks. Because these brain stem systems also receive large inputs from descending pathways and from sensory inputs, we think that the cerebellum modulates and initiates, rather than controls, the descending commands to the spinal cord.Purkinje neurons in the intermediate part of the cerebellar hemispheres project to the interposed nucleus. Some axons of the interposed nucleus exit through the superior cerebellar peduncle and cross to the contralateral side of the brain to terminate in the magnocellular portion of the red nucleus. Axons from the red nucleus cross the midline again and descend to the spinal cord (Figure 42-9). Other axons from the interposed nucleus continue rostrally and terminate in the ventrolateral nucleus of the thalamus. Neurons in the ventrolateral nucleus project to the limb control areas of the primary motor cortex.By acting on the neurons that give rise to the rubro-spinal and corticospinal systems, the intermediate cerebellum focuses its action on limb and axial mus-culature. Because cerebellar outputs cross the midline twice before reaching the spinal cord, cerebellar lesions disrupt ipsilateral limb movements.

What are the pathological and histological clues of Parkinsons' and Huntington's disease?

Parkinson patients have reduced substantia nigre pigmentation as a result of a decrease in dopaminergic cells. Huntington patients have severe decrease of white matter and enlargement of ventricles.

What deficits might be expected is a patient with dysfunctional muscle spindles? This is known as kinesthesia.

Patient would not have any sense of muscle extension because somatosensory information from the spindles would be lost. Depending on the degree of loss we would expect that the patients movements would be very disappointed and awkward and that the patient requires significant focus on those motor intent in order to perform simple things like standing and opening their hand Ed - A patient with dysfunctional muscle spindles will fail to recruit more motor neurons, not being able to generate great force. Additionally, the patient will have a poor sense of proprioception requiring enormous concentration to make intended movements.

Describe the experiment performed by Georgopoulos in 1986. What was his conclusion?

Recorded from the primary motor cortex while a monkey reached in different directions from a central starting position toward targets arrayed on a circle in the horizontal plane. Individual neurons responded during many movements, not just a single one. Every neuron's activity was strongest for a preferred direction and often weakest for the opposite direction, as Evarts had found for single-joint movements. However, each cell also responded in a graded fashion to directions of movement between the preferred and the opposite directions. Its activity pattern thus formed a broad directional tuning curve, maximal at the preferred direction and decreasing gradually with increasing difference between the preferred direction and the target direction. Cells with similar preferred directions were located at several different sites in the arm motor map, and nearby cells often had different preferred directions. Despite the apparent complexity of the response properties of single neurons, Georgopoulos found that the global pattern of activity of the entire population provided a clear signal for each movement. He represented each cell's activity by a vector pointing in the cell's preferred direction. This vectorial representation implied that an increase of activity of a given cell is a signal that the arm should move in the cell's preferred direction, and that the strength of this directional influence varies continuously for different reach directions as a function of the neuron's directional tuning. Vectorial addition of all of the single-cell contributions to each output command produces a population vector that corresponds closely to the actual movement direction As a result, neurons in all parts of the arm motor map contribute to the motor command for each reaching movement, and the pattern of activity across the motor map changes continuously as a function of the intended direction of the reaching movement.

Describe feedforward control and feedback control mechanisms and how they are exhibited in the motor system. Give an example of an incorrect feedforward model.

Sensory feedback from the arm provides information about both the progress of an ongoing arm movement and deviations from the intended path that should be corrected. Feedback corrections during movement are implemented by neural circuits at many levels of the motor system, ranging from reflex responses in the spinal cord to corrective adjustments of voluntary motor commands from the motor cortex. Sensory feed-forward control involves continuously adjusting the level and distribution of neuronal activity throughout the cortical motor map to reflect the limb's current state of posture and movement. By pretuning the pattern of activity in the motor-cortical map and spinal motor apparatus as a function of the limb's motor state before the onset of a movement, somatic sensory input helps to assure that the appropriate motor command is generated in the motor cortex and converted into the appropriate patterns of muscle activity at the spinal level.

Describe the experiment performed in primary motor cortex by Evarts in 1968. What question was he looking to answer? What happens when he puts on a load opposing flexors? What happens when he puts on a load assisting flexors? What does he conclude?

Set out to answer" do these neurons encode the kinematics or the kinetics of an intended movement" Using a system of pulleys and weights, he applied a load to the wrist of a monkey to pull the wrist in the direction of flection or extension. To make a particular movement the animal had to alter its level of muscle activity to compensate for the load. As a result, the kinematics (direction and amplitude) of wrist movements remained constant but the kinetics (forces and muscle activity) changed with the load. The activity of many primary motor cortex neurons associated with movements of the hand and wrist increased during movements in their preferred direction when the load opposed that movement but decreased when the load assisted it. These changes in neural activity paralleled the changes in muscle activity required to compensate for the external loads. This was the first study to show that the activity of many primary motor cortex neurons is more closely related to how a movement is performed, the kinetics of motion, than to what movement is performed, the corresponding kinematics. Signals about both the desired kinematics and required kinetics of movements may be generated simultaneously in different, or possibly even overlapping, populations of primary motor cortex neurons. Rather than representing only what movement to make (kinematics) or how to make it (kinetics), the true role of the motor cortex may be to perform the transformation between these two representations of voluntary movements.

What electrical stimulation experiments did Hitzig, Ferrier and Penfield perform? What did Penfield generate from the results of his research?

Showed that electrical stimulation of the surface of a limited area of cortex of different surgically anesthetized mammals evoked movements of parts of the contralateral body. The electric currents needed to evoke movements were lowest in a narrow strip along the rostral bank of the central sulcus. Their experiments demonstrated that, even within this strip of tissue, discrete sites contained neurons with distinctive functions. Stimulation of adjacent sites evoked movements in adjacent body parts, starting with the foot, leg, and tail medially, and proceeding to the trunk, arm, hand, face, mouth, and tongue more laterally. When they lesioned a cortical site at which stimulation had evoked movements of a part of the body, motor control of that body part was perturbed or lost after the animal recovered from surgery. These early experiments showed that the motor strip contains an orderly motor map of the contralateral body and that the integrity of the motor map is necessary for voluntary control of the corresponding body parts. Penfield demonstrated that the same general topographic organization is conserved across many species. One important discovery was that the motor map is not a point-to-point representation of the body. Instead, the most finely controlled body parts, such as the fingers, face, and mouth, are represented in the motor map by disproportionately large areas, reflecting the larger number of neurons needed for fine motor control.

How does spinal cord injury affect the excitability of motor neurons?

Spinal cord injury: •loss of monoaminergic input should hurtlocomotion, decrease motoneuron excitability butincrease the excitability of many interneurons Spinal injury predictions: -Loss of communication from cortex to spinal cord: no voluntary movements -Loss of communication from vestibulospinal,reticulospinal: no posture regulation -paralysis Spinal injury prediction for loss of excitabilitycontrol via brainstem monoaminergic systems : -Increased high threshold interneuron excitability, increased flexion reflex system-Decreased group I interneuron excitability, moderate-Decreased CPG excitability-Sharply reduced motoneuron excitability-Adding monoaminergic drugs should restore these deficits 2/11/13 Summary for spinal injury • Persistent currents in motoneurons are highly regulated • Disruption of this regulation in trauma or disease hasimportant consequences • Similar effects in interneurons expected but not yetstudied. • Drugs acting at monoaminergic receptors could beimportant in both trauma and disease Ed - After spinal cord injury, the patient loses monoaminergic system. Shortly after the SCI, patients show very low motoneuron excitability. However, after few weeks of injury, the serotonin and norepinephrine receptors of motoneurons act constitutively, causing spasms. This is due to PIC recovery.

What are some properties of spiny projection neurons? What is driving striatal activity?

Spiny projection neurons, are a special type of GABA-ergic inhibitory cell representing 95% of neurons within the striatum, a structure located in the basal ganglia. Medium spiny neurons have two primary phenotypes (i.e., characteristic types): D1-type MSNs of the "direct pathway" and D2-type MSNs of the "indirect pathway". Direct pathway MSNs excite their ultimate basal ganglia output structure (e.g., the thalamus) and promote associated behaviors; these neurons express D1-type dopamine receptors, adenosine A1 receptors, dynorphin peptides, and substance P peptides. Indirect pathway MSNs inhibit their output structure and in turn inhibit associated behaviors; these neurons express D2-type dopamine receptors, adenosine A2A receptors (A2A), DRD2-A2A heterotetramers, and enkephalin. Both types express glutamate receptors (NMDAR and AMPAR) and CB1 receptors.

What is the flexion-crossed extension reflex? Be familiar with the circuitry.

Stimulation of cutaneous receptors in the foot (by stepping on a tack, in this example) leads to activation of spinal cord local circuits that serve to withdraw (flex) the stimulated extremity and extend the other extremity to provide compensatory support.

Review the anatomy of the primate basal ganglia.

Striatum Caudate Putamen 2. Globus Pallidus external segment (GPe) internal segment (GPi) 3. Subthalamic Nucleus (STN) Substantia Nigra a. pars compacta (SNc) b. pars reticulata (SNr)

Know that the autonomic nervous system sends fibers to peripheral ganglia rather than directly innervating its target organs. What neurotransmitter do these signals rely on? Co-transmitters? Note the difference between parasympathetic and sympathetic.

Synaptic transmission in the peripheral autonomic nervous system was originally thought to be a simple tale of two neurotransmitters, ACh and norepinephrine. According to this idea, all preganglionic neurons in the sympathetic and parasympathetic systems use ACh as their neurotransmitter, binding and exciting ionotropic nicotinic ACh receptors on ganglionic neurons and thus opening nonselective cation channels similar to the nicotinic ACh receptors at the neuromuscular junction. The resulting action potentials propagate to postganglionic synapses with end-organs in the periphery. At these synapses parasympathetic neurons release ACh that activates muscarinic receptors whereas sympathetic neurons release norepinephrine that activates α- and β-adrenergic G protein-coupled receptors. The consequences can be either excitatory or inhibitory, depending on the type of target cell and its receptors Today we know that many transmitters are coreleased at a single synapse, activating multiple receptor types and contributing to functional diversity. Many autonomic neurons release co-transmitters, often together with ACh or norepinephrine.

List with the six extraocular muscles and the directions they move the eye upon contraction. How would you test for a lesion of the superior rectus? The superior oblique?

The actions of the extraocular muscles are determined by their geometry and by the position of the eye in the orbit. The medial and lateral recti rotate the eye horizontally; the medial rectus adducts, whereas the lateral rectus abducts. The superior and inferior recti and the obliques rotate the eye both vertically and torsionally. The superior rectus and inferior oblique elevate the eye, and the inferior rectus and superior oblique depress it. The superior rectus and superior oblique intort the eye, whereas the inferior rectus and inferior oblique extort it.

Know that the baro-reflex pathway adapts. Is this advantageous? If so, when is it not?

The baroreceptors are stretch-sensitive mechanoreceptors. At low pressures, baroreceptors become inactive. When blood pressure rises, the carotid and aortic sinuses are distended further, resulting in increased stretch and, therefore, a greater degree of activation of the baroreceptors. At normal resting blood pressures, many baroreceptors are actively reporting blood pressure information and the baroreflex is actively modulating autonomic activity. Active baroreceptors fire action potentials ("spikes") more frequently. The greater the stretch the more rapidly baroreceptors fire action potentials. Many individual baroreceptors are inactive at normal resting pressures and only become activated when their stretch or pressure threshold is exceeded. Baroreceptor action potentials are relayed to the nucleus of the tractus solitarius (NTS), which uses frequency as a measure of blood pressure. As discussed previously, increased activation of the NTS inhibits the vasomotor center and stimulates the vagal nuclei. The end-result of baroreceptor activation is inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system. The sympathetic and parasympathetic branches of the autonomic nervous system have opposing effects on blood pressure. Sympathetic activation leads to an elevation of total peripheral resistance and cardiac output via increased contractility of the heart, heart rate, and arterial vasoconstriction, which tends to increase blood pressure. Conversely, parasympathetic activation leads to decreased cardiac output via decrease in heart rate, resulting in a tendency to lower blood pressure. By coupling sympathetic inhibition and parasympathetic activation, the baroreflex maximizes blood pressure reduction. Sympathetic inhibition leads to a drop in peripheral resistance, while parasympathetic activation leads to a depressed heart rate (reflex bradycardia) and contractility. The combined effects will dramatically decrease blood pressure.

Make sure that you understand slide 15. Compare force due to the muscle plus the stretch reflex to the force due to the muscle alone. How does the muscle spindle act as a predictive element?

The main role of the stretch reflex is to enhance the stiffness of the muscle. Here, the yielding behavior of muscle on its own (red line) is contrasted with the dramatically stiffer behavior of muscle plus the stretch reflex. Yielding is avoided and overall stiffness is greatly increased. The blue line is the length of the muscle The red line is the muscles response, notice the force axis starts at 10, in other words it is already being activated be the nervous system, so it is steadily being contracted. The muscle initially behaves like a spring, force will increase in proportion to length and we want this, but after a short time the muscle gives up, this is called yielding, the initial range is called the short range difference where the muscle behaves well by itself. As you stretch the cross bridges enough they start cycling and the cycling is too slow to keep up with the force so we get yielding When we add sensory innervation to the muscle which adds the stretch reflex (muscle spindles) we see more recruitment of more motor neurons all coming in proportional to the stretch, although it isn't a straight line, it is better than the red line. Point is we have fast acting and the main goal is not to control the trajectory but to make sure that the muscle behaves itself and acts spring like

States of the urinary bladder provide an example of "voluntary" autonomic nervous system. Describe the give and take of the contract-ant versus relaxant states. What controls this system? What happens when you lesion the spinal cord?

The micturition reflex is another example of a physiological cycle resulting from coordination between sympathetic and parasympathetic systems. In this cycle the bladder is emptied by the parasympathetic pathway, which contracts the bladder and relaxes the urethra. The sympathetic system allows the bladder to fill by stimulating the urethra and inhibiting the parasympathetic pathway, thus inhibiting the reflex for bladder emptying. The sensory feedback required for this behavior is integrated with the motor outflow at both spinal and supraspinal levels. Spinal components of the reflex are most influential during the storage phase of the micturition cycle, when sympathetic and somatic motor effects predominate. When the bladder is full, its distension triggers a sensory signal sufficient to activate the pontine micturition center. Parasympathetic mechanisms then predominate to empty the bladder. Somatic control of the external urinary sphincter, which consists of striated muscle, contributes to both phases of the micturition cycle and is a voluntary behavior that originates through forebrain mechanisms (Figure 47-7). Patients with spinal cord injuries at the cervical or thoracic levels retain the reflex but not voluntary control of urination because the connections between the bladder and the pons are severed. Figure 47-7 The micturition reflex requires interplay between the parasympathetic and sympathetic divisions of the autonomic system. When bladder volume is low, urinary outflow is inhibited because activity in sympathetic pathway is greater than activity in parasympathetic pathway. Mild distension of the detrusor (storage portion of the bladder) initiates a low level of sensory activity, which reflexively activates spinal preganglionic neurons. The resulting low level of preganglionic activity is effectively transmitted and amplified by the sympathetic inferior mesenteric ganglion but filtered out by the parasympathetic bladder ganglion because of differences in patterns of synaptic convergence in the two ganglia. The resulting predominance of sympathetic tone keeps the detrusor relaxed and the urethra constricted. Sympathetic postganglionic fibers also reduce parasympathetic activity by inhibiting preganglionic release of acetylcholine. In addition to their effects on the autonomic outflow, the sensory signals are sufficient to keep the external urinary sphincter closed When filling causes the bladder to reach a critical volume, the associated increase in sensory activity reaches a threshold that allows for impulses to pass through the pontine micturition center (Barrington's nucleus). Descending activity from this nucleus then further excites the parasympathetic outflow. The resulting increase in parasympathetic preganglionic firing promotes summation of fast EPSPs and initiation of postsynaptic action potentials in the bladder ganglion as it switches to its "on" state. During the emptying process descending pathways also inhibit the sympathetic and somatic outflows through inhibitory spinal interneurons. Inhibition of somatic motor neurons in Onuf's nucleus causes relaxation and opening of the external sphincter. In this figure the sacral spinal cord is enlarged relative to the other slices.

Walk through the circuitry between the omnipause neuron, burst neuron, tonic neuron, and motor neuron. • In what brain region are these neurons found? • Input from which brain region drives this whole circuit? • How does the tonic neuron act as a neural integrator? • Which cell type is responsible for the pulse component of the movement? The step?

The signal for horizontal saccades originates in the paramedian pontine reticular formation, adjacent to the abducens nucleus to which it projects (Figure 39-9A). The paramedian pontine reticular formation contains a family of burst neurons that gives rise to the saccadic pulse. These cells fire at a high frequency just before and during ipsiversive saccades, and their activity resembles the pulse component of ocular motor neuron discharge. A second class of pontine cells, omnipause neurons, f ire continuously except around the time of a saccade; f iring ceases shortly before and during all saccades. Omnipause neurons are located in the nucleus of the dorsal raphe in the midline (Figure 39-9A). They are GABA-ergic (γ-aminobutyric acid) inhibitory neurons that project to contralateral pontine and mesencephalic burst neurons. If the motor neurons received signals from only the burst cells, the eyes would drift back to the starting position because there would be no new position. Different neurons provide different information for a horizontal saccade. The motor neuron provides both position and velocity signals. The tonic neuron (nucleus prepositus hypoglossi) signals only eye position. The excitatory burst neuron (paramedian pontine reticular formation) signals only eye velocity. The omnipause neuron discharges at a high rate except immediately before, during, and just after the saccade.

Visual pursuit: Explain the components of the eye movements that underlie this behavior and their time courses.

The smooth-pursuit system holds the image of a moving target on the fovea by calculating how fast the target is moving and moving the eyes at the same speed. Smooth-pursuit movements have a maximum angular velocity of approximately 100 degrees per second, much slower than saccades. Drugs, fatigue, alcohol, and even distraction degrade the quality of these movements. Smooth pursuit and saccades have very different central control systems. This is best seen when a target jumps away from the center of gaze and then slowly moves back toward it. A smooth-pursuit movement is initiated first because the smooth-pursuit system has a shorter latency and responds to target motion on the peripheral retina as well as on the fovea. As the target moves away from the target before the saccade is initiated (Figure 39-2B). The subsequent saccade then brings the eye to the target.

Optokinetic nystagmus: How does the optokinetic reflex complement the VOR?

The vestibulo-ocular reflexes represent movement imperfectly. They are best at sensing the onset or abrupt change of motion; they compensate poorly for sustained motion at constant speed during translation or constant angular velocity during rotation. In addition, they are insensitive to very slow rotations or linear accelerations. Thus vestibular responses during prolonged motion in the light are supplemented by Optokinetic nystagmus refers to the response to full-field visual motion; pursuit involves the fovea following a small target. Although the two reflexes are distinct, their pathways overlap.

What might the role of the cerebellum be in cognitive processing?

Transynaptic viral tracers have revealed that cerebellum is reciprocally interconnected with numerous cerebral cortical areas and dentate is activated during complex motor strategy planning. Compared to visually guided task, dentate is more activated during insanity task in which requires higher cognitive planning and less movement.

What is a baroreceptor? Where are they found?

When a recumbent person stands up, the sudden elevation of the head above the heart causes a transient decrease of cerebral blood pressure that is rapidly sensed by baroreceptors in the carotid sinus in the neck. Other important pressure sensors are located in the aortic arch and in the pulmonary circulation. When neurons in the ventrolateral medulla detect the decrease in afferent baroreceptor activity produced by low blood pressure, they produce a reflexive suppression of parasympathetic activity and stimulation of sympathetic activity. These changes in autonomic tone restore blood pressure by increasing heart rate, the strength of cardiac contractions, and the overall vascular resistance to blood flow through arterial vasoconstriction.

What are causes and treatments of Dystonia?

abnormal co- or sequence of contraction of agonist and antagonist muscles 3rd most common movement disorder most common are primary (idiopathic) rare genetic forms linked to at least 17 genes e.g. rapid onset dystonia parkinsonism, due to mutation in the alpha 3 isoform of the NaKATPase, most onsets of dystonia are caused by brain lesions secondary due to focal brain lesions treatments BOTOX, DBS, anticholinergics they did deep brain stimulation of basal ganglion to alleviate symptoms

Physiological nystagmus: What might be an advantage and a disadvantage of arc tremor in light?

arc tremor or micosaccades keep the image on the retina from being sensitized and disappearing due to prolonged activation. This also means that due to the miscrosaccades our vision is never completely in focus

What is the cause of Huntington's disease? How are the direct and indirect pathways affected in this disease?

completely penetrant autosomal dominant hereditary disease, caused by an abnormal number of CAG repeats in exon 1 of the huntingtin gene. 4-10: 100,000 affected (25,000 in the US) number of CAG repeats related to disease expression < 35 no disease 35-39 enhanced risk, variable onset 40-75 years > 40-50 disease onset 30-40 years > 50 early onset disease symptoms, first there is increase aggression/personality change, followed by progressive hyper/dyskinesias followed by akinesia and dystonia and dementia/psychoses. movement disorders look like parkinsons associated with nuclear and cytoplasmic inclusions containing mutant huntingtin and other proteins interestingly all neurons express the mutant form of huntingtin/polyglutamine but striato-GPe neurons die first, followed by striato-GPi neurons and finally more widespread neurodegeneration

How does deep brain stimulation (DBS) disrupt this activity?

electrodes in subthalamic nuclei causes the synchronous activity to be disrupted because the stimulation is so hard that the neurons cant keep up which causes a short term depression of activity that produces a fragmented output which increases movement ability.

Know the spinal reflex circuit. What is the function of Ia inhibitory interneuron? What is their postsynaptic partner?

muscle spindle -> Ia afferent fiber -> motor neuron (flexor muscle) muscle spindle -> Ia afferent fiber -> Ia inhibitory interneuron -> motor neuron (extensor muscle) The Ia inhibitory interneuron regulates contraction ion antagonist muscles in stretch-reflex circuit.

Be familiar with the anatomy of the descending motor control system of the cerebrum, brainstem and spinal cord

there are three major brainstem regions that project to the spinal cord: the red nucleus, the brainstem reticular formation and the vestibular nuclei. Spinal projecting fibers are also found within the superior colliculus, but they are less numerous. These sub-cortical systems have been divided into lateral and medial systems, based on the location of their terminations in the spinal cord, which largely overlap those from the cerebrum.

Review the general anatomy of the cerebellum - know the nuclei, cell types, layers of cortex

three pairs of deep nuclei: the fastigial nucleus, the interposed nucleus ( the emboliform and globose nuclei), and the dentate nucleus the cerebellum arise from the deep nuclei and project through the superior cerebellar peduncle. The main exception is a group of Purkinje cells in the flocculonodular lobe that projects to vestibular nuclei in the brain stem. The cerebellum is also divisible into three areas that have distinctive roles in different kinds of movements: the vestibulocerebellum, spinocerebellum, and cerebrocerebellum The vestibulocerebellum consists of the flocculonodular lobe. It receives vestibular and visual inputs, projects to the vestibular nuclei in the brain stem, and participates in balance, other vestibular reflexes, and eye movements. The spinocerebellum comprises the vermis and intermediate parts of the hemispheres. It is so named because it receives somatosensory and proprioceptive inputs from the spinal cord. The vermis receives visual, auditory, and vestibular input as well as somatic sensory input from the head and proximal parts of the body. It projects by way of the fastigial nucleus to cortical and brain stem regions that give rise to the medial descending systems controlling proximal muscles of the body and limbs. The vermis governs posture and locomotion as well as eye movements. The adjacent intermediate parts of the hemispheres also receive somatosensory input from the limbs. Neurons here project to the interposed nucleus, which provides inputs to lateral corticospinal and rubrospinal systems and controls the more distal muscles of the limbs and digits cerebrocerebellum comprises the lateral parts of the hemispheres Almost all of the inputs to and outputs from this region involve connections with the cerebral cortex. The output is transmitted through the dentate nucleus, which projects to motor, premotor, and prefrontal cortices. The lateral hemispheres have many functions but seem to participate most extensively in planning and executing movement.