Areas of Breadth
Neuroscience Program Qualifying Exams

Below is a consolidated list of areas of breadth that were defined by students' examination committees in the Neuroscience program.  These should serve as useful guides in developing your own areas of breadth.

Synaptic integration
Neurochemical bases of drug abuse
Biophysics of neurons
Motor learning
Hippocampal and cerebellar systems - anatomy, physiology and role in behavioral learning.
Membrane excitability - structure and function of Na and K channels, membrane currents, action potentials.
Mechanisms of synaptic transmission - receptors, role of Ca.
Second messenger systems - role in modification of ion channels and gene expression.
Calcium and the regulation of synaptic transmission and homosynaptic plasticity (PPF, depression)
Mediotemporal lobe and implicit-explicit forms of memory
Ion channels, e.g. sodium channels- role in AP propagation and pathophysiology
Cellular organization-axonal transport
Chemical synaptic release-excitatory synapse morphology, vesicle recycling

EXAMPLES

Below are examples of test questions used to examine students in the Neuroscience Program for the breadth portion of the advancement to candidacy exam.

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The synthesis, storage and release of vesicles is dependent on many fundamental neuronal properties.  With this general frame of mind address the following points:

1)      Describe the formation and basic composition of a vesicle destined to release transmitter.

2)      Contrast differences in vesicles that undergo constitutive release from those that undergo triggered release.

3)      Describe how two membranes can fuse.  What are the energy barriers and how are these barriers overcome?  Are specific lipids or proteins involved?  If so what are they?  As part of this answer describe at least two techniques used to assess neurotransmitter vesicle fusion at presynaptic terminals and contrast their strengths and limitations.

4)      Describe the ionic transitions at the terminal that mediate vesicle release and briefly review the ionic basis of the resting potential.

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You have recently identified a novel neuronal heptahelical membrane receptor that correlates with incidence of schizophrenia. Preliminary studies suggest engagement of the receptor with its cognate ligand shows increased tyrosine phosphorylation of the receptor and cell differentiation.

1)   What types of signaling pathways might be regulated by this receptor?

2)   Which cascades might be recruited to regulate gene expression changes in these cells?

3)   How would you test the relationship between phosphorylation and receptor activity?

4) Discuss possible therapeutic/pharmacological interventions?

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Since its discovery by Bliss & Lomo in 1973, long-term potentiation (LTP) has been hypothesized to be a cellular mechanism underlying learning and memory.  The phenomenon has been studied mostly in the hippocampus.

(A)   Discuss the different types of memory that have been proposed to depend on an intact hippocampus.  Include discussions of declarative memory, episodic memory, relational learning, and cognitive mapping.  What are some types of memory that are independent of the hippocampus?

(B)   What are the properties of LTP that make it such an attractive candidate for a cellular mechanism of learning and memory?  Your answer should include descriptions of the electrophysiological characteristics of LTP; a discussion of the concept of a Hebbian synapse; and a discussion of how the properties of the NMDA receptor make it suitable for underlying the Hebbian synapse.

(C)   While LTP increases synaptic strength, long-term depression (LTD) has the opposite effect.  Interestingly, both types of plasticity require activation of the NMDA receptor.  Describe how activation of the same receptor can give rise to opposite effects on synaptic strength.  Your answer should include known molecular and cellular changes, as well as other plausible mechanisms.

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Damage to different parts of the motor system can result in a host of different symptoms.  Understanding the circuitry and functions of different components of the motor system is critical for understanding these often contrasting symptoms.

(A)   Damage to the basal ganglia can result in a resting tremor, whereas damage to the cerebellum can result in an intention tremor.  Describe the difference between these two symptoms and explain why each results from damage to its respective brain area.

(B)   Damage to lower motor neurons results in a decrease in muscle tone and a hypoactive stretch reflexes, whereas damage to upper motor neurons results in an increase in muscle tone and a hyperactive stretch reflex.  Describe the concepts of upper and lower motor neurons and explain why damage results in their particular symptoms.

(C)   Damage to one part of the basal ganglia can result in a poverty or slowness of movement, whereas damage to a different part can result in uncontrollable, involuntary movements.  Explain how the site of damage can result in these opposing symptoms.

(D)   The motor system often displays a remarkable degree of recovery of function after parts of it are damaged.  Describe how this recovery can take place.  Your answer should include discussion of different brain systems and tracts in the motor system, as well as plasticity within these systems.

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Glutamate activates a variety of receptors that produce different pre- and post-synaptic effects.  The intracellular effects span a time frame of many orders of magnitude (ms to hours, maybe days).  Briefly classify the different types of glutamate receptors by the types of changes that they produce in second messenger pathways.  Draw an excitatory synapse and describe the localization of these receptor subtypes.  Place in the diagram detailed pathways for the second messengers generated by the different glutamate receptor subtypes.  Discuss the temporal nature of the activation of these pathways (how long are signals generated and what are their lifetimes) and where cross-talk exists between the pathways.  Describe 3 mechanisms whereby the activation of these pathways feeds back into changes in ion channel and receptor function to alter synaptic transmission or membrane excitability.

(A) Both the hippocampus and the cerebellum have been touted as approachable experimental systems because of the relatively simple circuit organization of each area.  Describe the anatomical connectivity of each area, including the major input and output pathways, the internal circuitry and the major cell types.

(B) Memory has been classified by some investigators into declarative and procedural memory.  Describe each type of memory and the various subtypes of each category. What types of memory do the hippocampus and cerebellum subserve?  What is some evidence that supports their respective roles?

(C) In the classically conditioned eyeblink response, an initially neutral conditioned stimulus (CS), typically a tone, is paired with an unconditioned stimulus (US), typically a puff of air that elicits an unconditioned response (an eyeblink).  After repeated trials, the CS begins to elicit an eyeblink conditioned response (CR) before the US occurs.  If the US overlaps in time with the end of the CS, then this learning is dependent on the cerebellum (this is called delay conditioning).  If there is a temporal gap between the CS and US, however, then the learning is dependent on both the cerebellum and the hippocampus (this is called trace conditioning).  Based on the above discussions, generate a hypothesis of what the roles played by the cerebellum and the hippocampus are in delay and trace conditioning and discuss an experiment to test this hypothesis.

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Each neuron in the central nervous system is constantly bombarded by synaptic inputs from other neurons. Some are excitatory some are inhibitory, some are strong others are weak; some terminate on the soma, some on the dendrite, others on axons and terminals.  These competing inputs are integrated in the postsynaptic neuron by a process called synaptic integration. 

A.  Describe in details how synaptic integration produces postsynaptic action potentials, emphasizing both on short-term and long-term mechanisms.
B.  Describe experiments that you would carry out to characterize each of these mechanisms in a model preparation.

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You are developing an animal model for substance abuse.

A. Discuss major neural pathways and neurotransmitter interactions that are involved in the self-administration of stimulants.  Include recent published data to critically address the question of whether dopamine is the major transmitter supporting self-administration of drugs.

B.  Discuss two behavioral adaptations that can occur with repeated or long-term exposure to stimulants.

C. Discuss the manner in which the behavioral changes in part B might be related to a model of substance abuse.
D. Give reasons why a model for substance abuse might also be related to other major psychiatric disorders.

E. Design an experimental strategy to validate a model of substance abuse.

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Neural plasticity that occurs either during development or during learning requires modulation of synaptic transmission.

A.  Describe in details two presynaptic mechanisms by which modulation of synaptic transmission can occur and provide a concrete example for each of these mechanisms.

B. Describe in details two postsynaptic mechanisms by which modulation of synaptic transmission can occur and provide a concrete example for each of these mechanisms.

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It has been hypothesized that a striato-pallido-thalamic pathway may be responsible for drug-induced states of both arousal and motivational activation.

A. Describe the neural substrate (or pathway) for the motor activating properties of psychostimulants.

B. Describe the neural substrate (or pathway) for the reinforcing properties of psychostimulants.

C. Which structure within these two pathways, do you think, constitutes a common substrate for both motor activating and reinforcing properties of psychostimulants.  Provide anatomical, behavioral, electrophysiological evidence that will support your selection.

D. Discuss mechanisms by which these two pathways could interact to mediate learning processes.

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Calcium plays a key role in several aspects of exocytosis of neurotransmitter, including the mediation of short-term synaptic plasticity.  Review the current understanding of the residual calcium hypothesis, providing arguments both for and against this important concept. Describe how calcium buffers are thought to influence paired-pulse facilitation and propose an experimental strategy to test this hypothesis.

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The medial temporal lobe has been implicated in declarative memory.  Recently, efforts have been made to more fully characterize the specific memory processes mediated by structures within the temporal lobe (i.e. hippocampus and adjacent parahippocampal cortical areas). Using pertinent examples from behavioral, electrophysiological, neuro-imaging and/or molecular activation (i.e. c-fos) experiments describe and contrast the role of the hippocampus, perirhinal and parahippocampal cortex in declarative memory.

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            Multiple sclerosis is an autoimmune disease that leads to progressive neurological degeneration.  In this disease that results from a combination of genetic and environmental factors, there appears to be an activation of autoreactive myelin T cells.  The activated T cells enter the circulation, express adhesion molecules and induce reciprocal changes in endothelia allowing access across the blood brain barrier.  The primary target of the immune attack is the oligodendrocyte which generates the myelin sheath of neighboring nerve axons in the central nervous system.  The consequence of the disorder is demyelination of axons within the localized lesions caused by the immune assault.  Characteristically there is a delay in the conduction of evoked potentials, spontaneous discharges, and an increase in the appearance of symptoms following a hot bath or vigorous exercise.  Describe in detail the molecular and biophysical basis of the changes in the electrophysiological properties of the affected axons compared to normal.

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Chemical signaling is an important form of communication within the nervous system function.  The "vesicular hypothesis" is a key tenant of chemical signaling.

A) Describe the possible fates of a synaptic vesicle that has just exocytosed its contents. What are the underlying molecular mechanisms associated with each fate?

B) A colleague has just created a transgenic animal in which the rate of endocytosis has been modified so that the fastest form of endocytosis in the presynaptic neuron of interest has a time constant of 2 seconds. Following low-frequency stimulation (0.1 Hz), what differences, if any, would you expect to see in active zone ultrastructure in this neuron when compared with an unstimulated control? How about after high-frequency stimulation (10 Hz)? Under which, if any, of these two conditions, might the synapse be prone to synaptic depression and by what mechanism?