Basal Ganglia D/os, Emotion, Reward/addiction

Front 1

Classic physiology of PD:

Back 1

DA neurons in Substantia Nigra Pars Compacta die.

Causes reduction in DA in the striatum, which causes increased inhibition of the motor thalamus.

Front 2

Basal ganglia output nuclei

Back 2

Globus pallidus internus; Substantia nigra pars reticulata

Front 3

Cortical excitation of the indirect pathway ______ movement and cortical stimulation of the direct pathway ______ movement.

Back 3

inhibits ; stimulates

Front 4

T/F dopamine (from SNpc) leads to facilitation of movement through both pathways because of the difference in receptors in the direct (D1- facilitory) and indirect (D2-inhibitory) pathways.

Back 4

T

Front 5

What is the direct loop?

Back 5

D1 receptors in striatum are stimulated by DA from SNc. The striatum then <b>inhibits</b> the SNr and GPi.

Front 6

What is the indirect loop?

Back 6

D2 receptors in striatum are inhibited by DA from SNc. These D2 receptor-bearing striatal neurons in turn inhibit the GPe, which inhibits the STN. The STN excites the SNr/GPi

Front 7

When DA is present, what is the net effect on the output nuclei of the basal ganglia (GPi and SNr)?

Back 7

They're inhibited. Because they're inhibiting the thalamus, inhibiting them ACTIVATES the motor thalamus.

Front 8

What NT do the D1 and D2 neurons use?

Back 8

GABA. They're inhibitory on their projects (GPi/SNr and GPe, respectively)

Front 9

What NT does the STN use? Implications?

Back 9

Glutamate. It's excitatory on its projections, the GPi/SNr. The GPi/SNr inhibit the motor thalamus, so exciting the STN INHIBITS THE MOTOR THALAMUS

Front 10

When DA is taken away (like in PD), what happens to the direct and indirect pathway?

Back 10

DIRECT: D1 neurons from striatum aren't inhibiting SNr/GPi as much, so they are more activate. Since SNr/GPi inhibit the thalamus, there is <b>more inhibition of motor thalamus</b>.

INDIRECT: DA inhibits D2. Since D2 isn't getting inhibited, it's providing MORE INHIBITION to the GPe. The GPe normally inhibits the STN, but since the it's inhibited strongly, the STN is overactive and EXCITES the SNr and GPi, resulting in <b>inhibition of the motor thalamus.</b>

Net result is <b>less inhibition of the output nuclei of the direct pathway and greater excitation of the output nuclei of indirect pathway.</b>

Front 11

4 cardinal features of PD

Back 11

1) Festinating gait
2) Resting tremors
3) Rigidity
4) Bradykinesia

Front 12

What is the festinating gait?

Back 12

Symptom of PD wherein patients find it hard to start walking, but can walk ok once they get going. When they come to an obstacle their steps shorten increasingly or they may freeze.

Front 13

What can help with freezing?

Back 13

Changing the action from an automatic motor program into a voluntary action.

Front 14

What is the UPDRS?

Back 14

Unified PD rating scale

Front 15

At the 10 year mark after dx, what %age of PD patients will fail on medications?

Back 15

75%

Front 16

If basal ganglia are lesioned, which cortex is affected?

Back 16

ipsilateral

Front 17

If basal ganglia are lesioned, deficits thru the pyramidal system are expressed on the ______ side.

Back 17

Contralateral

Front 18

Side effects of DA agonists

Back 18

Compulsive gambling, abnormal sexual urges

Front 19

What is pallidotomy?

Back 19

Destruction of GPi. Older PD surgery. Significant side effects

Front 20

Why is cell transplantation not used in PD?

Back 20

It was tried but only demonstrated 18% improvement and some patients had uncontrollable dyskinesias. Researchers aren't quite sure what went wrong.

Front 21

What is targeted in DBS for PD?

Back 21

STN or GPi

Front 22

How is a very small and specific area targeted in the brain for neurosurgery?

Back 22

Stereotactic frame while obtaining image; Ventriculogram (catheter placed in ventricles and inject dye, ventricles can be visualized); listen to signature sound of neurons in nucleus as they are firing with spontaneous activity and observed how that changes (microelectrode recording)

Front 23

What are the Cycling effects –called on-off phenomena in PD?

Back 23

Patients have to take their medication more and more frequently to avoid freezing
The dose required to keep them moving often causes dyskinesias
They spend their days in 2-4 hour cycles of freezing (being off), too much movement ( on with dyskinesias) and relatively normal function

Front 24

Microelectrode recording : what is it good for? What's the physiological principal behind it?

Back 24

-allows physiologic definition of a nucleus and its borders

-MER is an indirect method of defining the effective area of stimulation


-based on idea that different brain areas have distinct activity patterns

Front 25

Which sx of PD is not reliably improved by DBS?

Back 25

speech

Front 26

What is main sx of essential tremor?

Back 26

Action tremor

Front 27

What's the pathophys of ET?

Back 27

unknown, but when electrode is inserted, certain cells fire in tune with patient's tremor

Front 28

What is stimulated in DBS in patients with ET?

Back 28

Vim nucleus of thalamus

Front 29

Overall effect of DBS in PD?

Back 29

On med scores
See a 25-44% improvement in best times
Off med scores
See a 40-60% improvement in worst times
Evens out the day
Reduces off time
See reduction or resolution of extra movements
dyskinesias and tremor

Front 30

What is dystonia?

Back 30

Contractions by antagonizing groups of muscles - war between opposing sides

Front 31

What is the DYT1 gene?

Back 31

Cause of a type of dystonia (DMD) that is very responsive to stimulation

Front 32

Pathophys of dystonia?

Back 32

Unknown

Possible mechanisms:
Relative over activity of direct pathway
Change in the pattern of pallido-thalamic firing
Loss of center-surround inhibition in motor cortex
Broadening of receptive fields of pallido-thalamic neurons

Front 33

To be a DBS candidate with ET, what must you have?

Back 33

Disabling tremor not controlled by meds
Has tried beta blocker and mysoline

Front 34

What part of brain is targeted in DBS for dystonia?

Back 34

GPi

Front 35

T/F Results for DBS in dystonia and PD are similar

Back 35

F. It takes time to see reversal of dystonia in contrast to the very fast effects with ET or PD

Front 36

T/F appropriate voluntary facial muscle movement can elicit the appropriate visceral emotional response including subjective feelings.

Back 36

T

Front 37

What is the Duchenne smile?

Back 37

The emotion-driven contraction of muscles surrounding the eyes and zygomaticus major. Conveys genuine expression of happiness, joy, and laughter

Front 38

What is the pyramidal smile?

Back 38

The voluntary smile. Forced. Contrived. Driven by motor cortex that communicates with brainstem and spinal cord via pyramidal tracts

Front 39

Patients with upper motor neuron syndrome have trouble making what kind of smile?

Back 39

pyramidal smile. They can smile in response to humor, however because pathways from regions other than classical motor cortex remain available to activate facial movements.

Front 40

What is emotional facial paresis?

Back 40

Descending extrapyramidal projections from medial forebrain and hypothalamus are impaired. Can produce symmetric pyramidal smile

Front 41

What is voluntary facial paresis?/

Back 41

They can smile in response to humor, however because pathways from regions other than classical motor cortex remain available to activate facial movements.

Front 42

T/F Hypothalamus is a crtical center for coordination of both visceral and somatic motor components of emotional behavior

Back 42

T

Front 43

What is sham rage?

Back 43

Behavior produced when cerebral hemispheres of a cat is removed. As long as the caudal hypothalamus was intact - if transected caudal to hypothalamus, cannot elicit it.

Front 44

T/F Exprsesion of coordinated emotional behaviors entails cortical processes

Back 44

F

Front 45

What is the reticular formation?

Back 45

Tangled web of nerve cells and fibers in the core of the brainstem. Contains many nuclei, including those associated with wakefulness, cardiovascular function, etc.

Receives hypothalamic input and feed into somatic and visceral effector systems.

Their activity can produce widespread responses often overriding reflex function (e.g., fight or flight resposne)

Front 46

hypothalamus primarily produces its effect by _________

Back 46

controlling nuclei in the reticular formation of the brainstem.

Front 47

What is the limbic lobe?

Back 47

Includes cortex on the medial aspect of the cerebral hemisphere that forms a rim around the corpus callosum and diencephalon, including cingulate gyrus and parahippocampal gyrsu

Front 48

What's in the Papez circuit?

Back 48

The original circuit postulated for cortical control of emotions

Includes mammillary bodies projection to anterior nucleus of dorsal thalamus to cingulate gyrus

Front 49

What structures make up the limbic system?

Back 49

Amygdala, orbital and medial PFC, ventral basal ganglia, mediodorsal n of thalamus, parahippocampal gyrus, cingulate cortex

Front 50

T/F The hippocampus is important for processing emotion

Back 50

F. It used to be thought so but now is not.

Front 51

Important regions for emotional information processing in the modern limbic system include:

Back 51

prefrontal cortex, ventral basal ganglia, amygdala, mediodorsal nucleus of the thalamus, and hypothalamus.

Front 52

Kluver-Bucy syndrome: causes and sx

Back 52

Cause: removal/dysfunction of much of temp lobes (esp amygdala)

Sx: Visual agnosia, bizarre oral behaviors, hypersexuality, hyperactivity, tameness to humans. No anger, fear

Front 53

Three main regions of amygdala

Back 53

1) Medial: extensive connections with olfactory system

2) Basolateral : especially large in humans. Major connections with cerebral cortex, especially orbital and PFC and associational cortices

3) Central: connections with hypothalamus and brainstem

Front 54

Which part of the amygdala is characterized by:

especially large in humans. Major connections with cerebral cortex, especially orbital and PFC and associational cortices

Back 54

Basolateral

Front 55

T/F neurons in amygdala response to stimuli from various senses

Back 55

T. Convergence of sensory info occurs.

Highly complex stimuli are often required to evoke a response.

Front 56

What is the conditioned fear resposne?

Back 56

Behavioral paradigm in rats whereby a tone is paired with a foot shock.

Once a foot shock is repeatedly given after a tone, the tone by itself will elicit a rise in blood pressure and postural freezing.

Front 57

What are the pathways in the rat brain that mediate the assn of auditory and aversive somatic sensory stimuli?

Back 57

1) Info processed by auditory system --> MGN of thalamus.

2) MGN projects to auditory cortex, which projects to amygdala. (not required!)

3) MGN also projects to amygdala itself (required)

Other projections exist to amygdala.

4) Amygdala projects to circuits that influence somatomotor and autonomic activity.

(Central n to hypothalamus and reticular formation)

Front 58

Central n. projections to hypothalamus produce what behavior in conditioned fear response?

Back 58

Increase in blood pressure

Front 59

Central n. projections to reticular formation produce what behavior in conditioned fear response?

Back 59

freezing

Front 60

It's been proposed that info in the ____ n of amygdala stores fearful memories

Back 60

basolateral

Front 61

What is the general model of associative learning in the amygdala relevant to emotional function?

Back 61

If neutral SENSORY input depolarize amygdala neurons at the same time as inputs from OTHER SENSATIONS with primary reinforcing value like pain, then associative learning occurs by strengthening synapses.

Amygdala output then informs a variety of integrative centers responsible for somatic and visceral motor expression of emotion.

Front 62

Urbach-Wiethe disease

Back 62

bilateral calcification and atrophy of anterior temporal lobes. Patient S.M. lesions restricted to amygdala.

Front 63

People with affective d/os show increased blood flow where?

Back 63

The triangular circuit that connects the amygdala, mediodorsal n of thalamus, and orbital and medial PFC.

Front 64

T/F The two hemispheres make different contributions to emotion

Back 64

T

Front 65

Right hemisphere role in emotion

Back 65

Impt for expression and comprehension of affective aspects of speech

Front 66

Aprosodia

Back 66

Inability to express emotion by modulating speech patterns. Similar lesions in left hemisphere produce Broca's aphasia

Front 67

_ hemisphere more involved with positive emotions, ____ more involved with negative emotions

Back 67

L, R

Front 68

What might lesion of L hemisphere produce in terms of mood?

Back 68

Depression

Front 69

What might lesion of R hemisphere produce in terms of mood?

Back 69

unusual cheerfulness

Front 70

Most individuals more quickly and fully express emotions where?

Back 70

With L facial musculature than R

Front 71

T/F Patients with dysfunctioning amygdala are compromised by their inability to respond appropriately in social situations. This is due in part to their inability to judge facial expressions.

Back 71

T

Front 72

Sensory information (visual or auditory) is more accurately assessed for emotional content by the ___hemisphere.

Back 72

right

Front 73

While addictive drugs have very different mechanisms of action, they cause addiction in a similar way: by acting in the ____ _____, in areas related to reward.

Back 73

limbic circuits

Front 74

VTA more related to liking or wanting something?

Back 74

wanting

Front 75

T/F Most drugs act on low levels of processing, leading to great consistency between animals and humans in reaction to drugs of abuse

Back 75

T

Front 76

what is the limbic loop?

Back 76

Cortical input to nucleus accumbens (striatum) (+) --> pallidum (-) --> mediodorsal nucleus of thalamus (-) --> ACC, orbital frontal cortex, amygdala (+)

Front 77

VTA releases DA into ______

Back 77

nucleus accumbens

Front 78

NA releases GABA into _______

Back 78

ventral pallidum (NA inhibits ventral pallidum)

Front 79

Mediodorsal nucleus of thalamus sends excitatory (GLUT) projections to______

Back 79

cortex (ACC, orbital frontal, amygdala)

Front 80

What inhibits the mediodorsal n of thalamus?

Back 80

Activation of ventral pallidum and SNr. This in turn reduces tahlamocortical activation.

Front 81

Activation of NA inhibits ventral pallidum, which will increase ________

Back 81

thalamocortical activation

Front 82

What facilitates activation of NA?

Back 82

Excitatory DA projections from VTA

Front 83

Where does VTA send DA to?

Back 83

NA, hippocampus, PFC

Front 84

Where does NA project?

Back 84

GABAergic projectsion to ventral pallidum

Front 85

T/F During associative learning, the activity of VTA neurons comes to signal the presence of the reward-predicting stimulus and diminished responsiveness towards the reward itself.

Back 85

T

Front 86

T/F The phasic release of DA signals presence of reward relative to its prediction, rather than the unconditional presence of reward.

Back 86

T

Front 87

What is mechanism of action relevant to addiction of benzos, cannabinoids, GHB, and opioids?

Back 87

They inhibit the inhibitory interneurons, thus facilitating DA projection release

Front 88

What is mechanism of action relevant to addiction cocaine, amphetamine, and ecstasy?

Back 88

They all target the dopamine transporter (DAT) on axon terminals. Cocaine inhibits it, amphetamine and ecstasy promote nonvesicular release. In both cases, DA levels in VTA, NAc, and PFC increase.

Front 89

What is the construct by which a stimulus increases probability of response/Drug makes you want drug more?

Back 89

Reinforcement

Front 90

What is the construct by which drug-induced changes in cell make it more resistant or more sensitive to drug

Back 90

Neuroadaptation

Front 91

pleasant stimulus increases probaility of continued drug use

Back 91

positive reinforcement

Front 92

incentive for continued use is the removal of a negative stimulus

Back 92

negative reinforcement

Front 93

stimulus associated with use can lead to similar rewards as unconditioned stimulus (drug) itself

Back 93

conditioned positive reinforcement

Front 94

stimulus associated with periods of withdrawal can induce drug use

Back 94

conditioned negative reinforcement

Front 95

What is experimental evidence that VTA-NAc circuit can learn and predict the occurrence of rewards?

Back 95

1) Presentation of unexpected reward (eg., fruit juice in monkey) provokes burst of activity in VTA DA neurons.

2) Following training to a conditioned stimulus, the CS presented causes burst of VTA DA activity, but NOT the reward itself anymore.

3) When CS is presented but NOT the reward, there is suppression in firing at about the same time the reward would have appeared.


therefore....addiction is likely characterized by increased wanting, but not increased liking.

Front 96

loss of effect of a drug with repeated administration

Back 96

tolerance

Front 97

increased response to a drug after repeated administration

Back 97

sensitization

Front 98

What is the role of the transcription factor CREB (cAMP reponse element binding protein) in tolerance?

Back 98

There is activation of CREB in NAc after exposure of many types of drugs of abuse.

Overexpression of CREB decreases sensitivity to rewarding effects of drugs.

It's a negative feedback mechanism that results in raising the threshold to obtain a reward.

Front 99

Blockage of CREB does what?

Back 99

Increases sensitivity of NAc

Front 100

T/F Drug-induced activation of CREB decreases individual's interest in natural rewards.

Back 100

T

Front 101

Activity of DA-synthesizing enzyme tyrosine hydroxylase increases secondary to what?

Back 101

increased CREB activity and upregulation of GluR1

Front 102

If CREB is overexpressed, sensitivity to rewarding effects of drugs __________

Back 102

decreases

Front 103

CREB mediates __________ while &Delta;FosB mediates ___________

Back 103

tolerance; sensitization

Front 104

Role of &Delta;FosB in sensitization

Back 104

&Delta;FosB is a transcription factor that is induced only to a small degree in response to initial drug exposures, but it takes awhile to go away, leading to accumulation.

Overexpression leads to increasing self-administration/greater sensitivity. Leads to greater drug sensitivity and increased compulsion for rewarding behavior (craving)

Front 105

What does accumulation of &Delta;FosB lead to?

Back 105

Sensitization and increased compulsion for rewarding behavior. It stays around for awhile.

Front 106

A) Produced in response to drug use and stays around for awhile, building up the more drugs are taken

B) Appears quickly after drug use and goes away quickly

Back 106

&Delta;FosB ; CREB

Front 107

Increase in GluR1 subunit in AMPA receptor contributes to drug ____________

Back 107

sensitization

Front 108

What is the pharmacokinetic sensitization?

Back 108

In alcoholics, lesions in liver caused by long-term alcohol intake can decrease the alcohol's degradation by the liver.

Front 109

In addiction, there is an _______ in basal glutamate levels in VTA-NAc circuit but a _____ in stimulated/phasic glu levels.

Back 109

Decrease; Increase

Front 110

In addiction, there is an _______ in basal DA levels in VTA-NAc circuit but a _____ in stimulated/phasic DA levels.

Back 110

Decrease; Increase