1
Q
2 gene activation/protein products that set time
A
- CLOCK (CLK)
- BMAL1
2
Q
Is CLOCK tied to circadian rhythm on its own?
When would it be secreted if left on its own?
If no CLOCK, what happens to circadian rhythm?
A
- CLOCK is not tied to circadian rhythm on its own
- It would be secreted day or night if left on its own
- No CLOCK»_space; NO circadian rhythm
3
Q
When does BMAL1 increase?
A
BMAL1 increases at night
4
Q
CLOCK and BMAL1 increase the transcription of what 2 genes?
What is important about the interaction between CLOCK and BMAL1?
A
- Period genes: Per1, Per2, Per3
- Cryptochrome genes: Cry1, Cry2
-The interaction between CLOCK and BMAL1 creates a neuronal circadian rhythm so that the neurons in the suprachiasmatic nucleus fire on a circadian rhythm
5
Q
What is special about cryptochrome genes and the relationship between the retina and hypothalamus?
A
Cryptochrome genes help certain photoreceptors in the retina to tell hypothalamus whether its night or day outside
6
Q
Which pair of genes fires later – BMAL1/CLOCK or Cry/Per?
A
Cry/Per genes fire a little bit behind BMAL1/CLOCK
7
Q
Explain the cycling of gene products and why its important.
A
- One set of neurons fires at dawn; another set fires at dusk.
- Circadian rhythm is set due to GENES and not due to visual input (blind people have a circadian rhythm!)
8
Q
The most important component of the circadian rhythm
A
Suprachiasmatic nucleus (in hypothalamus)
9
Q
The suprachiasmatic nucleus creates a day that is how many hours?
A
25 hours!
10
Q
What goes into the process of entrainment (making day match day; night match night) in terms of the hypothalamus? What NTs are used for day and for night?
A
- Information from cryptochrome genes in the retina make their way to the hypothalamus via the retino-hypothalamic tract.
- Once in the hypothalamus, GLUTAMATE causes neurons in the SCN to fire @ dawn when its really dawn.
- MELATONIN @ night – similar path, but making dark match dark.
11
Q
Most of our time is spent in (REM/non-REM) sleep.
A
Most of our time is spent in NON-REM sleep.
12
Q
How many stages are in non-REM sleep and what do we see on EEG?
A
- 3 stages – N1, N2, Deep sleep
- Progressive slowing of EEG waves
13
Q
What is REM sleep and what do we see on EEG?
A
- REM = Rapid Eye Movement (left/right)
- EEG: high frequency, low amplitude
14
Q
Sleep induction involves the first 4 hours (1st half) of sleep, which is called what?
What kind of sleep occurs?
A
- Sleep Homeostasis (“need for sleep”)
- Non-REM sleep comes after Sleep Homeostasis
15
Q
Which type of sleep – REM or non-REM – begins in the 2 half of sleep and occurs more often?
A
-2nd half of sleep = REM sleep
16
Q
How do certain medications like antihistamines interfere with the sleeping process?
A
- Antihistamines can interfere with the process of transitioning from 1st half (non-REM) to 2nd half (REM) of sleep.
- Pt can go to sleep but cannot stay asleep!
17
Q
The Ventral Preoptic Area (VPO) is crucial to what?
A
Sleep Induction (non-REM)
18
Q
What is the proposed mechanism of sleep starting with PGD2 in the blood?
A
PGD2 in the blood binds to DP receptor on epith cell of leptomeningeal capillary»_space;
Cells release ADENOSINE into CSF»_space;
Adenosine binds to 2a receptors in VPO
19
Q
Increased adenosine in CSF»_space;
A
More likely to fall asleep
20
Q
Cytokines and hormones also induce sleep.
Name 2 substances that induce sleep during illness.
What other substance is present in sleep and deals with growth?
A
During illness: IL-1b and TNF-a
-Bind to VPO cell and induce sleep through same neurons that adenosine acts on
-GHRH – growth occurs during sleep
21
Q
IL-1b, TNF-a, and GHRH all stimulate what?
This leads to the production of what?
A
- IL-1b, TNF-a, and GHRH all stimulate NFkB
- Incr NFkB»_space; nitric oxide synthase»_space; NITRIC OXIDE
22
Q
Lateral pontine tegmentum releases ACh in what location?
This location sends the input to which cortex?
A
- Lateral pontine tegmentum releases ACh in the Geniculate Body
- Geniculate Body sends input to the OCCIPITAL cortex
23
Q
Explain the influence of the locus ceruleus in muscle “paralysis” in REM sleep.
TQ: Lesions of the locus ceruleus would cause what?
What areas are spared?
A
- The locus ceruleus inhibits alpha-motoneurons (large muscles)
- Lesions of the LC»_space; REM sleep becomes assoc w/ movements that are consistent with “acting out” the dream that is being experienced
- Spares the diaphragm and small muscle groups
24
Q
The hypothalamus is now known to control _______ as well as sleep induction.
A
The hypothalamus is now known to control AROUSAL as well as sleep induction.
25
What area of the hypothalamus is one of the only sources of Orexin A & B in the brain?
Lateral hypothalamus
26
Orexigenic inputs from the lateral hypothalamus are sent where?
Tuberomammillary nucleus
27
Orexigenic inputs from the lateral hypothalamus are sent to the tuberomammillary nucleus, which then releases what onto where?
Tuberomammillary nucleus releases HISTAMINE on the LOCUS CERULEUS
28
The histamine released in the locus ceruleus binds to what type of receptors, which (activates/deactivates) neurons in the locus ceruleus?
Therefore, how would OTC anti-histamines act?
- H1 receptors – ACTIVATES neurons in the locus ceruleus
- Anti-histamines block histamine from reaching the LC >> block NE release from LC >> stimulates REM sleep >> stay asleep (no arousal)
29
What doe locus ceruleus neurons release upon activation?
Does this stimulate or suppress REM sleep?
What is the result?
- Locus ceruleus neurons release NOREPINEPHRINE
- SUPPRESSES REM sleep
- Leads to AROUSAL (waking up)
30
Describe ALPHA waves on EEG.
- frequency
- amplitude
- when do they occur?
- where are they most prevalent?
- Origin
- 8–13 Hz (high frequency, low amplitude)
- 50 uV
- occur during QUIET wakefulness (i.e., thinking) w/ EYES CLOSED
- most prevalent over OCCIPITAL cortex
- disappear during sleep!
- requires connection between thalamus and cortex
- GABAergic neurons "force" coordination of neuronal activity
- FEEDBACK oscillation between thalamus and cortex
31
Describe BETA waves on EEG.
- frequency
- amplitude
- when do they occur?
- where are they most prevalent?
- conversion of alpha waves to beta waves is called what?
- Origin
- 14–80 Hz (highest frequency, lowest amplitude)
- < 50 uV
- occur during ALERT wakefulness w/ EYES OPEN
- most prevalent over FRONTAL cortex
- conversion of alpha waves to beta waves is called ALPHA BLOCK
- thalamocortical oscillations (same as alpha)
- sensory input "disrupts" the oscillation to some extent
32
Describe GAMMA waves on EEG.
- frequency
- amplitude
- when do they occur?
- may be replaced by even more irregular activity with what?
- may require what area of brain?
- 30–80 Hz (oscillation)
- occur when individual is AROUSED and FOCUSED on something
- replaced by even more irregular activity if plan motor response
- may require HIPPOCAMPUS
33
Describe THETA waves on EEG.
- frequency
- amplitude
- when do they occur? children vs. adults?
- where are they most prevalent?
- Origin unclear, but what area may be involved?
- 4–7 Hz (slower, higher amplitude)
- 100 uV
- children = normal (parietal or frontal cortex)
- adults = occur w/ FRUSTRATION and DISAPPOINTMENT
- seen in N1 stage (light sleep) in non-REM sleep
- HIPPOCAMPUS
34
Describe DELTA waves on EEG.
- frequency
- amplitude
- when do they occur?
- requires connection between thalamus and cortex?
- 3–5 Hz (lowest frequency, highest amplitude)
- 100–200 uV
- deepest non-REM sleep in adults (should not be present in adults, except for deep sleep)
- does NOT require connection between thalamus and cortex (represents *DISSOCIATION between thalamus and cortex*)
35
In general: incr mental/neuronal activity is assoc w/ (incr/decr) activity on EEG (higher freq, low amplitude)
In general: incr mental/neuronal activity is assoc w/ INCREASED activity on EEG (higher freq, low amplitude)
36
Changes in the EEG:
| What kind of wave activity is seen in infants? What about over occipital region?
In infants:
- Fast BETA-like activity
- SLOW over occipital region (0.5–2 Hz)
37
What happens to the activity over the occipital region as an infant ages into childhood?
When do adult alpha waves appear?
- Activity over the occipital region gradually incr in frequency throughout childhood
- Adult alpha wave appears during adolescence
38
Frequency of alpha waves decrease by: (4)
- Decr glucose (hypoglycemia)
- Decr body temp (hypothermia)
- Decr adrenal glucocorticoids
- Incr PaCO2
39
How long is the first sleep cycle of the night?
| What is the ratio of deep sleep to REM?
- 70–100 min (most variable)
| - More deep sleep to REM
40
How long are the later cycles of sleep?
| What is the ratio of deep sleep to REM?
- 90 min
| - Decr deep sleep, incr REM
41
What is the ratio of REM to deep sleep in children?
More time in REM
More time in deep sleep
Increased sleep time altogether
42
What sleep cycle patterns are seen in the elderly in terms of REM and deep sleep, awakenings, and total sleep?
What does this say about their circadian rhythm?
- Fewer REM epochs
- Almost NO deep sleep
- More frequent awakenings (bladder)
- Less total sleep
Circadian rhythm not as strong anymore.
43
Describe N1 stage of slow wave sleep.
- what level of sleep?
- eye movements?
- EMG
- EEG
- what waveform?
- Light sleep – drowsiness/earliest sleep stage
- Slow, rolling eye movements
- EMG: muscle activity
- EEG: low voltage, slowing of frequency
- THETA waves
44
Describe N2 stage of slow wave sleep.
- what level of sleep?
- EMG
- EEG
- True sleep
- EMG: muscle activity, but quiet
- EEG: incr voltage, slowing of frequency, SLEEP SPINDLES (preceded by K complex)
45
Stage N2 of non-REM sleep is characterized by what 2 events?
- Sleep spindles
| - K complexes (occur right before sleep spindles)
46
Describe N3 stage of slow wave sleep.
- what level of sleep?
- EEG
- what waveforms?
- Deep sleep
- EEG: incr voltage, slowing of frequency
- THETA/DELTA waves
47
Describe REM sleep.
- eye movements?
- dreams?
- EMG (effect of locus ceruleus?)
- EEG
- Rapid Eye Movements (left/right)
- dreams occur
- EMG: very quiet (locus ceruleus suppresses alpha-motoneurons in large muscles)
- EEG: rapid, low voltage, similar to BETA waves
- most likely to wake up
48
What are the 2 anatomic substrates for procedural ("implicit," "non-declarative," "reflexive") memory?
- Cerebellum: motor skills
| - Nucleus accumbens: non-motor
49
What is declarative ("explicit") memory?
What are the 2 forms of declarative memory?
What are each form responsible for remembering?
- Declarative memory is the conscious recognition/recollection of learned facts and experiences
- 2 forms: episodic and semantic
```
Episodic = memory of events
Semantic = words, language, rules
```
50
What type of memory allows you to recreate the answer needed for an exam question or lets you remember a phone number as you use your phone?
Working memory
51
What is post-tetanic stimulation? What does this lead to?
How long does it last?
TQ: What is the mechanism?
- Brief high-frequency discharge of PREsynaptic neuron leading to incr NT release
- Lasts 60 sec (1 min)
- Mechanism = the high level of stimulation >> more Ca++ to enter terminal than could be dealt with
52
Describe long term potentiation.
- assoc w/ gene transcription related to incr in what?
- link to change in what?
- Incr post-synaptic response to the released NT and incr NT release with future APs
- assoc w/ gene transcription related incr in CREB
- long term potentiation is the link to STRUCTURAL CHANGES!
53
Describe neuronal plasticity.
- assoc w/ gene transcription related to incr in what?
- pre-, post-synaptic, or both?
- what 3 kinds of proteins are produced?
- like LTP, also assoc w/ incr in CREB
- involves both pre- AND post-synaptic cells
- produces NT enzymes, NT receptors, and proteins for growth/synapse formation
54
What are the 4 steps in creating declarative (explicit) memories?
1. Encoding
2. Storage of info
3. Consolidation
4. Retrieval
55
Storage:
For short-term memory, what 3 anatomical substrates are used?
What physiological substrate is used in short-term memory?
Anatomical:
- Hippocampus
- Parahippocampal cortex
- Prefrontal cortex
Physiological: LTP
56
TQ
For short-term memory, besides the main 3 anatomical substrates, we use interconnections to neocortex and amygdala via what?
What kind of signaling is involved and what dz are we targeting specifically?
- interconnections to neocortex and amygdala via NUCLEUS BASILIS OF MEYNART
- cholinergic projection hit hard in Alzheimer's dz
57
What are the 3 anatomical substrates of the consolidation process of memories?
What is the purpose of the consolidation process?
- Papez circuit
- Temporal lobes
- Hippocampus
-Purpose is to make memories permanent
58
Going around the Papez circuit during consolidation is specifically important in order to do what?
In the consolidation process, memories are repeatedly sent through Papez circuit because it sets up conditions to induce LTP and neuronal plasticity.
59
Appears that long-term memories are stored in area of cortex related to ________ of individual components.
(E.g., visual info stored w/in visual cortex)
Appears that long-term memories are stored in area of cortex related to MODALITY of individual components.
(E.g., visual info stored w/in visual cortex)
60
What is the physiological starting point for consolidation?
Where does it go after that?
This helps to create what?
- LTP
- Papez circuit (continued activation)
- Helps to create new synapses in required brain areas (visual, auditory, etc...)
61
Long term memory ("Reassembling") requires what 3 anatomical substrates?
- Neocortex
- Parahippocampal regions
- Hippocampus
62
What is the process of recalling/retrieving memories?
```
Info related to each component of the memory (visual, auditory, etc...) >>
Parahippocampus >>
Hippocampus >>
Parahippocampus >>
Cortex
```
63
TQ: What is the main role of the hippocampus in the recalling/retrieving process of memories?
In the hippocampus, the entire memory is "reconstructed"
64
What is the main role of the parahippocampus in the recalling/retrieving process of memories?
The parahippocampus is important in keeping the cortical "trace" of the memory
65
TQ
| What part of the declarative (explicit) memory process is unique in that memories can be lost or modified?
Memories can be lost or modified in the recalling/retrieval process (the last step)
66
What is the 3-component model of working memory?
| Where is each component located in the brain?
3-component model:
- Phonological loop: Broca's and Wernicke's assoc w/ words
- Visuospatial loop: Occipital cortex assoc w/ vision
- central executive: Pre-frontal cortex (ending point)
67
TQ
Describe spatial memory.
What is made and where?
What is the name of the neurons involved and what specific region are they located?
- Detailed spatial map is made in the hippocampus
| - "Place" neurons in CA1 region of the hippocampus respond to specific locations w/in space
68
TQ
| Why is spatial memory important in terms of the ability of the hippocampus to make a spacial map?
The map is believed to "anchor" the entire memory.
69
As with other areas of the neocortex, most of the association cortex is composed of how many layers?
What kind of cells produce extensive synaptic interactions, leading to cognition?
TQ
What is unique about the axons of these cells?
Why is this impt?
- 6 layers
- Pyramidal cells
- Axons of pyramidal cells give off recurrent collaterals (branching) that synapse onto the cell that activated it and neighboring cells
- Allows a feedback system and ability to store info (the "cloud")
70
What is the Mediational pathway?
| What areas are involved in the Language Implementation Area?
The *Mediational pathway* relays info to the Language Implementation System (Broca's, Arcuate fasciculus, Wernicke's areas), which allows us to speak or read the word in question.
71
The *conceptual system* for language is a broadly distributed set of pictures that provides what?
Conceptual system *provides the concepts* underlying our language.
(e.g., the noun mediation area overlaps with the ventral visual pathway)
72
How old are babies when they're "language universalists" – they recognize all sounds that might be language as distinct sounds?
< 6 months old
73
At what age do babies' brains start to change to recognize the specific language sounds of their native language?
When does the 'babbling' stop and "talking" begin?
- 6–9 months old
| - Talking begins @ 1 year
74
T/F: A second language learned during the language acquisition phase activates the SAME pathway as the first language.
TRUE
75
TQ
| What is activated when a second language is learned AFTER the language acquisition phase?
An adjacent region of Broca's area is activated (not the same pathway as first learned language)
76
What are the 2 major functions of the prefrontal cortex?
- Planning of complex motor actions
| - Carrying out of "thought processes"
77
Planning complex motor actions by the prefrontal cortex requires interaction with what?
Parieto-temporal-occipital (PTO) association area and all levels of motor cortex
78
In order to carry out "thought processes" by the prefrontal cortex, what other part of the brain must be involved?
What type of memory is assoc w/ this part of the brain?
Carrying out "thought processes" also deals with what?
- Hippocampus (major component)
- Hippocampus >> working memory
- Judgment (mostly limbic)
79
The Limbic association area is extensively involved in the interpretation of:
emotional context
80
When integrating the inputs (step 2), the pre-frontal cortex has 3 probably roles, which are what?
- Reward processing (orbitofrontal): with the amygdala, we link new stimulus to a primary reward
- Integration of bodily signals (ventromedial prefrontal) – "gut feeling"
- Top down regulation – especially towards delayed gratification
81
Social cognition can be divided into what 2 components?
- Emotion comprehension (recognition)
| - Theory of Mind
82
Emotional Comprehension
Step 1: Perceptions of facial expressions requires that we identify a FACE as something special.
TQ
What 2 locations in the brain are in charge of recognizing facial expressions (and therefore faces)?
- Superior temporal sulcus
| - Fusiform gyrus (fusiform face area) ***
83
Emotional Comprehension
Step 2: Bring in the emotional component.
Remember that the same emotional circuitry that produces emotion in us *recognizes it in someone else*
TQ
What 3 areas (1 major) are involved in recognizing emotions?
- Amygdala*** (identification of facial expressions, directing gaze) ... (also detects fear and anger)
- Anterior Cingulate Cortex
- Prefrontal cortex
i.e., Amygdala + limbic = Emotional Comprehension
84
TQ
| What is the result of B/L lesions of the amygdala in terms of the eyes?
B/L lesions of the amygdala disrupt the ability to look at the eyes of another person.
(i.e., an individual with damage to the amygdala spends very little time looking at the eyes of another and doesn't methodically scan the face)
85
Social Cognition also involves Mirror neurons to recognize emotions.
TQ
What are the 3 components of Mirror neurons and their main function together?
- Posterior sector of the superior temporal sulcus = provides the visual input (seeing what they're doing)
- Posterior Mirror neuron system = identifies the motion (describing what they're doing)
- Anterior Mirror neuron system = identifies the goal (purpose) of the motion (tells why they're doing what they're doing)
* Main function: To imitate other people's emotions. ("mirror" neurons)
86
TQ
| The circuit for *imitative behavior* is believed to interact with limbic structures via what?
The INSULA
87
TQ
| What is the information sequence for the perception of *prosody* and what happens at each step? (3 steps)
- Primary auditory cortex – identifies pitch, loudness, other sound characteristics >>
- Right posterior superior temporal sulcus – piece together the 'meaning' >>
- Frontal cortex – judgment of the emotional content (still modality independent at this point)
88
"...an individual's ability to infer the emotional state of another from observable information such as prosody and facial expression."
Emotional comprehension
89
Takes emotional cognition to a higher level – not just recognizing the emotion, but recognizing the beliefs that lead to that emotion and that different people have different beliefs.
Theory of Mind
90
TQ
What 4 components of the brain are required in the Theory of Mind?
(the 1st 3 comprise the core pathway)
- Amygdala
- Medial temporal lobes
- Orbitofrontal areas
- Accessory pathways
i.e., Amydala + medial temporal / orbitofrontal areas = Theory of Mind
91
The "accessory" pathways in the Theory of Mind involves what 2 aspects?
TQ
Which one is believed to serve as the "scaffold" for Theory of Mind?
- Language* – believed to serve as scaffold of Theory of Mind
- Executive functioning (frontal lobes)
92
What 3 structures are involved in the Stimulus Encoding System in the decision making process?
- Orbitofrontal cortex
- Ventromedial prefrontal cortex
- Striatum
93
What is the main role of a Stimulus Encoding System?
*Evaluate the evidence* available in making the decision.
| "Predicts the consequences of actions."
94
What is the main role of an Action Selection System (w/in Anterior Cingulate Cortex)?
Learn from mistakes, encodes results. (last step)
| -Also involved in error detection
95
What 4 structures are involved in the Expected Reward System in the decision making process?
- Amygdala
- Basal ganglia
- Insula cortex
- Intraparietal cortex
96
What is the main role of an Expected Reward System?
Predict the expected reward
| "What are the rewards?"
97
A decision in which the risks are explicit (known) relies most heavily on which system?
Stimulus Encoding System
98
What 2 systems are relied on in decisions in which the *risks are unknown* (ambiguous risk)?
Expected Reward System, and eventually, the Action Selection System
99
TQ
| In autism/ASD, what kind of growth/size pattern do we see in the cerebrum and in the cerebellum?
- Increased cerebrum growth during early childhood (esp frontal lobes)
- Cerebellum is initially larger, then decreases in size, with fewer Purkinje neurons
100
What can be said about the dendritic spine number in autism/ASD compared to normal?
The dendritic spine number increases more rapidly and to a greater extent than normal, then declines at a similar rate, but will always be increased due to the initial spike at early age.
101
TQ
| What are the 3 main genes assoc w/ autism/ASD?
- Neuroligin 3 *
- Neuroligin 4 *
- Neurexin 1 *
102
TQ
| In all genes assoc w/ autism/ASD alone, what do the proteins encode for?
Post-synaptic function
| dendritic spines ARE the post-synaptic elements
103
TQ
| Children and adults with autism/ASD show minimal/absent activation of the ______ ______ ______.
Children and adults with autism/ASD show minimal/absent activation of the MIRROR NEURON SYSTEM.
104
Because the Mirror Neuron System does not develop in autism/ASD, what can be said about imitative behavior in these affected individuals?
No Mirror Neuron System >> imitative behavior does NOT occur
105
Failure to fixate the gaze on faces is assoc with autism/ASD, so what 2 parts of the brain may be affected (face recognition area)?
- Superior Temporal Gyrus
| - Fusiform gyrus (fusiform face area)
106
TQ
| What 3 brain changes do we see in schizophrenia?
- Decreased neural volume in cortex
- Decreased neural volume in subcortical structures (thalamus, caudate, putamen, amygdala)
- Increased size of lateral ventricles
107
What can be said about the dendritic spine number in schizophrenia compared to normal?
The number of dendritic spines ascends normally but then drops off much quicker than normal after peaking.
108
```
Name 4 (+) symptoms assoc w/ schizophrenia.
TQ
What do these symptoms reflect in terms of dopamine activity?
```
- Hallucinations
- Delusions
- Thinking disturbances
- Disorganized speech/illogical statements
Abnormal increase in dopaminergic activity.
109
During self-reported auditory hallucinations, what 3 areas were active in the brain?
- Broca's area
- Inferior frontal gyrus
- Wernicke's
110
Other activated areas in the brain during auditory hallucinations include the SMA, verbal memory regions, and self-awareness regions, leading to the theory that what?
Leads to the theory that many of the hallucinations are the result of normal internal cognition ('self-talk') not being recognized as arising from self.
111
What are 6 (–) symptoms assoc w/ schizophrenia?
TQ
These symptoms reflect disruptions of what NT systems?
- Apathy
- Blunted affect
- Anhedonia
- Poverty of speech
- Inattention
- Avolition
Disruption of EAA systems.
112
Reminder from Addiction lecture:
What is the sequence of events in preventing pleasure starting from the release of EAA from prefrontal cortex, amygdala, and hippocampus?
- Release of EAA from prefrontal cortex, amygdala, and hippocampus onto NAc >>
- Nucleus Accumbens (NAc) releases GABA back onto prefrontal cortex >>
- Absence of pleasure
113
Contrary to (+) symptoms (increase dopamine), Cognitive symptoms, such as disorganization, impaired working memory, and impaired exec function, demonstrate what about dopaminergic activity?
DECREASED dopaminergic activity >> Cognitive impairments in working memory and exec function
i.e., decr cerebral dopamine >> cognitive difficulties
114
Cognitive symptoms are the result of what 2 aspects in terms of neuronal number in the thalamus and the number of dendrites in the prefrontal cortex?
- Decreased number of neurons in thalamus
| - Decrease dendrites (neuropil) in prefrontal cortex
115
The (+) symptoms present in schizophrenia are thought to be link to what?
(+) — overactivity of the dopaminergic system
(most drugs used to treat it act at dopaminergic synapses)
i.e., incr dopamine >> hallucinations [(+) symptoms]
116
Reminder from Addiction lecture:
What is the sequence of events leading to pleasure with overactivity of dopamine release from the Ventral Tegmental Area (VTA)?
- VTA releases increased amt of dopamine onto NAc >>
- NAc decreases GABA output onto the prefrontal cortex >>
- Pleasure is then perceived
117
What are the 3 main genes that have been implicated in the origin of schizophrenia?
- Dysbindin
- DISC-1 ("Disrupted In SChizophrenia")
- COMT
118
Describe the Dysbindin gene.
What chromosome?
What does it bind to?
Component of (pre-/post-) synaptic density?
What receptor clustering does it regulate, which influences synaptic plasticity and signal transduction?
- Chr 6p22.3
- Binds to alpha- and beta-dystrobrevin (normally assoc w/ muscle, complex found in brain)
- Component of POST-SYNAPTIC density
- Regulates NMDA and nAChR
119
TQ
| How does dysbindin interact in the pre-synaptic terminal and where?
Dysbindin interacts inversely with the vesicular transport protein for EAA (VGlutT1) in the HIPPOCAMPUS
i.e., altered EAA in vesicles!!!
120
(increased/reduced) levels of dysbindin are documented in the hippocampus of schizophrenics.
REDUCED levels of dysbindin are documented in the hippocampus of schizophrenics.
121
What would the reduction in dysbindin in the hippocampus lead to in terms of EAA?
Decr dysbindin in schizophrenics >> INCR EAA release >> death of post-synaptic cell, which alters cognition and behavior
i.e., incr EAA >> (–) symptoms
122
Would the excitotoxicity of the post-synaptic cell in schizophrenics be consistent with the decreased number of dendritic spines?
YES! If post-synaptic cells are dying, you would expect the number of dendrites to decrease.
123
By using a typical antipsychotic (dopaminergic), what happens to the release of EAA in the cortex?
Release of EAA in the cortex is REDUCED
124
What happens if the DISC protein is interrupted transiently during development in terms of dopamine function and behavior as an adult?
DISC protein interruption during development >> dopaminergic dysfunction >> behavior deficits in the adult
125
DISC was recently shown to be a player in regulating what?
DISC – regulating the growth of dendritic spines at glutamatergic synapses
126
Bottom line.... What is the relationship between mutated DISC and schizophrenia?
The changes produced with mutated DISC are consistent with the observed changes in the brain that are assoc w/ schizophrenia.
127
Explain the multiple-hit process of schizophrenia.
- Genetic mutation of neurons
- Add'l stress which tips balance (birth trauma, neonatal viral infection, or drugs of abuse)
- The abnormal changes in the brain gives rise to more abnormal changes
128
TQ
Depression reduces volume/thickness on what 2 areas of the brain?
What add'l cortex contributes to suicide (separate from major depressive disorder)?
- Nucleus Accumbens/basal ganglia *
- Frontal and prefrontal cortex **
-Parahippocampal cortex – suicide
129
TQ
| Depression is often attributed to decreased activity of what 2 NT systems?
- Noradrenergic
| - Serotonergic (Raphe nuclei)
130
TQ
| Genetic evidence in depression/anxiety shows a polymorphism where?
Promoter region of the 5HT-transporter protein
i.e., less NT into vesicle for release with every AP
131
In people with the short allele for depression, what was the amygdaloid response to threatening visual images?
enhanced
i.e., short allele = increased anxiety
132
More importantly, what happens to the coupling between the cingulate cortex and the amygdala, which normally extinguishes the amygdaloid response?
The coupling in the carriers of this mutation is severely diminished.
i.e., more uncoupling = more anxiety
133
What 3 areas of the brain are glucocorticoid receptors (GRs) found?
- Cortex (mainly LIMBIC)
- Hippocampus
- Paraventricular nucleus of hypothalamus
134
TQ
Since *GR activation helps decrease response to stress*, animals in which the GR of the forebrain is 'knocked out' would show what 2 things?
What drug is used to reverse the effect?
- Chronic high levels of steroids
- Develop a depression-like syndrome
Imipramine reverses the depression-like syndrome
135
TQ
Anatomic changes in bipolar disorder are similar to depression and has also been related to a disruption in the neural circuits, which produce what?
Circadian rhythm
| suprachiasmatic nucleus ***
136
T/F: The multiple-hit model is believed to be crucial in leading to the expression of bipolar disorder.
TRUE
137
TQ
What is the most notable gene implicated in bipolar disorder?
What does the enzyme cause?
What drug inhibits the enzyme? What is the result in terms of neuron death/survival?
What gene does it regulate/alter physiologically?
- Glycogen synthase kinase 3-beta ***
- Enzyme promotes neuron apoptosis
- Lithium inhibits glycogen synthase kinase 3-beta *** >> neurons survive
- Regulates CLOCK gene**
138
TQ
| How does lithium help with bipolar disorder?
-Reduces apoptosis, increases neuroprotection
Neuro 2 Final
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