Unit 3 Flashcards
1
Q
Development of the Nervous System in a nutshell
A
- Gastrulation (transcription factors and diffusible molecules)
- Neural Tube Forms (transcription factors and diffusible molecules)
- Unequal cell division causes bulges in tube (transcription factors and diffusible molecules)
- Fates of cells are specified along dorsalventral and rostral/caudal axes (transcription factors and diffusible molecules)
- Neurogenesis (transcription factors and diffusible molecules)
- Cell migration (CAMs - cell adhesion molecules)
- Neurons grow neurites (diffusible molecules and cell adhesion molecules)
- Synapse formation (cell surface and diffusible molecules)
- Synapse refinement
2
Q
Central concept of developmental biology
A
Positional information is important; cells release factors in early development that help other cells differentiate and find right position
3
Q
What layer does the neural tube form from?
A
Ectoderm
4
Q
Neural tube formation
A
Neural plate folds on itself, forming the neural tube: a fluid filled cavity surrounded by neurons
5
Q
Bulges in tube result because…
A
Different rates of cell division occur
6
Q
Overall steps of development of the neural tube
A
- Differential rates of division cause bulges to grow in certain places in the tube (telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon)
- Position of cells within the tube determines what kind of cell they become (e.g. cell at caudal end becomes a LMN)
- Cell fate is a result of transcription factors and diffusible factors
7
Q
Transcription Factors Role in Cell Fate
A
Factors that are expressed in cells and help define developing anterior-posterior axis in humans
- Particular example: Hox genes-help with determination of groups of cells to develop into particular structures (think fruit flies!)
8
Q
Diffusible Factors Role in Cell Fate
A
- Shh (SONIC HEDGEHOG WOOOO!)
- Dorsal: less Shh, near roof plate, sensory
- Ventral: more Shh, near floor plate, motor
- Determine the ventral/dorsal patterning of cells
- Too much Shh initially would change gradient - interneurons would be higher
9
Q
Causes of diseases of early development
A
- Environmental factors: lack of folic acid, exposure to alcohol
- Diffusible factors: mutations in shh cause eye defects and brain cancers; retinoic acid interferes with shh signaling
- Transcription factors: mutations can cause eye and defects and Waardenburg syndrome
10
Q
What happens after patterning (dorsal/ventral, rostral/caudal)?
A
Neurogenesis - MASS mitosis
11
Q
Migration of Cells
A
Migration from ventricles to final position
- controlled by CAMs (delta/notch reelin, L1CAM)
- In CNS, migration is fairly short (goes layer 6 (inner most) to layer 1 (outer most))
- In PNS, long distance migration is frequent
12
Q
Neural Crest Derivatives
A
- Sensory ganglia
- Autonomic ganglia
- Adrenal chromaffin cells
- Melanocytes
- Schwann cells
- Enteric Nervous System
13
Q
True or false: migration is inside out for the cortex
A
True: goes layer 1 through 6
14
Q
Role of reelin
A
glycoprotein that is expressed in high levels during developing brain; plays a major role in white matter and ventricle development
15
Q
Mutation in reelin results in
A
Less white matter, enlarged ventricles, disrupted sulci and gyri, and various other disorders
16
Q
Lack of reelin results in
A
Lissencephaly: smooth brain
17
Q
Axon and dendrite growth happens how?
A
- Growth cones with receptors that grow along and follow molecules that they’re attracted, but die if they’re close to repulsive molecules
- Example: netrin and slit; netrin attracts growth cone to midline, then slit turns off the receptor for netrin so that they don’t cross the midline again
18
Q
Semphorin’s role in growth of neurons
A
- Repulsive gradient
- Low semaphorin = dorsal (get repulsed quickly)
- Lots of semaphorin = ventral (don’t get repulsed until a lot of semaphorin is present)
19
Q
Synapse formation
A
- Neurexin: presynaptic
- Neuroligin: postsynaptic
- Confer specificity of synapses
- A lot of redundancy of proteins involved in the process, so mutations in one protein shows little effect
20
Q
Synapse Elimination - How To
A
- Neurons compete for a limited supply of survival factors, such as the neurotrophins NGF, BDNF, and NT3
- Competitive: more neurons produced than can be sustained, more axons innervate targets than necessary, target tissue produce limited number of factors, and only neurons that receive enough of the neurotrophic factors
21
Q
Synapse Refinement at Neuromuscular junctions
A
- Similar system, but we don’t know what the trophic factors are
- Each muscle fibers has one NMJ, one LMN per muscle fibers
22
Q
Innate behaviors
A
Present at birth without learning and parental input
23
Q
True or false; synapses are not lost during development of CNS
A
FALSE, they are lost during development
24
Q
Hebb’s Postulate
A
Neurons that fire together wire together
25
Critical period
Plasticity is maximal during certain periods of the developing brain
26
Developmental Diseases Examples
- Down Syndrome
- Trauma
- Spina bifida
- Fragile X
- Rett
- Autism
27
Where are most excitatory synapses in the cortex?
On dendritic spines
28
How do dendritic spines differ with LTD vs LTP?
LTP: increase in AMPAR leads to progression of spines
LTD: decrease in AMPAR leads to reverse of spinogenesis
29
When do spines increase?
During development; get more complex during development
30
Down Syndrome (general)
- Triplication of chromosome 21
- 100s of extra genes
- Sx: dysmorphic facial features, intellectual disability, stunted growth, seizures, early onset AD, obesity
31
Genes involved in DS
APP, SOD1, OLIG1/2, and KCNJ6
32
Theories based on genes in DS
- Enhanced GABA activity (GIRK2 increase and Olig1/Olig2)
- Synaptic vesicle proteins
- Developmental processes
- Neurodegeneration (APP increase and SOD1 increase)
33
True or false: GABA-ergic activity increased in DS
True; LTP decreases and LTD increases
34
Treatment for DS
- Blocking GABA-R restores normal phenotype (could cause seizures)
- Basminsanil
- Prozac: blocks GIRK2S
35
Spine Morphology in DS
Less spines, but spines are larger!
35
Fragile X Syndrome General
- X Chromosome - affects boys more than girls
- CGG expansion that causes silencing of FMR1gene (TNRE disease)
36
Molecular Pathology of FXS
FMR1 normally inhibits mGluR proteins, but if it is mutated, it allows excess mGluR signaling which leads to LTD and abnormal spines
37
Rett Syndrome General
- X linked
- Affects girls most
- Somatic mosaicism
- Normal development, but regression occurs at 6 to 18 months
38
Molecular Pathology of Rett
- MeCP2 mutation
- Normally binds methylated CpGs and allows BDNF activity dependent transcription (influx of Ca2+ = CAMKII = phosphorylates MeCP2 = dislocates from BDNF promoter to activate its transcription)
- Rett Syndrome lacks MeCP2 dependent release so BDNF is decreased
39
Spine Density in Rett
Decrease in number and size
40
Treatment of Rett
- BDNF could restore spine density in Rett Syndrome neurons
- Use bone marrow microglia to select for 50% of MECP2 wild type cells
41
ASD Sx
Deficits in social communication and interaction, repetitive behaviors, language difficulties
42
Physical vs Intentional Causality in ASD
Physical causality is not impaired (interactions with objects)
Intentional causality IS impaired (interactions dealing with people)
43
True or false: there is decreased synapses in ASD
FALSE - increased synapses!!!
44
Hypoconnectivity in Autism
Local hyperexcitability (more synapses) and longer range hypoexcitability (decrease in network connections)
45
Genes in ASD
- Neuroligins (regulate spine morphisms and connect spines; disruption can alter spine dynamics and stability)
- Shank3
- Ubiquitin protein ligase E3
- Reelin
46
Role of Emotions
- Critical to survival
- Emotional circuits appraise stimuli and activate physiological pathways
47
Negative vs Positive Emotions
Negative: inputs from danger and pain and lead to escape, avoidance, protection (ESCAPE)
Positive: inputs from food, safety, comfort (SOCIAL INTERACTION)
48
Mood
Predominant emotional state and mood interacts with emotional responses to certain stimuli
49
Hypothalamus role in Emotion
- Controls a lot of the visceral functions of emotion
- Controls homeostasis
- Receives contextual information from the brain and sensory inputs from the body
- Controls outputs to autonomic nervous system (ANS) and pituitary gland (HPA axis)
50
Sham Rage
- Controlled by hypothalamus
- Doesn't occur if hypothalamus isn't connected
- Shows that the cortex is inhibitory on hypothalamus
51
ANS and Hypothalamus
- One of the ways the hypothalamus controls visceral emotional response
- Two divisions: sympathetic and parasympathetic
- Sympathetic: fight or flight (short pre ganglionic, long post ganglionic: ACh and NE)
- Parasympathetic: rest and digest: long pre ganglionic, short post ganglionic: both ACh)
52
HPA Axis and Hypothalamus
- Hypothalamus --> CRH --> anterior pituitary --> ACTH --> Adrenal cortex: produces glucocorticoids
53
Role of glucocorticoids
Activate stress responses which leads to heightened awareness, vigilance, alertness, and attention. Also involves in memory consolidation (particularly emotional)
54
Limbic areas involved in emotion and mood
- Cingulate gyrus
- Ventral striatum (nucleus accumbens = reward)
- Hypothalamus (visceral responses)
- Amygdala (fear)
- Hippocampus (inhibitory to fearful responses)
55
Amygdala and Emotional Circuits
- Overall effect: arousal, vigilance, enhanced memory
- Input to amygdala is from thalamus and cortex
- Output from amygdala goes many places (hypothalamus, aminergic cell bodies - locus coeruleus (NA), Raphe (5HT), and ventral tegmental area (DA))
56
Cues vs Context in Perception of Fear
Amygdala: cue, subject of fear, emotional memory
Hippocampus: context of the cue, cognitive and contextual
*context affects our perception of fear
57
DA is made in
Substantia nigra and ventral tegmental area
58
NE is made in
Locus coeruleus
59
Serotonin (5HT) is made in
Raphe nuclei
60
Overall synthesis of monoamine neurotransmitters
1. Amino acids (tyrosine or tryptophan)
2. Hydroxylase
3. Decarboxylase
61
Breakdown Processes of Catecholamines and Serotonin
1. Reuptake (DAT, NET, SERT)
2. Enzymatic degradation (MAO - DA, NE, and SER break down; COMT - only catecholamine break down)
62
Anxiety and Fear Circuits
Anxiety: state of preparation for danger but is triggered in the absence of an immediate danger signal
- abnormal regulation of amygdala-based fear circuitry, often involving extended amygdala and more generalized activation of pathways
63
Treatment of Anxiety
1. Non-drug treatment (CBT and EMDR)
2. GABA Pathways (benzodiazepines, barbiturates, alcohol)
3. Antidepressants (inhibit enzymes that degrade monoamines and one monoamine transports)
4. Beta-blockers
64
Mood disorders (general)
- Grief
- Secondary depression
- Clinical (unipolar) depression
- Bipolar depression (manic depressive illness)
65
Dx Criteria for Depression (unipolar and bipolar)
1. Depressed or irritable mood
2. Decreased in pleasurable activities and abilities to experience pleasure
3. Significant weight gain or loss
4. Insomnia or hypersomnia
5. Psychomotor agitation
6. Fatigue or loss of energy
7. Feelings of worthlessness or guilt
8. Diminished ability to think or concentrate
9. Recurrent thoughts of death or suicide
66
Dx Criteria for Mania in Bipolar Disorder
1. Inflated self-esteem or grandiosity
2. Less need for sleep
3. More talkative
4. Ideas or thoughts are racing
5. Easily distracted
6. Increased goal oriented activity
7. Excessive pleasurable activities
**episodes of dep and then episodes of mania
67
True or false: areas involved in depression are mostly parts of the basal ganglia
FALSE: mostly parts of the LIMBIC SYSTEM
68
Structural changes in depression
- Decreased gray matter volume and functioning in the prefrontal cortex and hippocampus
- Activity increased in amygdala and is a lot bigger
- ACC - usually activated with pain and conflict, but in depression ACC activation may indicate conflict between goals and performance
69
Hippocampus pathway
Trisynaptic hippocampal circuit in hippocampus --> DG --> CA3 --> CA1 --> out
70
Mood Stabilizing Drugs that affect the hippocampus
Lithium: strengthens pre and post synaptic activity of CA1 neurons (BDNF release helps LTP!
71
Hippocampal neurogenesis is increased by
Exercise, sex, enriched environment, anti-depressant, and seizures
72
Hippocampal neurogenesis is decreased by
Stress (social defeat, physical restraint), stress hormones
73
Stress pathway, BDNF, and Depression
- Stress decreases spines and dendrites decrease in hippocampus
- Antidepressants increase BDNF in hippocampus and cortex; also increase dendritic arborization
- Activity-dependent increased expression of BDNF and via ionotropic and metabotropic receptors
74
HPA Axis role in Stress
- Overactive hypothalamus
- Higher levels of glucocorticoids
- Hippocampus usually inhibits HPA, but because it is atrophied in depression, the HPA axis is a lot less inhibited
75
Epigenetics and depression
Acetylation of histones activates transcription, while methylation of cytosines represses transcription
(removing acetyl groups decreases transcription)
76
Drug Target for Depression
- 5HT and NE increase in synaptic cleft
- SSRI = specific to 5-HT
- SNRI = not specific
77
Treatments for Depression
1. MAOI - monoamine degradation inhibitor
2. Tricyclics
3. SSRIs and SNRIs
4 . Psychotherapy
5. ECT
6. Ketamine
7. Placebo effect
78
What is a big problem with anti-depressants?
They work rapidly molecularly, but therapeutic effects re only felt after several weeks
79
Ketamine in Depression
- low doses
- Increases glutamate = increases excitation in limbic system
- Acts as a NMDAR antagonist on GABA-ergic interneurons = less GABA
80
Bipolar Depression Treatments
1. Lithium = improves move, affects GSK3
2. Antiseizures/anticonvulsants = similar to depression
81
SZ General
- Tragic neuropsychiatric illness
- No good biomarkers
- Dx usually made in late teens based upon sx like eccentricity, social isolation, blunted affect, speech deficits, and lack of motivation
82
True or False: SZ has the same progression
FALSE: there are different progressions (baseline of sx can increase over time or always be the same regardless of episodes)
83
3 Categories of Sx in SZ
1. Positive (psychosis, hallucinations, delusions. Treated with antipsychotics)
2. Negative (absence of emotion or motional flatness, depression. Treated with lithium and SSRIs)
3. Cognitive deficits (executive function especially in memory)
84
Brain Regions that Change in SZ
- Dorsolateral prefrontal cortex atrophies (loss of dendritic spines)
- Enlarged lateral ventricles
- Neuronal number stays the same, instead atrophy is due to loss of dendrites
*** Depression atrophies in medial ventral prefrontal cortex
85
Synaptic changes in SZ
Reduced synapse number due to developmental over-pruning in SZ
86
True or False: frontal lobe is important for working memory and planning
True; working memory - cognitive control
87
Possible Hypotheses for SZ
1. Dopamine hypothesis and psychosis
2. Glutamate hypothesis
3. GABA hypothesis and gamma oscillations
4. Acetylcholine hypothesis
5. Genetics and synaptic changes
6. White matter changes
88
Dopamine hypothesis of SZ
- Activation of D2 receptors causes psychotic behavior
- Blocking D2 inhibits psychosis
- However, there is no decrease in D2 receptor number, so there likely secondary changes in glutamate
89
Glutamate hypothesis of SZ
- Loss of NMDAR causes SZ sx in animals
- Could be due to a hypofunction of NMDAR
- Less glutamate = less feedback to SNc = doesn't inhibit SNc = DA release gets increased (and increased DA causes psychotic behavior)
90
GABA Hypothesis in SZ
Reduced GABA leads to an impaired balance of E/I in DLPFC --> could lead to lower gamma oscillations (amplitude is a lot lower in individuals with SZ) which could lead to a deficit in binding the various elements that form the narrative of a cognitive task
91
Overall explanation of molecular impacts on bx
- Dopamine produces motivational salience. Too much DA = wrong importance is attached to stimuli, so it can lead to confusion of external vs internal sources
- Impairments in Glu-GABA balance alters gamma-oscillations thereby affecting the binding of inputs into a cohesive story
92
ACh Hypothesis of SZ
- Smoking
- Alpha7 subunit of nAChR reduced in SZ = affects cognition
- Smoking can reduce likelihood of developing the disease
93
Genetic Risks of SZ
- Concordance of 50% with identical twins
- Genes:
1. DISC1 = synaptic pruning
2. COMT = degradation of catecholamines
3. NRG-1 = synapse formation and myelination
4. Neurexin = Development of pre-synaptic specialization
**Overall could be due to the developmental dysfunction of synapses and spines
94
Environmental risk factors of SZ
- Urban living
- Living in a minority group
- Moving between school groups
- Maternal infection
- Vitamin D insufficiency
- Drug use
- Age
- Cannabis (increase in MJ = increase in SNPs in AKT1 and COMT = HR SZ)
95
True or false: white matter doesn't get affected in SZ
False! There is a 27% reduction of oligodendrocytes in the frontal lobe and the fornix and cingulum
96
Treatment of SZ
- Typicals (D2 antagonists = antipsychotics)
- Atypicals (weaker antagonists and act more on 5HT and other receptors)
- Antidepressants (negative sx)
- Lithium (inhibits GSK3 and allows activation of Akt1 which alleviates bx deficits)
- NMDAR enhancement (indirect activation via mGluRs, allosteric modulation with D-seirn and glycine, and redox regulation by mopping up ROS and attenuating inflammation by using GSH)
97
Experimental Treatments of SZ
- Nicotine
- Electroconvulsive therapy
- TMS - alter gamma oscillations
- Vitamin D
98
Reward Pathway
- Most drugs activate reward pathways initially, but then addiction pathways can be activated with continued use
- Main reward pathways include DA pathways of ventral tegmental area that project to nucleus accumbens, as well as pre-frontal cortex, amygdala, hippocampus, hypothalamus
- Drugs tend to increase DA in synapses of NAc = rewarding and reinforcing effects
99
What basal ganglia loop does DA mediate in addiction?
Non-motor loops, such as the prefrontal loop and the limbic loop (limbic system --> nucleus accumbens --> ventral globus pallidus)
*CORTICAL-STRIATAL-THALAMIC LOOP
100
Looking at DA with C-Raclopride
- C-Raclopride = PET tracer that binds to D2Rs
- Less C-Raclopride binds when more DA is released, because both compete to bind to D2Rs
101
Overall Addiction Pathway
Cortex - NAc - internal GP - thal - MDN
102
If reward probability is high and expected reward is big, you would expect ____ DA release
increased
103
D1R is associated with ____ while D2R is associated with _____
Reward, punishment (DA inhibits the negative feeling of doing something)
104
True or false: the best drug is one that is fast and large enough to stimulate both D1R and D2R
True!
105
Relationship of uptake and reward
Faster brain uptake leads to more reward!
- more rapid intake = bigger high
106
Overall Drugs of Abuse
- Psychostimulants
- Opiates
- Ethanol
- Nicotine
- Cannabis
- PCP and Ketamine
- Hallucinogens
107
Cocaine
Inhibitor of DAT
108
Amphetamine
Inhibitor of NET and DAT
109
Methamphetamine
More of an effect on 5HT
110
MDMA
similar to Methamphetamine: more 5HT effects and less NE and DA effects
111
Opiates vs Opiods
Opiates are derived from the poppy (morphine and codeine)
Opiods are manmade (heroin, hydrocone, oxycodone, fentanyl)
112
Endogenous opiods
Enkephalins, endorphins, dynorphins
113
Opioid Receptors
mu (enkephalin, endorphins, morphine)
kappa (dynophin)
delta (enkephalin)
114
Mu Opioid Receptors
MOR are present in many areas of the brain where they transduce the analgesic, hedonic and respiratory effects of opiates and opioids
- particularly in the medulla = BAD FOR OVERDOSE
115
Opioids and DA Pathway
- Opiate and opiod drugs inhibit GABA-ergic interneurons in the VTA so VTA allows more DA release into NAc
- Also act on mu opioid receptors on NAc neurons = act as DA agonists
- Drugs of abuse increase endogenous opioids in VTA and NAc!
116
Ethanol
- CNS depressant
- Positive allosteric GABAa ionotropic receptors
- Inhibits NMDARs
- Unclear how DA gets increased due to ethanol
117
Nicotine
- Agonist at the nAChR in VTA
118
Marijuana
- Binds to CB1 receptors (high levels in hippocampus, cerebellum, amygdala, Sn, striatum, hypothalamus)
- Endocannabinoids - released in a retrograde fashion due to Ca2+ influx, diffuse through membranes
119
PCP and Ketamine
- Can be used as an antidepressant
- NMDAR antagonists (stop glu release as feedback loop leads to overactivity of VTA neurons)
120
Hallucinogens
- LSD, MDMA, DMT, psilocybin
- Act on 5HT2a receptos = psychedelic activity
- Ecstacy = more direct input to VTA neurons from glu and 5HT neurons in DR = more reward/reinforcing pathways
121
Overall NAc and Dopamine Role in Addiction and Drugs
- NAc is central to the action of many drugs of abuse
- All drugs of abuse seem to act to increase DA extracellularly in the striatum
122
Summary of All the Drugs
- Stimulants: increase DA in NAc by blocking/reversing transporters
- Opioids: inhibit GABA interneurons in VTA is DA neurons are disinhibited and inhibit Glu input on NAc MSNs
- Nicotine: nACHR activation on neurons in VTA and could activate endogenous opioids
- Ethanol: acts on GABA and Glu receptors in VTA and could activate endogenous opioids
- Cannabinoids: act presynaptically to inhibit Glu and GABA neurons in striatum
- PCP and Ketamine: inhibit Glu receptors in striatum
123
Addiction and DA release
- Less raclopride binding in addicted individuals = less DA release
- Increase in addiction = diminished DA release
124
Role of Dopamine Receptors
D2Rs - chronic drug use leads to reduced D2Rs in striatum = less inhibition of the indirect pathway = less activity in prefrontal cortex!
125
Long Term effects of addiction
- PFC activity decrease
- Decrease in gray matter, fMRI activity, and cortical thickness
- Contributes to changes in executive function limbic system excitation, and salience of rewards
126
Plasticity in Reward Pathways
- Alteration of LTP and LTD
- Change in spines in MSNs
- BDNF levels in NAc
- Epigenetic changes
127
Epigenetics in Reward Pathways
- Methylation of DNA, acetylation of histones, production of miRNAs, all of which are affected in addiction
128
Drug Treatment of Addiction
- Psychostimulants: DA agonist or antidepressants
- Opiates: weak mu agonist (so no withdrawal) or opiate antagonists
- Ethanol: Benzodiazepines
- Nicotine: nicotine patches or anti-depressants
129
Non-drug treatments of Addiction
- TMS to the DLPFC
- DBS: in MSNs in NAc ?
