Final Flashcards
(212 cards)
1
Q
What is an animal model?
A
A living non-human animal used during the research and investigation of biological process and or human disease
2
Q
What is the purpose of an animal model?
A
Gain better understanding cellular and organismal function and disease processes
3
Q
Why are animal models important?
A
Help us understand how the body functions and the pathology of diseases
Contributed significantly to human welfare
4
Q
What are examples of things developed because of animal models?
A
Polio vaccines (studied transmission of Polio in monkeys, rats and mice)
Antibiotics (researcher infected mice then treated them with penicillin)
5
Q
What is an effective antibiotic that saves thousands of lives every year?
A
Penicillin
6
Q
What are some examples of animal model contributions?
A
Vaccines
Treatment of Type I diabetes by insulin
Cellular therapies (tissue regeneration using stem cells)
Surgical techniques
7
Q
What can we learn from a sea slug (aplysia)?
A
Relatively simple CNS
Small group of neurons respond to individual behavior
Allows researchers to study the biological aspect of learning and memory
8
Q
How is a fruit fly (drosophila melanogaster) used to study brain disorders?
A
Many important genes for human development have been characterized by studying the role of similar genes in flies
Relatively simple to manipulate individual genes in the fruit fly
9
Q
What do researchers assess in drosophila?
A
Neural degeneration and dysfunction
10
Q
Why are tiny worms (c elegans) a good model to study brain aging?
A
C elegans only live about 2 weeks and display aging signs within that time
11
Q
What are C elegans a transgenic(DNA alteration) model for?
A
Alzheimer’s disease and other neurodegenerative diseases
12
Q
What are zebrafish models used for?
A
Investigate development, genetics, immunity, behavior, physiology, and nutrition
13
Q
Which animal is the most commonly used organism in research?
A
Mice (Mus musculus)
14
Q
Why are mice the most commonly used?
A
Their genetic, biological and behavioral characteristics are similar to humans and allow researchers to study human diseases
15
Q
How is learning and memory tested in mice?
A
The Morris Water Maze
16
Q
What is the Morris Water Maze?
A
One of the most commonly used behavioral tests to study spatial learning and memory, which is hippocampus dependent, in mice
17
Q
What mouse model is used to test mice for AD?
A
Behavioral test battery
18
Q
What are transgenic animal models?
A
Organisms that are genetically modified to have their genome altered
Allows you to knock in or knockout human disease related genes
19
Q
What are the two types of animal models?
A
Organism specific (invertebrate, vertebrate)
Disease specific (multiple models per disease)
20
Q
How are diseases generated in animal models?
A
Genetic manipulation
Drug-induced
Lesion
21
Q
What is the knocking in or out of human disease genes called?
A
Gene editing
22
Q
What animals are used to study PD?
A
Cell based assays (yeast)
Transgenic C elegans, Drosophila and fish (zebrafish and medaka fish)
Rodent models
Mice
Non-human primates (monkeys)
23
Q
Are there laws and regulations for animal use in research and if so what are they?
A
Yes
Animal Welfare Act
The U.S. Department of Agriculture
Institutional Animal Care and Use Committee (IACUC)
24
Q
What can we use to study complicated human diseases?
A
Simple systems
25
What can we use to track genes?
Florescent protein markers (jellyfish gene)
26
How can we generate transgenic animals?
By inserting human disease genes into DNA of animals to generate disease model to help understand human diseases
27
What models have provided important insight into human neurodegenerative diseases?
Transgenic mouse models
28
What do humans and mice have in common?
Conservation of many genes
Similar brain organization
29
What are some caveats to animal models?
Not all neuropathological events may develop in animal's lifespan
Animal proteins may differ from human proteins
Cellular/organismal responses may differ from animals to humans
30
What is a stem cell?
Can make precise copies of themselves over and over (self-renewal) and can differentiate or mature into different cell types
31
Stem cells can:
Replicate & differentiate into many cell types
32
Where are stem cells important?
Developing organisms
Mature organisms
33
What do stem cells do in developing organisms?
Generate tissue during development
34
What do stem cells do in mature organisms?
Maintain proper tissue homeostasis or as an internal repair system to replace lost cells or dying cells
Ex. skin, blood cells
35
Where are embryonic stem cells (ESCs) derived from?
The inner cell mass of blastocysts
36
Where are multipotent (adult) stem cells located?
Located in different tissues
37
What are totipotent cells?
Most versatile
Have the potential to give rise to any type of cell, so they can give rise to an entire functional organism
After a few days of embryonic development, they specialize into pluripotent stem cells
38
What are pluripotent cells?
Can give rise to all cell types in the body
However, cannot give rise to an entire organism
39
What are embryonic stem cells considered?
Pluripotent stem cells
40
What are multipotent cells?
Less plastic and more differentiated stem cells
Can still develop into more than one cell type
More limited than pluripotent cells
Give rise to a limited range of cells within a tissue type
41
What is the order for stem cells?
Totipotent --> Pluripotent --> Multipotent
42
Pluripotent=
Embryonic stem cells
43
Multipotent=
Adult stem cells
44
Where are pluripotent stem cells derived from?
Inner mass of the blastocyst (ESCs)
45
Why are there ethical implications with collecting ESCs?
Results in the destruction of the blastocyst
46
How often can embryonic stem cells propagate?
Indefinitely in an undifferentiated state
Can also carry the risk of tumor formation
47
What do embryonic stem cells have the potential for?
Cell replacement therapies
Tissue engineering
Disease modeling
48
What kind of cells are adult stem cells?
Multipotent (committed to a particular "fate")
49
What quantities are adult stem cells present in?
Present in small quantities
50
What qualities do adult stem cells have?
Often difficult to isolate/purify
Not as plastic as ESCs (cannot differentiate into as as many different cell types as ESCs)
May contain DNA abnormalities caused by UV light, toxins or errors (mutations during DNA replication for cell division)
51
What is less common in adult stem cells?
Less likely to form tumors or cause immune rejection
Less moral implications associated with their use
52
What different tissues can adult stem cells be isolated into?
Muscle
Liver
Bone marrow
Brain tissue
Fat
53
What is true about neuron replacement in the nervous system?
Relatively quiescent(inactive) and do not participate in tissue renewal or replace neurons lost to injury or disease
54
What kind differentiation are neural stem cells?
Multipotent
55
Where are neural stem cells found?
In the adult brain
Can also be derived from embryonic and fetal brain tissue
56
What can neural stem cells differentiate into?
Astrocytes
Oligodendrocytes
Neurons
57
How much can neural stem cells isolate?
Cannot isolate in large number
58
Where does neurogenesis occur in the human adult brain?
In rodents (and possibly humans) adult neurogenesis is in the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the dentate gyrus within the hippocampus
However some studies indicate existence of neurogenesis while others don't
59
How are Induced Pluripotent Stem Cells (IPSC) created?
By reprogramming a differentiated cell such as a skin cell into an embryonic like stem cell state
Can generate any cell in the organism
Can surpass ethical concerns
60
What do IPSCs have the potential to do?
Revolutionize biomedicine
Host rejection minimized
Disease modeling potential
Ideal tool for personalized medicine
61
What has the potential to generate a whole organism?
Totipotent stem cells
62
How can we treat neurodegenerative diseases with stem cells?
3 main strategies:
-Replace or repair damaged tissue or group of cells that can't heal itself
-Use stem cells to provide nutrients to sick cells
-Enhance endogenous neurogenesis
63
What do stem cell therapy for neurodegenerative diseases do?
Designed to target dopamine neurons to help with the creation of new neurons
Clinical trials have been controversial
64
What does stem cell replacement therapy do?
Replace damaged tissue
65
What are the caveats (warnings) with neurodegenerative diseases?
Tumor formation
Immune rejection
New transplanted cells may develop the same pathology
66
What is an alternative strategy for stem cell therapy?
Stem cells can be used to deliver trophic or neuroprotective factors to the brain
67
What does the FDA say about stem cell therapies?
Be aware of unscrupulous people selling unproven stem cell therapies
68
What is the most commonly used stem cell-based therapy?
Bone marrow transplantation
69
What are neurodevelopmental disorders?
A group of conditions that appear during childhood involving some alteration or disruption in the development of the CNS. These disorders are associated with deficits or impairment in the brain function
70
What are the main types of neurodevelopmental disorders?
Intellectual disability (ID)
Autism spectrum disorder (ASD)
Attention deficit/ hyperactivity disorder (ADHD)
Communication disorders (vision and hearing impairments)
Neurodevelopmental motor disorders (cerebral palsy)
Specific learning disorders (dyslexia)
71
What is intellectual disability (mental retardation)?
Failure to acquire intellectual abilities across cognitive domains at a normal rate (before 18 years old)
IQ less than 70
Difficulties in adaptive functioning/life skills such as communication, self care, home living and social or interpersonal skills
72
What are some causes of intellectual disability?
Genetics
Infections
Substances
Metals/chemicals
UV radiation
Lack of nutrition
Oxygen deprivation
Head injury
73
What are the 4 classes of intellectual disability based on severity?
Mild, moderate, severe and profound
74
What are the genetic causes of intellectual disability?
Chromosomal abnormalities (down syndrome)
Copy number variations (CNVs)-- abnormal number of copies of one or more sections of DNA
Single gene mutations (amino acids repel water which bring folding and a change in function which can be new or a defect
75
Why does down syndrome occur?
Person has an extra (full or partial) copy of chromosome 21
Most frequent form of intellectual disability
Down syndrome is a consolidation of symptoms
76
What are the clinical features of down syndrome?
Dysmorphic features (abnormal body structure)
Seizures
Psychomotor slowing
Congenital malformation
77
What are the physical features of down syndrome?
Low muscle tone
Small stature
Upward slant to the eyes
Single deep crease across the center of the palm
78
What is true about the severity of down syndrome?
Severity has a variety but they all have the same abnormalities
79
What are the 3 chromosome abnormalities that cause down syndrome?
Trisomy 21(nondisjunction), translocation and mosaicism
80
What is trisomy 21(nondisjunction)?
When an error in cell division occurs, called non disjunction and results in an embryo with three copies of chromosomes instead of two
Happens in chromosome 21
81
What is translocation?
When the total number of chromosomes in the cells remains 46 however an additional full or partial copy of chromosome 21 attaches to another chromosome, usually chromosome 14
82
What is mosaicism?
When an individual has a mixture of two cell types, some containing the usual 46 chromosome and some containing 47
83
How is down syndrome diagnosed?
Prenatal screening
Karyotype (a profile of a persons chromosomes)
84
What are the clinical presentation brain related features of down syndrome?
Morphosyntax, verbal short term memory and explicit long term memory (impaired language and verbal memory abilities)
Seizures
Early onset dementia that resembles Alzheimer's disease
85
What are the macroscopic brain related features of down syndrome?
Reduced brain volume in frontal and temporal areas and cerebellum
Functional disturbances in hippocampus
86
What are the microscopic brain related features in down syndrome?
Alterations in dendritic spine structure
Decreased number/distribution of neurons
Synaptic degeneration
Reduced neurogenesis
Alzheimer's disease related pathology
87
What relation does AD have with down syndrome?
Most people with Down syndrome develop AD pathology by middle age (presence of plaques and tangles)
The "gene dosage" effect of having 3 copies of the APP gene results in AB overproduction
APP (amyloid precursor protein) is a gene located on chromosome 21
Rare DS translocation cases where APP is triplicated do not develop AD
88
What did they find in DS mouse models?
They replicate several features of DS including behavior deficits, alterations in brain structure, neurodegeneration, etc
Mice don't develop AD or plaques
89
What are some other human aneuploidies (missing or extra chromosome)?
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edwards syndrome)
90
A case of DS caused by chromosomal translocation may have:
Some or all chromosome 21 genes triplicated
91
What are some available therapies for people with down syndrome?
Special Ed
Speech therapy
Physical therapy
Occupational therapy
Treatment for other medical symptoms (anti-seizure, hormone replacement therapy, treatment for sleep apnea, surgery)
All meant to increase quality of life
92
What is fragile X syndrome?
Genetic condition that causes intellectual disability (ID)
93
How is fragile X syndrome inherited?
Inherited in an X-linked dominant pattern
Located on the X chromosome
Caused by a mutation in a single gene on the X chromosome
94
How is fragile X different from a normal gene?
Normally the gene containing a stretch of DNA that is repeated but in fragile X there is an abnormal repetition of this DNA, creating a microscopic appearance of a gap
95
What is fragile X caused by?
Caused by a mutation in which a DNA segment, known as the CGG triplet repeat is greatly expanded within the FMR1 gene
Normally repeated from 5-40 times
In fragile X the CGG is repeated more than 200 times
96
What do abnormally expanded CGG segments do in fragile X?
Turns off the FMR1 gene, which prevents the gene from producing FMRP protein
(Silencing of the gene)
No messenger RNA or protein
97
What does the deficiency of FMRP do in fragile X?
Disrupts nervous system functions (synaptic connectivity) and leads to the signs and symptoms of fragile X syndrome
98
What are the clinical symptoms of fragile X?
Visuospatial and verbal impairments-- cluttered or nervous speech
Behavioral characteristics-- stereotypic movements (hand clapping) and atypical social development (shyness, limited eye contact, difficulty with face encoding)
Some meet diagnostic for autism
Physical features-- narrow face, large head, large ears, flexible joints, flat feet and prominent forehead
99
What is autism spectrum disorder?
Affects 2% of children
Prevalence increasing worldwide
Boys 4x more likely than girls
Refers to a broad range of conditions characterized by challenges with social skills, repetitive behaviors, speech and non verbal communication
Expressed very differently-- wide range of abilities, strengths and limitations
100
What impairments are there in the brain for autistic disorder?
Impairments in areas of the brain responsible for social interaction, communication, and imaginative play
101
What parts of the brain are affected by autism?
Cerebral cortex
Basal ganglia
Corpus callosum
Cerebellum
Brain stem
Hippocampus
Amygdala
102
What causes autism?
Both genetic and environmental factors
Fragile X and DS both exhibit higher incidence of ASD
103
What is the main treatment for ASD?
Behavioral therapies
104
Autism is characterized by which of the following
Impaired social and verbal skills
105
What are other treatments for ASD?
CBT
Early intervention
Educational and school based therapies
Joint attention therapy
Medication treatment
Nutritional therapy
Occupational therapy
Parent mediated therapy
Physical therapy
Social skills training
Speech language therapy
106
Why is the CNS important?
Receives 15% of the blood that the heart pups to all the body's organs and tissues under resting conditions
CNS has a high rate of metabolic activity compared to other tissues thus, it has a high demand for glucose and oxygen
107
What is cerebrovascular?
Blood flow in the brain
108
How much oxygen and glucose consumed goes to the brain?
20% of all oxygen and 50% of all glucose
109
What two arteries carries blood to the brain?
Internal carotid arteries (front)
Vertebral arteries (back)
110
What do arteries do?
Deliver oxygenated blood, glucose, other nutrients to the brain
111
What do veins do?
Carry deoxygenated blood back to heart, removing carbon dioxide, lactic acid and other metabolic products
112
What is true about CNS blood flow?
Adequate blood flow to the CNS must be maintained at all times
113
Why is the CNS sensitive to interruptions in blood flow?
1) Unlike other tissues, cells of the CNS cannot store glycogen and therefore must obtain glucose directly from blood
2) Most cells of the CNS don't have access to fatty acids for energy, which increase demands for glucose
3) CNS cells can't obtain energy from anaerobic metabolism during periods of reduced oxygen availability, thus requiring uninterrupted oxygen and glucose support to stay alive
114
What is a stroke?
AKA a transient ischemic attack or cerebrovascular accident
Occurs when blood flow to the brain is blocked
When there isn't enough blood flow to the brain to meet metabolic demand the limited oxygen supply leads to brain tissue damage and loss of neurological function
115
What are the two types of strokes?
Ischemic stroke
Hemorrhagic stroke
116
What is the most common stroke type?
Ischemic stroke (80-85% of all strokes)
117
What is Ischemic stroke?
Blockage inside a blood vessel that deprives an area of the brain from glucose and oxygen
118
What are the two types of blockages in an ischemic stroke?
Embolic or thrombotic
119
What is a thrombotic ischemic stroke?
Caused by a thrombus (blood clot) that develops in the arteries and occludes the artery
Usually seen in older people with high cholesterol, diabetes and atherosclerosis
120
What are thrombotic ischemic strokes preceded (before) by?
One or more "mini-strokes" or transient ischemic attacks (TIAs)
TIAs may last for a few minutes or up to 24 hours, often a warning sign that a stroke may occur
121
What are transient ischemic attacks?
Tell tale sign for future strokes
TIAs result from a temporary blockage of an artery
Stroke symptoms resolve in less than 24 hours, usually in 15-20 mins
More than 1/3 of people will go on to have an actually stroke
122
What is an embolic ischemic stroke?
Occurs when a plaque or blood clot that forms elsewhere in the body (embolus), breaks off, travels to the brain and blocks the artery
Often result from heart disease or heart surgery
Occurs rapidly and without any warning signs
123
What is a hemorrhagic stroke?
Occurs when a blood vessel that supplies blood to the brain ruptures and bleeds
When this happens the brain cells and tissues do not get oxygen and nutrients
Pressure can also build up and irritation and swelling can occur leading to further brain damage
124
What are the two main categories for hemorrhagic strokes?
Intracerebral hemorrhage: bleeding is from the blood vessels within the brain
Subarachnoid hemorrhage: bleeding is in the subarachnoid space
125
What causes hemorrhagic strokes
Hemorrhage (from high blood pressure)
Ruptured aneurysm (aneurysm: a weakened, ballooned area of the artery wall)
Arteriovenous malformations (AVMs) (AVM: consists of a disorderly tangled web of arteries and veins
126
What are some risk factors for strokes?
Medications
Obesity
Stress
Heart disease
Diabetes
Physical inactivity
High blood pressure
Alcohol
High blood cholesterol
Smoking
Medications
127
What are the symptoms of a stroke?
Sudden numbness or weakness, especially on one side of the body
Sudden confusion or trouble speaking or understanding speech
Sudden trouble seeing in one or both eyes
Sudden trouble walking, dizziness, or loss of balance or coordination
Sudden severe headache with no known cause
128
What is the penumbra and its relation to strokes?
Zone of reversible ischemia around the core of the irreversible infarction-- salvageable in the first few hours after ischemic stroke onset
First 3 hours
Dissolves the clot
129
What is the treatment for ischemic strokes?
Tissue plasminogen activator (tPA)-- helps dissolve clot and improve blood flow (must be within 3 hours of stroke onset)
Endovascular or mechanical thrombectomy (clot in large artery)
Carotid endarterectomy (severe buildup of plaque)
130
What is the treatment for hemorrhagic strokes?
Surgery to clip aneurysm (stop bleeding), remove blood, reduce pressure (shunt)
131
Which of the following involves a rupture of a blood vessel in the brain?
Hemorrhagic stroke
132
What is a traumatic brain injury?
Non-degenerative, non-congenital insult to the brain from an external mechanical force
Possibility of temporary or permanent impairments of cognitive, physical and psychosocial functions
Associated with a diminished or altered state of consciousness
TBI is one form of acquired brain injury
133
What is the "silent epidemic"?
Most people don't know about brain injury or its consequences or impact on behavior
Minor blows to the head or concussions are not perceived as brain injuries, yet 15% of these individuals will have chronic problems post injury
Most people assume one needs to lose consciousness to have a brain injury
134
What are the severities of TBI?
Mild: 85% of all TBIs, seen ER or MD office, identified as a concussion, not followed by medical community in most cases
Moderate to severe: 15% of all TBIs, typically hospitalized, identified as TBI, known and followed by medical community
135
What is mild TBI/ concussion?
85% have a full recovery 3-6 months post event
15% experience chronic symptoms which significantly interfere with their daily functioning
An unknown number of individuals fail to seek any medical attention: (Domestic violence, bar room brawls, child abuse/shaken baby syndrome, sports injuries)
136
What are the signs of a concussion (seen by someone other than the patient)?
Loss of consciousness
Disorientation
Incoherent speech
Confusion
Memory loss
Dazed or vacant stare
137
What are the symptoms of a concussion (only felt by the patient)?
Headache or dizziness
Difficulty concentrating
Sensitivity to light
Ringing in ears
Fatigue
Vomiting
138
What is moderate to severe TBI?
Documented loss of consciousness
Potential skull fractures
Significant period of coma
Significant loss of information for a period post event
Significant chronic thinking, physical and emotional changes
After 1st TBI, risk of second injury is 3x greater
After 2nd TBI, risk of third injury is 8x greater
139
What is the treatment for mild TBIs?
No treatment other than rest and over the counter pain relievers to treat headaches
140
What is the treatment for moderate/severe TBIs?
Focuses on making sure the person has enough oxygen and adequate blood supply, maintaining blood pressure and preventing any further injury to the head or neck
Medications (anti-seizure drugs, coma-inducing drugs, lowering body temperature)
Surgery
Rehabilitation
141
What risk factor comes along with TBIs?
Later neurological diseases
In TBI patients deaths from neurodegenerative disease are 3x higher
Chronic traumatic encephalopathy (CTE) is a progressive brain disease that can result from repeated head injuries such as concussions or blows to the head)
Slowly gets worse over time and leads to dementia, but help and support can manage symptoms
No cure
Accumulation of tau (AD)
142
What is a mental disorder?
A condition that causes significant distress or impairment in the normal psychological functioning of a person
Characterized by a clinically significant disturbance in a person's cognition, emotional regulation or behavior/personality
143
What classifies a mental disorder?
To be a disorder it must be a cause of distress and disability
Must not be situational (eg. grief of a loved one)
144
What are the 6 categories of mental disorder?
Anxiety disorder: anxiety or fear that interferes with normal functioning
---phobias, social anxiety disorder, OCD, PTSD
Mood disorder: disordered affective processes (mood)
---major depression, bipolar disorder, mania
Psychotic disorder: belief, language, or perception become dysregulated (delusions, hallucinations)
---schizophrenia
Personality disorder
Eating disorder
Sleep disorder
145
How did the pandemic affect mental health?
Exacerbated the mental health crisis for teens
Depressive anxiety symptoms in youth doubled during the pandemic
Symptoms of depression had already been rising in teens in recent years
In 2021 ER visits in the US for suspected suicide attempts were 51% higher for girls and 4% higher for boys compared to 2019
146
What are the 5 mood disorders?
Major depression
Dysthymia
Bipolar disorder
Cyclothymia
Hypomania
147
What is major depression?
A type of depressive disorder characterized by a depressed mood of at least 2 weeks in duration
148
What is dysthymia?
Chronic low-level depression
149
What is bipolar disorder?
A type of affective disorder characterized by episodes of mania and depression that typically continue throughout a persons lifetime
150
What is cyclothymia?
One of the bipolar disorders characterized by less intense episodes of mania and depression than are seen in the bipolar disorder
151
What is hypomania?
A milder form of mania in which occupational or social functioning is not impaired
152
What is depression also known as?
Also known as major depression, major depressive disorder, clinical depression
153
What characterizes depression?
Depressed mood or loss of interest in activities for more than 2 weeks
Impaired function: social, occupational, educational
154
What is the DSM-5 diagnostic criteria for depression?
Five or more symptoms during a two week period and one of the symptoms should be either 1) depressed mood or 2) loss of interest or pleasure
1. Depressed mood
2. Diminished interest or pleasure
3. Weight gain or loss
4. Insomnia or hypersomnia
5. Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Feelings of worthlessness or guilt
8. Diminished ability to think, concentrate or decide
9. Recurrent thoughts of death, recurrent suicidal ideation
155
What are the risk factors or potential causes of depression?
Genetics:
--family history of mood disorder may increase risk
--twin studies indicate 40-50% heritability
Environment:
--history of physical emotional or sexual abuse
--major life events
--other mental illness
--other serious illnesses
--history of or current substance abuse
--stress
156
What are the effects of stress on the hippocampus?
The hippocampus has a high concentration of glucocorticoid receptors which activated by stress
1) Reduces excitability (more difficult to learn)
2) Inhibits neurogenesis in the hippocampus
3) Retracts dendrites in the hippocampus
157
What is the etiology biological factors of genetics in depression?
3 fold increase of major depressive disorder in first degree relatives
Estimated heritability: 37%
No mendelian transmission(single gene)-- likely the contributions of multiple genes and epigenetic factors that interact to increase the risk of depression
158
What are the etiology biological factors of neurotransmitter (monoamine hypothesis) in depression?
Patients with depression have low levels of monoamines (serotonin, norepinephrine and dopamine)
Discovered accidentally through iproniazid, which works by inhibiting the monoamine oxidase(MAO) enzyme-- breaks down destroys) serotonin and dopamine
--inhibition of MAO enzyme, which destroys neurotransmitters, results in increased monoamine levels in the brain and elevated mood
Issues: onset of antidepressant effects, moderate treatment efficacy, monoamine depletion doesn't cause depression in healthy individuals
159
What are the etiology biological factors of brain circuitry abnormalities in depression?
Neuroanatomical model called the limbic-cortical model or cortico-limbo model is proposed to explain the biological findings in depression
People with depression have alterations in specific brain regions and associated circuitry
--hyperactivity in brain regions in response to negative stimuli and hypoactivity in response to positive stimuli
160
What changes in the brain with depression?
Reduced gray matter volume in orbitofrontal cortex, hippocampus, amygdala, entorhinal cortex, basal ganglia, and thalamic nuclei
This atrophy gets worse when left untreated
161
What do pet scan reveal about the brain in people with depression?
Lower than normal activity during depressive episodes and higher than normal activity during manic episodes
Reduction is especially apparent in the left frontal cortex for depression
Decreased blood flow and metabolism have been found in the cingulate gyrus and the basal ganglia of depressed individuals
162
What 2 regions of the prefrontal cortex are dysfunctional in depression?
Ventromedial (vmPFC) is hyperactive
--implicated in processing risk and fear and inhibition of emotional responses; associated with generating negative emotion
Dorsolateral (dlPFC) is hypoactive
--associated with memory, planning, reasoning; associated with reappraisal and suppression of negative emotions
163
What does the imbalance of the vmPFC and dlPFC lead to?
Negative bias and rumination(sustained downward spiral of only thinking negative emotions/thoughts) of negative thoughts/memories
164
What are the pharmacological treatments for depression?
Monoamine oxidase inhibitors (MAOIs)
--prevent breakdown of monoamines
Tricyclic antidepressants (TCAs)
--block reuptake of monoamines
Selective serotonin reuptake inhibitors (SSRIs)
--block reuptake of 5HT (prozac, paxil, zoloft, lexapro)
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
--block reuptake of 5HT and NE (cyymbalta, effexor)
Norepinephrine-dopamine reuptake inhibitors (NDRIs)
--block reuptake of DA and NE (wellbutrin)
165
What is psilocybin and its relation to major depression?
A compound found in magic mushrooms
Psilocybin produces visual and auditory hallucinations and profound changes in consciousness
Significantly relieved anxiety and depression in people with life threatening cancer
May be effective in the much wider population of patients who suffer from major depression
166
How can psychedelics help treat depression?
Psychedelic compounds such as psilocybin, DMT and LSD have chemical structures that resemble the neurotransmitter serotonin
The structural similarity to serotonin allows them to stimulate serotonin sensitive neurons in the brain
Many drugs of abuse act directly on specific parts of the dopamine pathway, whereas psychedelics act primarily through the serotonin pathway
167
How can ketamine help treat depression?
Doesn't slow breathing or heart rate so patients don't need a ventilator
Used on agitated patients rescued after a suicidal attempt, realized its big effects against depression and suicidal thoughts
Ketamine can produce feelings of unreality, visual and sensory distortions, a distorted feeling about one's body, temporary unusual thoughts and beliefs and euphoria
Associated with rapid and sustained antidepressant action in treatment resistant patients
168
What are the potential risks of using ketamine to treat depression?
Unconsciousness
High blood pressure
Dangerously slow breathing
Fatal if taken with alcohol
Abuse potential
Dissociative properties
May exert acute(bad) changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressants
169
What are some nonpharmacological treatments for depression?
Physical exercise
-- enhances hippocampal neurogenesis, increases BDNF production, increases endorphins which counteract depressive symptoms
MBCT or CBT
--works as well as medication to prevent relapse, reduces anxiety symptoms, those who experience depression early benefit more from MBCT
ECT
--for drug resistant depression, disadvantages: high relapse rate, memory deficits, a right unilateral ECT works as well as bilateral application with fewer side effects
Repetitive transcranial magnetic stimulation (rTMS)
--promising alternative treatment, non-invasive non-systemic treatment that utilizes MRI strength magnetic pulses to stimulate areas of the brain known to be underactive in depression
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What is schizophrenia?
A severe mental disorder where people interpret reality abnormally
Positive, negative and cognitive symptoms
Appears in early adulthood
Prodromal period frequently precedes the first psychotic episode
Lifetime prevalence 1%
Associated with reduced life expectancy
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What are the positive symptoms of schizophrenia?
Delusions: false beliefs that aren't based in reality
Hallucinations: seeing, hearing, smelling, tasting, or feeling things that don't exist
Disorganized thinking(speech): ways of thinking that are unusual or illogical
Extremely disorganized or abnormal motor behavior: abnormal body movements
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What are the negative symptoms of schizophrenia?
Loss of motivation
Loss of interest or enjoyment in daily activities
Withdrawal from social life
Difficulty showing emotions
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What are the cognitive symptoms of schizophrenia?
Problems in attention, concentration and memory
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What is catatonia?
Prolonged motor immobility states that alternate with periods of excitability
Signs and symptoms: sitting or standing in the same position for hours (hold odd positions, resist movement of extremities)
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What are hallucinations?
Sensory experiences that happen in the absence of environmental stimulation
--most commonly auditory (hearing voices)
--are not in the patients head but are actually perceived through sensory regions of the brain(auditory cortex) which are active during hallucination
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What are delusions?
Beliefs held with strong conviction despite evidence to contrary
--grandeur: patient believes he/she is somehow special or has supernatural powers, famous or immortal
--persecution: patient believes he/she is being targeted, followed, conspired against, spied on or attacked(paranoid)
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What are the environmental risk factors for developing schizophrenia?
Exposure to environmental factors during brain development:
--pathogenesis begins early in neurodevelopment although disorder appears in early adulthood
--increased rates of in utero adversity (maternal infections, starvation during pregnancy), obstetric problems (pre-term birth and preeclampsia)
--altered ectoderm development, mild cognitive and motor impairments in childhood
--obstetric complications
--childhood trauma
--urban living
--substance abuse
--stressful psychosocial factors
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What are the genetic risk factors of schizophrenia?
Genome-wide association studies have identified more than 100 loci significantly associated with schizophrenia (meaning its a polygenic disorder)
2-3% of people have genetic variants involving copy number variants
Many genetic and environmental factors associated with schizophrenia may also be associated with other psychiatric disorders, suggesting overlap in risk factors and potentially mechanisms
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What are the molecular pathways in schizophrenia?
Identified genes involved in regulation of postsynaptic membrane, synaptic transmission, voltage gated potassium channels
Post-mortem brains show lower levels of synaptic proteins, dendric spines and GABAergic and glutamatergic markers
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What happens to synaptic connections in patients with schizophrenia?
Early development has the production of synaptic connections which continues during childhood until a switch in adolescence to synaptic pruning
Leaves 1/2 of the synapses present in adult
Hypothesis: these processes regulating synaptic pruning are disrupted in schizophrenia-- leading to impairments in neural communication and cognitive deficits
Evidence: increased gray matter loss and aberrant network organization at illness onset
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What happens to brain networks in schizophrenia?
They are disrupted
Cognitive processes such as working memory are supported by synchronized neural oscillation, this is disrupted in schizophrenia
--Oscillations occur due to finely tuned balance of inhibitory and excitatory neurons
GABAergic interneurons play a central role in regulating the firing of pyramidal neurons required for the generation of high frequency rhythms
There is a loss of dendric spines in pyramidal neurons
Microglia altered in individuals
Excitatory and inhibitory imbalance leads to negative symptoms like depression
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What is the dopamine hypothesis in schizophrenia?
Striatal dopamine synthesis and release capacity is higher in schizophrenia and associated with psychosis onset
Suggests that depleting striatal dopamine levels or blocking dopamine receptors reduces psychotic symptoms
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What is the flow chart of the dopamine hypothesis?
Stress during childhood/adolescent and genetic vulnerability
l
V
Aberrant synaptic pruning
l
V
Cortical E/I imbalance ---> Cognitive + negative symptoms
l
V
Increased excitatory drive to subcortical regions
l
V
Disinhibition of dopaminergic mesolimbic neurons
--> psychotic symptoms
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What are the non-pharmacological treatments of schizophrenia?
CBT
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What are pharmacological treatments of schizophrenia?
All current pharmacological treatments involve blocking the D2 family of postsynaptic dopamine receptors
D2-- dopamine receptor blockers reduce symptoms, particularly positive symptoms
Side effects: sedation, weight gain, extrapyramidal/movement-associated symptoms
40% response rate
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What is the most common mental disorders?
Substance abuse
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How many deaths is drug addiction responsible for?
11.8 million deaths each year
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Why are drugs misused?
Pleasurable effects
Alteration of mental state
Improve performance
Self-medication for a mental disorder
Repeated use can result in addiction
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What is true about the differential vulnerability of developing addiction?
Only a portion of individuals will develop drug addiction after several exposures
Individual vulnerability likely linked to both genetic and environmental factors
Drug addiction is highly polygenic (hundreds of genetic variations combined result in variable vulnerability)
Several environmental factors have been characterized and interact with individual genetic background
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What factors increase risk of addiction?
Home and family
--genetics and epigenetics
--lack of family involvement
--home environment
Presence of mental disorders
Peer and school
--school performance
--social skills
Early use
--effect on developing brain
--early social and biological risk factors
Taking a highly addictive drug
--route of administration
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What are the epigenetic processes?
DNA methylation: add a methyl group to DNA, process alters expression of genes by activating or repressing them
Histone modification: epigenic factors can attach to histone tails and affect how tightly wound DNA is around the histone; DNA that is more tightly wound will not easily ne activated and vice versa
Other processes: acetylation, phosphorylation, ubiquitylation, sumolyation
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How is epigenetics and drug use related?
When histones are tightly compacted, genes on the DNA are "hidden" within the nucleosome and not exposed-- so cannot be activated or turned on
To turn on genes or read and express them, the structure chromatin has to be altered
Multiple drugs of abuse produce changes in histone acetylation in the brain
Stress plays are role
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What does it mean to be addicted?
A compulsive drive to take a drug or engage in drug seeking behavior, with an impaired ability to control the urge to take the drug despite serious adverse consequences
Also refers to drug or substance dependence
Physical dependence refers to withdrawal symptoms when drugs are discontinued-- effects are different from those that underlie addiction
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What is substance use disorder?
Recurrent use drugs that cause clinically and functionally significant impairment, such as health problems, disability and failure to meet major responsibilities at work, school or home
depending on severity, this disorder is classified by mild (2-3 symptoms), moderate (4-5 symptoms) or severe (6+ symptoms)
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What is addiction?
A term used to indicate the most severe, chronic stage of substance use disorder, in which there is substantial loss of self control, as indicated by compulsive drug taking despite to desire to stop taking the drug
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What are the 4 areas of diagnostic criteria for substance use disorder?
Impaired control
Social impairment
Risky use
Pharmacological/dependence
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What is tolerence?
A need for increased amounts to achieve a "high"
Marked diminished effect with continued use
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What are withdrawal symptoms?
Psychological and or physical syndrome caused by the abrupt cessation of the use of a drug
Taking the substance often in larger amounts over a longer period than was intended
Having a persistent desire or unsuccessful efforts to cut down or control substance use
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What do studies show about repeated drug use?
Leads to long term changes in brain regions responsible for motivation, reward and inhibitory control in addicted individuals
Drug addiction is a brain disease and abnormal behavior is a result of dysfunctional of the brain
Control processes are disrupted despite initial drug use being voluntary
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What does aberrant behavior that occurs during addiction viewed as?
Traditionally viewed as bad choices that are made voluntarily by the addict
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What are the 10 classes of drugs the DSM-5 recognizes?
Alcohol
Caffeine
Cannabis
Hallucinogens
Inhalants
Opioids
Sedatives
Hypnotics or anxiolytics
Stimulants
Tobacco
The pharmacological mechanisms for each class are different but the activation of the reward system is similar across substances in producing feelings of pleasure or euphoria
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What is the reward system?
Group of brain structures and neural pathways that are responsible for 1) craving for a reward and motivation, 2) associative learning (positive reinforcement) and 3) emotions associated with pleasure
Motivates animals to approach stimuli or engage in behavior that increases fitness
In drug addiction, substances over activate or hijack the reward circuit, leading to compulsive substance seeking behavior
Mesolimbic and mesocortical pathways
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What are the 3 main brain regions involved in the reward system?
Ventral tegmental area (VTA)-- where dopamine is synthesized
Nucleus accumbens (NAc)-- when stimulated, produce feelings of reward and satisfaction
Prefrontal cortex (PFC)-- reward based decision making, creates emotional associates with rewards, working memory- control cravings
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Where do all drugs converge?
The Ventral tegmental area (VTA) and Nucleus accumbens (NAc)
Through different initial mechanisms drugs of abuse increase the release of dopamine in the NAc from the VTA
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What do addictive drugs to the the brain?
Activate reward regions in the brain by causing sharp increases in the release of dopamine
--nicotine, cocaine, amphetamine: directly increase synaptic dopamine levels
--opiates, alcohol: indirectly increase dopamine by inhibition of GABA on dopamine neurons
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How does chronic drug use become an addiction?
The brain of a person that misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit or by reducing the number of receptors that can receive signals
As a result, the persons ability to experience pleasure from naturally rewarding activities is also reduced
This is why these people eventually feel flat or depressed and is usually unable to enjoy things that were previously pleasurable
Now the person needs to keep taking drugs to experience even a normal level of reward or even larger amounts (higher tolerance)
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What happens in the VTA and NAc with addiction?
When drugs stimulate opioid receptors, cells in the VTA produce dopamine and release it into the NAc giving rise to feelings of pleasure (during chronic use, fewer dopamine receptors in the NAc)
Normally feedback from the PFC to the VTA helps overcome drives to obtain pleasure through actions that may be unsafe of unwise
--after long term use, this feedback is compromised in individuals who become addicted to drugs
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What are pharmacological treatments for drug abuse?
Agonist therapies(produce similar response)-- work to prevent withdrawal and reduce cravings, disadvantage: patients can develop dependence and tolerance
Antagonist drugs(stops receptor)-- works to prevent any opioid drug from producing effects, disadvantage: does not alleviate cravings so run a high risk of relapse if dose is skipped or not taken
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Which neurotransmitter is most implicated in addiction and normally supports the brain's reward system?
Dopamine
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What are other treatments for substance abuse?
CBT
Contingency management
Motivational enhancement therapy
Family therapy
Twelve-step facilitation (TSF)--12 week program
Deep brain stimlation
Repetitive transcranial magnetic stimulation
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What is fentanyl?
Synthetic opioid similar morphine but 50-100 times more potent
Prescription drug used to treat severe, pain, especially after surgery
Involved in overdose death
Drug dealers mix fentanyl with other drugs because it take very little to produce a high (cheaper option)
Since their bodies aren't used to fentanyl it can more likely lead to overdose
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How does fentanyl work?
Like heroine and morphine, fentanyl works by binding to opioid receptors which are found in brain areas that control pain and emotions
Medication with behavioral therapies have been shown to be effective in treating people with fentanyl addiction
