ap exam 2 AD/Schizophrenia/ anxiety/ stress/depression Flashcards
- Describe the main symptoms of Alzheimer’s disease
- clinical hallmark: progressive impairment in memory, judgment, decision making, and orientation to surroundings, and language
- neurodegeneration in the cortex and hippocampus
- pathological hallmarks: neuronal loss, extracellular senile amyloid plaques, and intracellular neurofibrillary tangles
- definitive diagnosis can only be made by autopsy
- both genetic and sporadic forms
- heritable = familial AD
- unknown cause = sporadic AD
- Describe the senile plaques
amyloid plaques (aka senile plaques)
- largely comprised of a protein called b-amyloid
- small protein (39-42 amino acids, ~4 kDa)
- normal protein, present in biological fluids in a soluble state at low levels
- in AD, b-amyloid self-associates; forms aggregates
- highly insoluble
- deposits extracellularly in the form of plaques
- Describe the neurofibrillary tangles
•Tangles (AKA Neurofibrillary Tangles –NFT)
§Hyperphosphorylated protein Tau causes fiber formations which twist among themselves
•Normal Tau
§Gene found on chromosome 17q21
qMAPT produces via alternative splicing
§Stabilizes microtubules
qBinds to tubulin
qAt distal axon
§Aids axonal transport
qAxon to soma and back
Like light-rail transportation
Genes implicated in Alzheimer disease: APP
most persons with Down’s syndrome develop AD neuropathology by 4th or 5th decade of life
- Ab plaques apparent in young
several different candidate genes considered as cause
- APP gene is located on chromosome 21
- most believe this is the cause of AD in Down’s persons
- evidence that extra copy of APP gene increases
amount of Ab42
- APP gene also harbors mutations that cause early onset FAD
• FAD w/ double mutation in APP at Ab N-terminus
- causes increased levels of Ab to be produced
- suggests high Ab levels can cause AD
• FAD w/ point mutations in APP at Ab C-terminus
- cause relatively more of the longer type of Ab42 (vsAb40)
- suggests that altering type of Ab can cause AD
- Describe the genes implicated in Alzheimer’s disease
Genes implicated in Alzheimer disease: presenilins
presenilins function as part of the gamma- secretase enzyme that determines C-terminal length of Ab
- presenilin mutations are the most common causes of FAD (70% in PS1 and 20% in PS2)
- persons with presenilin mutations show high levels Ab42 in brains
-more likely to aggregate
- Describe the role of apolipoprotein E alleles in AD
- apolipoprotein E (apoE)
- not a mutation, but a risk factor
- three normal alleles : e2(10%), e3(75%), e4(15%)
- allele e4 associated with increased risk of late-onset AD
- allele e2 associated with reduced risk
- apoE is involved with lipid transport; the e4 allele is associated with hypercholesterolemia
- apoE may be involved in clearance of Ab
- apoE e4 may have poor function than other isoforms
• Can baptists and Tauists work together?
all genetic links to AD implicate b-amyloid as cause of AD
- presenilin mutations increase total Ab, and ratio of bad Ab: good Ab (longer 42 aa. form; aggregates more)
- apoE involved in Ab clearance, may affect aggregation
- chromosome 21 changes increase total Ab levels
- Describe the role of acetylcholine transmission in AD
- acetylcholine signaling important for learning & memory and it is affected early in AD
- therefore increase ACh signaling as treatment strategy to partially restore/improve neural function
- acetylcholinesterase (ACh-E) inhibitors include
Aricept (aka donepezil),
Cognex (aka tacrine),
Exelon (rivastigmine),
Reminyl (galanthamine)
- Describe the role of excitatoxicity in neurodegenerative diseases such as AD
newest FDA-approved medication for AD
- Namenda (aka memantine)
- memantine has low - moderate affinity for NMDA subtype of glutamate receptor
- over-activation of NMDA receptors causes excessive excitability in neurons that can lead to cell death
- called excitotoxicity
- excitotoxicity thought to contribute to neurodegenerationin AD
Agonist:glutamate, NMDA
Coagonist: glycin, D-serine
Antagonist: AP5, 5-7 di-CL-KYN
- Describe the three phases of stress response
- Hans Selye: threatàthree stage response
- The Stress Response and the General Adaptation Syndrome
§Phase 1 – Alarm response (sympathetic arousal)
§Phase 2 – Resistance (mobilized coping and action)
§Phase 3 – Exhaustion (chronic stress, permanent damage)
- Describe the HPA axis and the hormones
§Neuroendocrine system
§Catecholamines and glucocorticoids
- Adrenal-medullary system
- Epinephrine
- Hypothalamic-pituitary-adrenal axis (HPA)
- Cortisol
•Function of the Hippocampus in HPA-Stress Response Cycle
§Hippocampus – Limbic system, responsive to cortisol
§Hippocampus helps to turn off the HPA cycle
§Chronic stress may damage cells in the hippocampus
§Hippocampal cell damage can keep the HPA loop going
HPA axis cycle throughout the body
- stress starts in the hypothalamus
- corticotropin releasing factor (CRF)
- Pituitary gland
- Adrenocoorticotropic hormone (ACTH)
- to adrenal cortex
- secreation of cortisol increases energy from storage and regulates immune system
Adrenal mudullary system
- autonomic nervous system (sympathetic division)
- adrenal medulla
- secreation of norepinephrine (increase heart rate, increase respiration, raise blood pressure)
- Describe how amygdala and hippocampus regulate HPA axis
Regulation of the HPA Axis by the Amygdala and Hippocampus
§Both regulate CRF neurons
- Amygdala projects to bed nucleus of the striaterminalis, which activates the HPA axis
- Hippocampus deactivates the HPA axis
ØGlucocorticoid receptors
ØFeedback loop
§Push-pull style regulation
- Describe the relationship between stress, NE and anxiety
•Stress and the brain
§Cortisol has a profound effect on the hippocampus which is critical in memory formation
- Impacts the size of hippocampal dendrites, as well as adult neurogenesis in the hippocampus
- Effective coping also influences hippocampal changes
stress and the brain
glucoccorticoids increase
BDNF decrease
atrophy and decreased survival
increased vulnerability
- Describe the limbic systems (components and function)
•The Papez Circuit
§Described by James Papez (1937)
§Interconnected limbic structures, including cingulate gyrus, hippocampus and hypothalamusthat are involved in emotion, short-term memory and automatic functions. It links conscious functions of cerebral cortex with autonomic functions of brain stem.
§Overtime, the concept is expanded to include other structures such as amygdala.
Structural Components of the Limbic System
•Limbic lobe of cerebral hemisphere:
–cingulate gyrus - plays a role in expressing emotions via gestures, and resolves mental conflict
–hippocampus - converts short-term memory to long-term memory…memories charged w/ emotion are often retained
•Fornix: tract of white matter
–connects hippocampus with hypothalamus
•Anterior nucleus of the thalamus:
–relays information from mamillary body (in hypothalamus) to cingulate gyrus
•Amygdala: deals with anger, danger, and fear responses
–interfaces limbic system, cerebrum, and sensory systems
•Reticular formation:
–stimulation or inhibition affects emotions (rage, fear, pain, sexual arousal, pleasure)
•The Heinrich Klüver-Paul Bucy Syndrome
-Temporal lobectomy in rhesus monkeys
qDecreased fear and anger
qDecreased vocalizations and facial expressions
-Temporal lobectomy in humans
qExhibit symptoms of Klüver-Bucy syndrome
qFlattened emotions
-Probably related to destruction of the amygdala
•The Amygdala and Fear
•The Amygdala and Fear
§Bilateral amygdalectomy reduces fear and aggression in all animals tested
§Anger, sadness, and disgust may also be affected
§Electrical stimulation of amygdala -> Increased vigilance or attention
§Fearful faces produce greater amygdala activity than happy/neutral faces
Serotonin and Aggression
•Neurotransmitter Serotonin
- Serotonergic raphe neurons project to the hypothalamus and limbic structures via the medial forebrain bundle
- Serotonin turn-over, aggression in rodents
- Drug PCPA blocks serotonin synthesis aggression
•Biological Bases of Anxiety Disorders
- Fear evoked by threatening stimulus: Stressor
- Manifested by stress response
- Stress à Corticotropin-releasing hormone (CRH, aka CRF)à adrenocorticotropic hormone (ACTH)à glucocorticoids
Regulation of the HPA Axis by the Amygdala and Hippocampus
- Both regulate CRH neurons
qAmygdala projects to bed nucleus of the stria terminalis, which activates the HPA axis
qHippocampus deactivates the HPA axis
- Glucocorticoid receptors
- Feedback loop
- Push-pull style regulation
•Pharmacological Treatments for Anxiety Disorders
- Anxiolytic Medications
- Role of GABA, Benzodiazepines
- Serotonin-selective reuptake inhibitors (SSRIs)
- Drug target: CRH receptors (at hypothalamus)
GABA-A receptors have binding sites for barbiturates and benzodiazepines
Barbiturates and benzodiazepines (BDZs) are non-competitive GABA-A receptor agonists and enhance the GABA-A currents
Several neurosteroids bind to GABA-A receptors and enhance GABA’s inhibitory actions.
Allopregnanolone is elevated during stress and has a calming effect. Might be endogenous anxiolytic.
Benzodiazepines are anxiolytic drugs used to
treat anxiety
They bind to GABA-A receptors and enhance GABA’s inhibitory actions.
Role of norepinephrine in anxiety
•Especially focused on panic disorder
§increased NE (on α2 receptor) triggers panic
- electrical stimulation of locus ceruleus
- α2 autoreceptors are inhibitory (Gi linked), they reduce NE release
- Yohimbine is an α2 autoreceptor antagonist
-Yohimbine increases NE release
-Yohimbine induces alert and fear responses
-Clonidine, α2 agonist, reduces NE release, anti-anxiety
•NE and HPA enhances each other
Integration of GABA, 5HT and NE: Drug effects on locus ceruleus cell firing and NE release
clonidine (α2 autoreceptor agonist) decreases NE release
- Describe the monoamine hypothesis of depression
Depression is associated with changes in serotonin and/or norepinephrine signaling in the brain. Most antidepressants cause changes in amine signaling.
MAO, monoamine oxidase;
NET, norepinephrine transporter;
PKC, protein kinase C;
PLC, phospholipase C;
SERT, serotonin transporter.
Acute and long-term effects of 1st generation antidepressant, MAO-Is, on synaptic function
Acute: increase of monoamines
long term: down regulation of receptors and up regulation of 2nd messengers
Effects of antidepressants on serotonergic cells (Part 1)
- Describe the general MOA of SSRIs
transporter inhibition
-[5-HT] increased acutely by SSRI…
Autoreceptor down
-After chronic treatment,
autoreceptor down-regulated in chronic, which leads to further increases in release.
what happens when there are Abnormal glucocorticoid levels in depression
§Elevated cortisol levels in patients compared to normal controls
§Loss of circadian cycle in cortisol levels in depression
Cushing’s syndrome
§high level of circulating glucocorticoid, prone to depression
qPituitary tumor, more ACTH
qAdrenal gland tumor, high cortisol
qTherapeutic glucocorticoid treatment
§Suicide victims show high level of cortisol
§Hospitalized patients of depression show elevated cortisol
Abnormal excitatory drive from other brain regions such amygdala causes
ANSWER: hypothalamus to release more CRF
A reduction in glucocorticoid receptor would reduce negative feedback and leads to greater ACTH release
Effect of stress and antidepressant treatment on BDNF in hippocampal cells
Chronic stress elevates glucocorticoid and decreases BDNF in hippocampus
Reduced BDNF is responsible for the loss of dendritic spines or the death of neurons
Chronic antidepressant treatment alters NE and 5HT and increases BDNF
BDNF production depends on
ANSWER: cAMP pathway
Acute action of antidepressant on the 5HT/NE in the synaptic cleft: increase
Chronic action: decrease of the receptors on the post-synaptic terminal
Chronic action: up-regulation of the cAMP pathway in several steps
New approaches in anti-depressant: CRF receptor antagonist or increase CREB
Schizophrenia epidemiology and key symptoms
Schizophrenia is a spectrum of related disorders, not a single disease.
Schizophrenia is the major neurobiological challenge in psychiatry.
Schizophrenia affects about 1% of the population.
Dissociative thinking, or impaired logical thought, is a key symptom.
Other symptoms include hallucinations,personalized delusions, and changes in affect (emotion).
Schizophrenia etiology
- Brain and neural mechanisms
- Cognitive function
Genetic:
- Having a father over age 55
- Identical Twin studies
- Gene-linkage studies
Environmental
- Living in a crowded city
- prenatal or childhood infection with the parasite Toxoplasma gondii
- people born in winter have a slightly greater chance of developing chizophrenia
- Describe the positive and negative symptoms of schizophrenia (2 Qs)
Positive symptoms are abnormal behaviors that are gained:
- Hallucinations
- Delusions
- Excited motor behavior
Negative symptoms are the result of lost functions:
- Slow thought and speech
- Emotional and social withdrawal
- Blunted affect or emotional expression
The rate of discordance suggests that other factors also contribute to the development of schizophrenia:
- Environmental influences
- Developmental difficulties, such as low birth weight and impaired motor coordination
- Describe the major structural changes and functional imaging findings in schizophrenia
Brains of some schizophrenic patients show structural changes.
Cerebral ventricles are enlarged, especially in males.
More-enlarged ventricles predict a poorer response to drug treatment. (antipsychotic drugs)
how does the hippocampus and amygdala differ in schizophrenics?
ANSWER: they are smaller
- Pyramidal cells of the hippocampus have a disorganized arrangement, occurring during development.
- A theory is that prenatal exposure to influenza may be the cause.
The hypofrontality hypothesis
The hypofrontality hypothesis –schizophrenia may be caused by lack of activity in the frontal lobes. It is believed to be responsible for the negativesymptoms of schizophrenia
•Mesolimbic pathway
§VTA projects to Nucleus accumbens
decrease in DA causes
•Mesocortical pathway
§VTA projects strongly to Prefrontal Cortex
Dopamine hypoactivity
negative, cognitive and affective symptoms
Amphetamine psychosis (neurochemical change)
– caused by repeated use of amphetamines; resembles schizophrenia with paranoia, delusions, and auditory hallucinations.
Amphetamine and other
drugs increase or prolong the activity at dopamine synapses
can treat amphetamine psychosis and schizophrenia.
Chlorpromazine – a member of the phenothiazine family
These neuroleptic or antipsychoticdrugs work by blocking dopamine D2receptors.
Typical neuroleptic drugs are all antagonists at
dopamine D2 receptors.
The dopamine hypothesis
The dopamine hypothesis – schizophrenia results from excess synaptic dopamine or increased postsynaptic sensitivity to it.
- Describe the Glutamate hypothesis and its supporting evidences (2Qs)
– schizophrenia is caused by hypofunction of glutamate receptors.
Phencyclidine (PCP) is a psychotomimetic, producing both positive and negative symptoms of schizophrenia.
PCP acts as a NMDA receptor antagonist,
-prevents glutamate from acting normally.
-When NMDA receptor underactivation is prolonged over long periods, symptoms ranging from memory loss to acute schizophrenia emerge.
illustration of putative functional alterations in DLPFC circuitry in schizophrenia
look at slide 57
