PSYT 500 midterm

how did COVID affect mental disorder prevalence?

MDD and anxiety increased a lot in young people, especially females

how did we used to think about mental disorders?

Freudian psychoanalytic theories

what suggested the biological basis of mental disorders in the 50s?

serendipitous discovery of drugs like chlorpromazine and lithium

chlorpromazine

mild tranquilizer; typical antipsychotic

lithium

anti-mania drug

DSM definition of mental disorder

clinically significant behavioural or psychological syndrome or pattern that occurs in an individual and that is associated with present distress and/or disability

what is the DSM?

a categorical classification that divides mental disorders into types based on criteria sets with defining features

not necessarily completely discrete entities

atheoretical regarding causes of mental disorders—classifies by symptoms, not cause

what is the point of the DSM?

trying to 'standardize' diagnoses a bit

critiques of the DSM

- genetic studies do not support the discreet classification system
- no biological basis for diagnoses

Research Domain Criteria Project (RDoC)

a new initiative that aims to guide the classification of mental disorders by underlying biology and quantifiable things

looks at genetics, imaging, cog sci, and other factors

constructs of RDoC

constructs \= the parameter you're measuring

what do you do with the RDoC constructs?

group them into domains of functioning based on vibes

domains of RDoC

negative valence systems, positive valence systems, cognitive systems, systems for social processes, and arousal/regulatory systems

valence

the value associated with a stimulus as expressed on a continuum from pleasant to unpleasant or from attractive to aversive.

how common is glutamate?

90% of neurons use glutamate; 80-90% of synapses are glutamatergice

how can glutamate signaling be precise if it's so common?

its release is quickly terminated and transporters reuptake it so there's no over-excitation

two flavours of GluR

iGluR; mGluR

mGluR

metabotropic GPCRs

why are NMDARs a sexy drug target?

NMDAR are involved in working memory and excitatory transmission, so good anaesthetic or learning drug!

why are NMDARs not a good drug target?

NMDAR cause psychosis when antagonized like you'd want for an anaesthetic (PCP, ketamine)

pros of ketamine as an antidepressant

fast-acting

extrasynaptic NMDARs

linked to cell death

synaptic NDMARs

linked to cell survival

norepinephrine

arousal and alertness, regulates memory formation by emotion

where are norepinephrine neurons?

locus coeruleus

locus coeruleus

area of the brainstem that contains norepinephrine; involved in memory formation

has all the NE cell bodies. project where they're needed

norepinephrine synthesis

Tyrosine -\> DOPA -\> Dopamine -\> Norepinephrine

what does dopamine B hydrozylase (DBH) do?

final step of dopamine -\> NE

what do mutations in DBH do?

lead to lack of arousal because no NE
- non-fatal
- patients do fine in school/life, but not sporty and faint a lot

experiment linking NE and memory

two groups of subjects read two different plots designed to elicit different reactions

the groups were asked to remember details later. You'd expect the arousal group to recall more accurate, vivid details/have a better remembering score compared to the neutral version

but when group with arousal plot treated with NE blocker (propranolol) they don't remember more compared to the neutral plot, so NE is def involved in the emotional content of remembering an event

amygdala

A limbic system structure involved in memory and emotion, particularly fear and aggression.

how does the amygdala affect the LC?

activates the locus coeruleus with CRH

CRH

corticotropin releasing hormone

How does the locus coeruleus affect memory formation?

fibers from LC release NE to the basolateral amygdala and hippocampus, activating neurons in regions related to fear AND memory \= stronger memories when you're scared

how does cortisol affect memory?

reduces the activity of the basolateral amygdala and central amygdala AND the dentate gyrus and CA1 neurons in the hippocampus \= less memory encoding during stress

dentate gyrus

a layer of neurons in the hippocampus that receives input from the entorhinal cortex

catecholamines

dopamine, norepinephrine, epinephrine


hormones secreted by the adrenal medulla that affect the sympathetic nervous system in stress response

what's the point of stress?

- heightened excitability or arousal
- induce aversiveness
- lack of controllability

glucocorticoids

Synthesized and released by the adrenal cortex, glucocorticoids raise blood glucose levels while decreasing protein synthesis to get you ready for the 'fight or flight'

mineralcorticoid receptors

activated at basal levels. does homeostasis

glucocorticoid receptors

activated at stress levels of cortisol. do stress response

HPA axis

the hypothalamus, pituitary gland, and adrenal cortex

Interaction between the nervous and endocrine systems to produce the body's response to stress. Elevated levels of one of these hormones may lead to depression

allostatic load

the long-term negative impact of the stress response on the body

allostasis

process by which the body achieves stability through physiological change

LONG TERM modification of body over the long term

allostasis/adaptation vs maladaptation

if you have some water to put out the fire, nice! if you have too much water, now you have damage caused by water

dopamine

reward! motivation! happy! addiction!

mesolimbocortical pathway

a set of dopaminergic axons arising in the midbrain and innervating the limbic system and cortex. involved in bipolar disorder

dopamine synthesis pathway

tyrosine --Tyrosine Hydroxylase--\> L-DOPA --Dopa Decarboxylase--\> Dopamine

cocaine MOA

Blocks dopamine and NE uptake in the reward receptors in the brain (floods dopamine and NE in the synapse)

amphetamine MOA

a substrate that is more preferred than dopamine \= dopamine agonist

forces active release of DA from terminal

5HT endogenous function

cardio, respiratory, sleep, aggression, sexual behaviour, nutrient intake, mood, motor output, nociception/analgesia, neuroendocrine fxn

SERT blockers do what?

antidepressant

raphe nucleus

A group of serotonin-containing neurons extending from the raphe nuclei, located in the pons and medulla throughout the limbic system and forebrain

subdivisions of raphe nucelus

- rostral -\> dorsal and median
- caudal

rostral raphe projections

brain—contain 85% of serotonin neurons in the brain!

caudal raphe projections

spinal cord

dorsal raphe neurons

fine and rarely make synaptic contacts

medial raphe neurons

coarser axons and synaptic specialization

5HT synthesis pathway

l-tryptophan -\> 5-HTP -\> 5-HT

SERT gene

SCL6A4

SERT gene polymorphisms

long GC-rich promoter w/ 16 repeats or short 14 repeats

long vs. short SERT polymorphism effects

short form increases risk of depression

what happens with chronic exposure to SSRIs?

decreases 5-HT uptake by internalization and degradation of SERT (chemical dependence)

non-vesicular release of 5HT caused by?

ecstasy

non-vesicular release of 5HT mechanism

ecstasy blocks VMAT, so 5HT builds up in cytoplasm, which reverses the presynaptic transporter, which then pumps out 5HT without vesicles

VMAT

vesicular monoamine transporter

magnetic resonance spectroscopy

a little more accurate than CSF taps

molecular genetic techniques to engineer proteins for neurotransmitter sensors

ex. fluoresce when in contact with a neurotransmitter
ex. measuring calcium influx

invasive; can't do in humans

changes in brain matter from age 5 to 20

frontal lobe develops until teenage years, pruning in other a reas

adult neurogenesis

in rodents, hippocampus and olfactory bulb have adult neurogenesis
issues with this can cause psychiatric disorders

evidence of adult neurogenesis in humans

in string players:
- modalities for string playing aren't necessarily used a lot in non-players
- certain areas expand through the experience of learning string instruments
- the representation of that brain area changes if you learn strings in childhood or even later in life (but to a lower extent) compared to controls
- this suggests that the brain remains plastic even when you're older (learning strings later in life)

chronic vs. acute stress

- allostatic load happens with chronic stress
- acute stress is needed for motivation, etc.

changes that occur with chronic stress

- stress mediators like NE and cortisol will induce changes in the brain
- detrimental to brain function and mental health in the long term

how are life events and mood disorders correlated?

high correlation between a negative life event in the month prior to an episode/attempt and the episode/attempt

levels of stress mediators in depressives vs. control

higher in depressives

effects of acute and chronic stress on hippocampal neurons (CA3)

chronic stress decreased the size of CA3 cell bodies a lot more than acute stress

chronic stress also decreased dendrites and arborization

CA3

A region in the hippocampus that receives input from the neurons of the dentate gyrus.

what showed the link between cortisol levels and shrinking neurons?

administering cyanoketone blocks stress hormone production and suggests a causal link between stress hormone level and hippocampal CA3 shrinkage

depression hippocampus phenotype in humans

smaller hippocampus volume

meta analysis of left hippocampal volume in depressed patients showed what?

decreased mean size in depressed patients vs. controls

why study hippocampal size in PTSD instead of depression?

depression is hard to study; it's chronic and you usually only get diagnosed after having symptoms for a while. But PTSD is easier to study because it develops suddenly with a defined time of onset

easier to see if hippocampal size difference is a predisposition or a result of the disease

PTSD hippocampus twin studies results

hippocampal size negatively correlates with severity of PTSD symptoms
so the size and severity is def related \= result of disease

but this correlation is still correlated with the size of the civilian twins \= ALSO predisposition

stress resilient vs. stress vulnerable

not everyone with the predisposition will get the thing

readouts:
- HPA axis
- ANS
- inflammatory mediators
- exploration, anxiety, anhedonia
- submissive behaviours
- active coping

early life stress

abuses or neglect during brain development periods

symptoms of people who experienced ELS

- internalizing symptoms (anxiety, avoidance)
- externalizing symptoms (aggression, hyperactivity)
- social impairment
- psychiatric disorders

intersection of ELS and 5HT promoter polymorphisms

short allele (the predisposition version) is only correlated with mood disorders when there is severe ELS

how is ELS measured in rats?

maternal care: active nurisng and licking and grooming \= more resilient pups

can also stress the dam with not enough bedding

effects of maternal care on HPA axis

pups with caring dams have lower corticosterone levels post-restraint than neglected pups

effects of maternal care on GR of pups

higher methylation of GR gene in low-care pups \= less glucocorticoid receptors \= less negative feedback \= heightened HPA axis response \= less resilient to stress

pups of high-LG-ABN dams have better response to stress bc they have more GR

adult neurogenesis studies in humans using BrdU

- gets incorporated into new cells
- shows new neuron formation in DG and C14 in human hippocampus
- limitation: can only be observed post-mortem, so BrdU is given to ex. cancer patients who will die soon

adult neurogenesis study in humans using markers of progenitor cells

found no neurogenesis in adult human DG (no progenitor cells)

adult neurogenesis studies using nuclear bomb test C-14 levels

above-ground nuclear testing happened, changing the ratios of C14 in the atmosphere, so we have traceable levels of C14 in people born pre-cold war above-ground nuclear testing
if there's no new neurogenesis, the level of C14 should be the same as air level depending on the years you're born-raised
if there's new neurogenesis, levels of C14 will be higher than air level

no new neurogenesis found in olfactory bulb, but was found in hippocampus!
people born pre-nuclear testing had higher levels of C14 than the air levels around the time their brains were developing, so their hippocampus was indeed incorporating carbon into new neurons throughout their life

questions that remain with adult neurogenesis

- how much neurogenesis is necessary to produce functional changes?
- how do we relate neurogenesis to functional changes?
- it's easier to see it in rodents than primates

drug effects on novelty suppressed feeding

- chronic antidepressants decrease latency to feed
- haloperidol does not decrease latency

NSF latency

more latency \= more anxiety

chronic fluoxetine effect on BrdU uptake

increases BrdU uptake \= increases neurogenesis in the DG

what is the SGZ

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs

ablation of SGZ experiment

used x-rays to ablate part of the hippocampus that does adult neurogenesis. Blocked the effects of fluoxetine on adult neurogenesis \= no uptake of BrdU after ablation despite SSRI administration

ablation of SGZ effects on behaviour

suppresses behavioural response to SSRIs—they no longer decrease NSF latency

what do the ablation studies suggest about SSRI's mechanism of action?

enhancing neurogenesis underlies part of their effects against anxiety