NPB 173 Exam 3

Neurological vs Psychiatric

Neuro: usually have more salient (obvious) signs of disease in the brain

Psych: usually deals with disorders of thought and behavior with less salient signs of disease in the brain (more challenging to understand)

Neurodevelopmental disorders

brain disorders that manifest in individuals as they grow up (brain undergoes large scale changes that don’t happen in adulthood)

tend to be more psychiatric than neurological

Examples of neurodevelopmental disorders

intellectual disability (ID), ASD, fragile X syndrome, ADHD, schizophrenia

r/K selection theory

r-selection = more offspring, faster growth rates, less parental care

K-selection = fewer offspring, slower growth rates, more parental care (long time to maturity and prolonged time of development)

senescence

normal, gradual deterioration of fxn with age

neurogenesis (and when it stops)

addition of new neurons

little to no neurogen post-birth

synaptic pruning

reduction of synpases in brain to stable level in adulthood

Fragile X Syndrome (FXS) basic definition

genetic and neurodevelopmental disorder

caused by mutation in fragile X messenger ribonucleoprotein 1 (FMR1) gene on X chrom

Signs and symptoms of FXS

intellectual disability, developmental delays, social impairments

some signs and symtoms are unrelated to brain fxn

high comorbidity with attention problems and hyperactivity

largest single genetic cause of autism

Sex-linked nature of FXS

more severe in males

MOre prevalent in mles

Males with FXS cannot have female offspring

X-inactivation

one of the X chrom copies in females in minimally used

happens randomly at early stage of multicell development

inactivated X chrom is packaged in Barr body → results in reduced transcription

Barr body

how inactivated X chrom is packaged in FXS

results in reduced transcription

mosaicism

different genotypes among cells within same individual

Sim to FXS

Epigenetics

heritable changes in gene fxn that do not involve changes to genotype

violation of central dogma of molecular biology

DNA methylation

addition of methyl group to DNA

histone modification

binding of epigenetic factors to histone tails

histone proteins

DNA in nucleus is packaged by being wound around histone proteins into nucleosome structures

nucleosomes

section of DNA wound around 8 histone cores

chromatin

DNA plus protein packaging

FMR1 gene

located on X chrom - has 17 exons

CGG nucleotide repeat section in the 5’ (start side) UTR → # of repeats differs btwn individuals and is critical for FXS

UTRs

untranslated regions of mRNA

oneon each side of gene

Inheritance of FXS

Males: carry or dont carry on their single X chrom, sperm with X is not viable (no female offspring), only having single X chrom leads to more severe FXS

Females: larger activation ratios of X chrom carying the mutation leads to greater severity but still less than in males

Amounts of CGG repeats and their effects

<45 → FMR1 is considered typical → normal expression of fragile X mental retardation protein (FMRP) → no FXS

>200 → full mutation of FMR1 → epigenetic mods that reduce transcription of FMR1, reduce lvls of FMRP, and causes symptoms of FXS → mediated by loss of fxn of FMRP

45-200 → premutation of FMR1 → epigenetic mods that inc transcription of FMR1 → gain of fxn RNA toxicity of FMR1 mRNA leads to dif set of impairments from FXS

FMRP’s fxns

FMRP is associated with stalled protein translation (many proteins under reg of FMRP are involved in synaptic plasticity)

Post-syn: FMRP counters influence of mGluR-mediated protein translation enhancement thru inhibition of translation of sim sets of proteins (FMRP + mGluR = fast control of protein expression)

Effects of FMRP mutations

Loss w/ full mutation: inc protein synthesis thry lack of FMRP-mediated protein synthesis inhibition, atypically depressed synapses + less control over synaptic plasticity (mGluR promotes weakening of synapse from high Glu w/o FMRP to counter)

FXS: proteins regulated by FMRP + mGluR5 are constutively expressed at high lvls

Manuals for mental disorders

DSM-5

ICD (WHO’s International Classification of Diseases manual)

Goal of the DSM

provide guide for proper diagnosis and criteria for differential diagnosis

Autism and ASD deficits

Neurodevelopmental (15-20% of autistic children are largely uneffected as adults)

Social (infant resistance to cuddling, toddlers on goring others and avoiding eye contact, lack of awareness of other’s feelings)

Behavior (stereotyped, compulsive, ritualistic behaviors, fixations - not motor impairment)

Communication (failure to acquire language at expected age, echolalia, reverse pronouns)

Theory of Mind, Face recognition, language development, early brain enlargement

echolalia

repeating what is heard rather than responding to it

reverse pronouns

not using first-person to refer to oneself

Asperger syndrome

part of the autism spectrum

involved reduced language deficits (usually milder form → higher fxning)

Dimensionality

number of variables needed to describe something

psychiatric disorders are often mutlidimentional

Prevalence of autism

Dramatically rising

debating if this is due to expanded criteria for diagnosis or actually increasing

Genetic contributions to autism

Use twin studies (both monozygotic and dizygotic)

Seems to have genetic link, not just environmental

Heritability = 0.7-0.9

Theory of Mind

ability to attribute mental states to others and understand those mental states may differ from your own

Mirror Neurons

some neurons in the frontal and parietal cortex that respond selectively during execution of specific behaviors AND ALSO respond when other ppl execute the same behavior

Might be important substrated for Theory of Mind (but no solid experimental support)

Face recognition + Autism

Difficulties with face and emotion recognition

Often better than control subjects on inverted face recognition → altered strategies and/or neural computations

Studies suggest that fusiform face area is less responsive in autistic ppl

Early brain enlargement w/ autism

Accelerated brain growth during early childhood (due to growth of existing neurons [dendritic arborization] and glia)

Followed by period of reduced growth (ending with sim sized adult brains as ppl w/o autism)

Dif brain growth speeds may be important to effects on neurodevelopment (critical periods)

Critical period

periods of time when NS is especially sensitive to certain enviro stim + learning based on those stims

Generally peak during childhood but timing differs for dif fxns

SHOWS THAT TIMING OF BRAIN PLASTICITY FOR NEURODEVELOPMENT IS IMPORTANT → disrupting timing could cause big changes

example order: senses → language → higher cognition

ADHD (gen info and gen impairments)

Attention deficit hyperactivity disorder

neurodevelopmental

Inattention, Hyperactivity, impulsivity

Symtoms appear before age 12 and (following DSM-5) last for at least 6 months

Inattention in ADHD

difficulty maintaining focus on singular stim or task → inc distractibility

Hyperactivity in ADHD

abronal lvl of physical activity (movement or other behaviora. output)

often involved difficulty staying still and/or quiet (general restlessness)

Impulsivity in ADHD

tendency to act without forethought, reflection, or full consideration of consequences

Standford Marshmallow test

Take marshmallow immediately or wait 15 minutes and get 2 marshmallows

Children with ADHD struggle to delay gratification due to inc impulsivity

Cocktail party effect

brain’s ability to focus on one stream of speech among many cometing background conversations and sounds

fMRI

Functional magnetic resonance imaging

non-invasive measures of changes in blood associated with brain activity (BOLD)

Haemodynamic response

change in blood to deliver oxygen to neurons that are most active

BOLD signal

blood-oxygen-level-dependent signal

measure of haemodynamic response in the brain

measured by fMRI

proxy for neural activity

lacks spatial and temporal resolution of neural activity

DTI

diffusion tensor imaging

alternative MRI-based methods to image brain

measure long-range axonal projection pathways

default mode network

common set of brain regions that are most active when individuals are awake but not focused on any external stim or engaged in a task

highly correlated with each other

involved in mindw andering + negatively correlated with control of attention

exogeneous

bottom up

facotrs driven by salient external stim

frontal cortex

inc neural response to attended stimuli

endogeneous

top down

factors driven by voluntary control

frontal cortex

movement planning

Default mode hypothesis of ADHD

inadequate regulation of default mode network may allow it to disrupt other neural poscesses and cause spontaneous fluctuations of attention

Evidence: neurotip = more fMRI activity in frontoparietal brain areas associated with goal directed exec control compared to ppl w/ ADHD —— ppl w/ ADHD show more activity in default mode network

temporal discounting

impairments in the ability to compare current and future rewards

High risk sensitivity vs low

high = risk averse

low = risk seeking

neural mechanisms of impulsivity

temporal discounting, altered risk sensitivity, lack of appropriate behavioral inhibition, inadequate consideration of alts in decision making

neural mechanisms of decision making

neurons from lots of brain regions (including posterior parietal cortex) activity depends on accumulated evidence during deliberation → reaches common lvl before decision report

Decision committment may be triggered when neural reponses that rep accumulating evidence reach criterion lvl/threshold

adjustments can alter balance btwn speen and accuracy (could account for impulsivity)

Striatum has been postulated to control decision committment thresholds in line with its control of action initiation

Basal ganglia circuits + ADHD

striatum has smaller gray matter vol in ADHD + reduced activity

other differences also reported but large variablility btwn studies

Stimulant treatment for ADHD

Ritaline and Adderall (block VMAT to increase DA in cleft)

Fear

experience triggered by presence of actual/perceived danger/threat

in some cases elicits fear-related behaviors

Anxiety

experience of dead or apprehension in anticipation of encountering danger or aversive experience

can be triggered internally by thoughts or with context-dependent triggers

Anxiety disorder

persistent excessive worry about various aspects of daily life

Common triggers: everyday life events, work, health, family

Panic Disorder

recurrent, unexpected panic attacks )intense physical symptoms = chest pain, shortness of breath, dizziness)

Triggers: no clear trigger, sometimes stress or certain situations

Social Anxiety Disorder

Intense fear of social situations, worry about being judged or embarrased

Triggers: social interaction, public speaking, meting new poeple

Specific phobias

extreme, irrational fear of a specific object or situation

Common triggers: heights, flying, animals, injection, enclosed spaces

Agoraphobia

Fear of situations where escape might be difficult or help unavailable

Common triggers: crowds, public transportation, open or enclosed spaces

Separation Anxiety Disorder

Excessive fear or anxiety about being separated from attachment figures

Common triggers: being away from home or loved ones, going to school or work

Anxiety disorders

lifetime prevalence around 30% → most common type of psychiatric disorder

Generalization in learning

Opposite of specificity (learning is balancing trade-offs btwn specificity and generalization)

Lack of: challenges when facing new stimuli or situations

Excessive: lack of discrimination of important differences

Cerebral cortex + memory

long-term declarative memory (things you know and can tell others)

Prefrontal cortex + memory

working memory (STM)

Cerebellum/Striatum + memory

procedural memory (motor mem: things you know and can show by doing)

Hippocampus + mem

memory formation

Amygdala + memory

emotional memory

Amygdala components

Lateral (LA)

Basolateral (BLA)

Central (CeA)

LA Amygdala

recieves inputs from other brain regions (sensory cortex, prefrontal cortex, hippocampus)

Input is processed within amygdala → induces large amount of internal inhibition via ITC

Intercalated cells

ITC cells - in amygdala

use GABA as NT for inhibition

CeA amygdala

sends outputs to other brain regions

a lot of this mediates fear reponses

Place cells

respond selectively when animals are in specific locations in space

within hippocapmpus

depend on context/specific to environment

stable over time, not purely sensory (still respond with lights off)

Respond based on where an animal “thinks” it is located

Associative learning

process of learning an association btwn two stim

Classical conditioning

Pavlovian conditioning

pairing unconditioned stim (instinctively elicits response) with previously neutral conditioned stim

Instrumental/operant conditioning

pairing reward or punishment with particular behavior

Memory consolidation

process where memories become more stable after initial acquisition

involved hippocampus (more so during earlier stages - LT mems less depepndent)

hippocampus likely provided contextual info necessary for memory formation

Synaptic plasticity

changes in synapse strength and number

critical mech for learning and mem

Hebb’s rule

Neurons that fire together wire together

Synapses are strengthened btwn neurons taht are active at sim periods of time

simple mech for effects of classical conditioning

Long term potentiation (LTP)

persistent strengthening of synapses based on recent patterns of activity

can be induced by high frequency stim (HFS) that causes synchronous presyn and postsyn activity → larger EPSP for each presyn AP

mediated by Glu NMDA receptors (can be blocked my Mg excpet when postsyn is also strongly depolarized (then pore ispermeable to ions that include calcium)

EPSP

Excitatory post-synaptic potentials

Mechnisms of LTP

Postsyn depolzarization allows NMDA to open to calcium

Calcium influx causes fast component of LTP mediated by protein kinases and AMPA receptors (not dependent on post-syn)

signalling pathways activated by Ca also cause slower late componet of LTP that leads to mod of protein expression and insertion of more AMPA R into posty syn neurons

Fear conditioning

can be caused by associative learning

Amygdala - recieved input fron neurons that repond to both unconditioned stim (shock) and conditioned stim (sound tone)

strengthens synapses from CS pathway onto the amygdala so that alone can trigger amyg

Freezing responses

can be conditions on both counds and context

inactivation of amygdala dec freezing to all conditions (suggesting generalized reduced fear/anziety reponses)

inactivation of hippo dec freezing only to context (sugge