Exam 2: Autism

Question 1

high functioning autism

Answer 1

repetitive behaviors only noticeable with support, needs support “quirky”

Question 2

___ children in US.

What influences it?

Answer 2

Genetic and environmental - more than 100 genes and 44 genomic loci

Sex differences

Aberrant connectivity between neurons (synapses)

Why more diagnosis? Understanding or increasing diagnosis?

Question 3

What is autism accompanied by?

Answer 3

Sensory hypersensitivities (auditory, somatosensory), seizures (hyperexcitability), sleep disorders (thalamus- sensory and sleep issues)

Gastrointestinal disorders

Anxiety, depression, OCD, and Attention issues

Question 4

More than 100 genes associated with autism. What about these genes?

Answer 4

Loss or gain of function genes. Ultimately, appears to be gene environment and sex differences. Males more. Fragile X- defect in X chromosome. Some due to sex differences.

Defect in function at the synapse. Neuronal or function of synapse.

Question 5

Cognitive Function

Answer 5

prefrontal cortex and associated circuity

Question 6

Hypothesis about cognitive function.

Answer 6

Autistic people lack reward response to social interaction unlike neurotypicals

Social-behavior network and reward circuitry. Do they not experience the joy of social reward?

Circuitry/molecular mechanisms - excitatory/inhibitory function

Question 7

Executive control connections to other brain regions

Answer 7

1 Access information from sensory areas

2. Ability to influence other sensory and motor areas
3. Short-term storage
4. Modifiable – ability to learn
5. Information about goals and means to achieve them

Question 8

Orbitofrontal cortex

Answer 8

functionally homologous to rodent OFC interconnects with amygdala limbic regions involved in

EMOTION/SOCIAL AWARENESS

Question 9

Ventrolateral areas (vl-PFC) and Anterior Cingulate

Answer 9

rodent mPFC – infralimbic, prelimbic –(long-term memory, retrieval)

Question 10

Dorsolateral prefrontal cortex (dl-PFC)

Answer 10

The dorsal lateral prefrontal cortex is especially interconnected with brain regions involved early sensory processing and motor outputs. Particularly important for attention, cognition (working memory etc) and action

Question 11

Connectivity Disruption in ASD

Answer 11

high interconnectivity in prefrontal cortex (short connections), low connectivity within the rest of the brain.

Weak long distance in temporal lobe, but Acc goes to LPFC and OFC, prefrontal very connected.

Focus on what they like, don’t interact with environment well.

Connected- short axons
disconnected= longer axons

focus areas highly connected

Question 12

Social behavior

Answer 12

Aggression. Affiliations, sexual behavior and parental care

For behavior to be adaptive it should be rewarding-

Dopamine released from VTA in social and motivated behaviors: response to sex, feeding and drugs of abuse

VTA- nucleus accumbens dopaminergic projections important for regulating reproductive behaviors pain sensitivity and parenting behaviors

Question 13

Reward circuitry

Answer 13

limbic loop
recognizing rewards and initiating their consumption

cortical input –> + stratium –> - –> pallidum –> - mediodorsal circuit –> + beginning

Question 14

Where does dopamine VTA go to?

Answer 14

mPFC, hippocampus, amygdala, GABAergic Nucleus Accumbens (NAc)

recognizing rewards and consuming them

Question 15

brain regions and circuitry mediating adaptive behaviors are…

Answer 15

conserved

social and reward circuit conserved across species

markers for dopamine existed for 100s of years

Autism and increase in diagnosis- high functioning might be evolutionarily adaptive in some ways.

Question 16

Circuit development and hyperexcitation in ASD

Answer 16

—-Hyperexcitability —> Epilepsy and epileptogenesis —> Cognitive and behavioral impairments

Circuit development —-Aberrant synaptic development/plasticity –> Cognitive and behavioral impairments

Question 17

Mouse models of ASD

Answer 17

autism like, not exact

study memory formation/spatial memory with maze

emotional memory, fear condition with social anxiety tests

axiolytic drugs reverse behaviors

Question 18

Mouse model of fragile X

Answer 18

mostly males

effects during development on synapse formation

ultimately, comorbid

Question 19

Elevation of E/I balance in ____ leads to social impairments

Answer 19

prefrontal cortex

Question 20

________ of E/I balance in mouse medial prefrontal cortex caused profound behavior impairments resembling social withdrawal

Answer 20

elevation, NOT reduction of cellular E/I balance

Question 21

E/I in mouse experiment how did they do it?

Answer 21

Express Rodpsin, excitatory cell in pyramidal cells. Test manipulation, then test social behavior.

Stimulate PV cells- no effect of social interaction

When stimulate excitatory network - decrease social interaction

Question 22

In mouse models across brain area, cell types, genotypes, what do they show?

Answer 22

mixed results

Question 23

Reduced inhibition:

Answer 23

Rett Syndrome - MeCP2-deficient

GABAergic neurons Fmr1 KO mice

– Scn1a+/- mice -–reversal of phenotype by enhanced GABAergic transmission;

Neuroligin2 (Nlgn2) - loss of inhibitory interneurons

– Shank1 – reduced excitation to inhibitory interneurons

Angelman Syndrome - Ube3a KO

Question 24

Reduced Excitation

Answer 24

Rett Syndrome – reduced activity in cortex

Nlgn4 – hypoexcitability in somatosensory cortex –

– Nlgn4 – disrupted cortico-cortical connections, not somatosensory cortex –

– Rett Syndrome – reduced frontal-motor connections

Question 25

Increased Inhibition

Answer 25

MEF2c cortex and hippocampus + decreased excitation,

; – Neuroligin3 mutation (Nlgn3) – layer II/III somatosensory cortex

Question 26

Neuroligin 2

Answer 26

Gaba

neuroligin, Gaba-R, gephyrin, neurexin

Neuroligin- one of the genes associated with ASD

Question 27

Neuroligin 1,3, 4,

Answer 27

glutamatergic

Ca2+ channel, synaptic vesicle binding proteins, AMPAR, NMDAR