Exam 2: Autism Flashcards
high functioning autism
repetitive behaviors only noticeable with support, needs support “quirky”
___ children in US.
What influences it?
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?
What is autism accompanied by?
Sensory hypersensitivities (auditory, somatosensory), seizures (hyperexcitability), sleep disorders (thalamus- sensory and sleep issues)
Gastrointestinal disorders
Anxiety, depression, OCD, and Attention issues
More than 100 genes associated with autism. What about these genes?
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.
Cognitive Function
prefrontal cortex and associated circuity
Hypothesis about cognitive function.
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
Executive control connections to other brain regions
1 Access information from sensory areas
- Ability to influence other sensory and motor areas
- Short-term storage
- Modifiable – ability to learn
- Information about goals and means to achieve them
Orbitofrontal cortex
functionally homologous to rodent OFC interconnects with amygdala limbic regions involved in
EMOTION/SOCIAL AWARENESS
Ventrolateral areas (vl-PFC) and Anterior Cingulate
rodent mPFC – infralimbic, prelimbic –(long-term memory, retrieval)
Dorsolateral prefrontal cortex (dl-PFC)
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
Connectivity Disruption in ASD
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
Social behavior
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
Reward circuitry
limbic loop
recognizing rewards and initiating their consumption
cortical input –> + stratium –> - –> pallidum –> - mediodorsal circuit –> + beginning
Where does dopamine VTA go to?
mPFC, hippocampus, amygdala, GABAergic Nucleus Accumbens (NAc)
recognizing rewards and consuming them
brain regions and circuitry mediating adaptive behaviors are…
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.
Circuit development and hyperexcitation in ASD
—-Hyperexcitability —> Epilepsy and epileptogenesis —> Cognitive and behavioral impairments
Circuit development —-Aberrant synaptic development/plasticity –> Cognitive and behavioral impairments
Mouse models of ASD
autism like, not exact
study memory formation/spatial memory with maze
emotional memory, fear condition with social anxiety tests
axiolytic drugs reverse behaviors
Mouse model of fragile X
mostly males
effects during development on synapse formation
ultimately, comorbid
Elevation of E/I balance in ____ leads to social impairments
prefrontal cortex
________ of E/I balance in mouse medial prefrontal cortex caused profound behavior impairments resembling social withdrawal
elevation, NOT reduction of cellular E/I balance
E/I in mouse experiment how did they do it?
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
In mouse models across brain area, cell types, genotypes, what do they show?
mixed results
Reduced inhibition:
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
Reduced Excitation
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
Increased Inhibition
MEF2c cortex and hippocampus + decreased excitation,
; – Neuroligin3 mutation (Nlgn3) – layer II/III somatosensory cortex
Neuroligin 2
Gaba
neuroligin, Gaba-R, gephyrin, neurexin
Neuroligin- one of the genes associated with ASD
Neuroligin 1,3, 4,
glutamatergic
Ca2+ channel, synaptic vesicle binding proteins, AMPAR, NMDAR
