anorexia and addiction: does hyperactivity of the pfc to ... · faa predicts weight loss p=.015...
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FAA predicts weight loss
p=.015r=-.773
vulnerable-to-resilient
THE BIG QUESTION
ANOREXIA NERVOSA VS ABA
Anorexia and Addiction: Does Hyperactivity of the PFC to Striatal Pathway Underlie Vulnerability? Sabrina George, Ishan Handa, Adrienne Santiago and Chiye Aoki
Center for Neural Science, New York University, New York City
APPROACH : ABA, an animal model of AN
What are the neural mechanisms behind the generation of AN-related hyperactivity?
P23-27 P28-35 P36-40 , 1st Baseline P41-44, 1st ABA P45-50 P51-54, 2nd Baseline P55-59, 2nd ABA P60-P66
Surgery Acclimation tosingle housing
Acclimation torunning wheel
Food access from 7pm-9pm only wheel access continues
Re-acclimation to wheel
Recovery
Food access from 7pm-9pm onlywheel access continues
Behavioral Data
Interpretation
Future Experiments• Individuals with AN are at the highest risk of substance abuse one year after discharge for
treatment• Addiction related and reward behaviors are primarily governed by the ventral striatum (VS)• Is the ventral striatum active during AN-related hyperactivity?• How do we quantify addictive behavior?
C21
DREADDs bidirectionally control firing in PFC-Pyr
ExcitationInhibition
DesignerReceptorsExclusivelyActivated byDesignerDrugs
• DREADDs allow us to transiently manipulate neuronal pathways by exciting or inhibiting them
• Cre-dependent DREADDs used to isolate neurons that project to a certain region of interest
• Cre activates production of receptors that can later be activated through the introduction of a ligand.
SalB
• C21 + Gq-DREADD mice run more than CON mice
• SALB + KORD is effective in suppressing wheel running compared to controls
• Excitation of the PFC à DS pathway during FAA causes hyperactivity
• Suppression during FAA reduces activity • No effect observed during recovery
OUR PLAN: • Use light microscopy to visualize PFC à DS projecting neurons• Quantify axon collaterals from PFC à DS pathway that project to VS
• Establish a threshold for brightness, pixel count = # of collateral boutons in a given region• Analyze wheel data to see how long each mouse stays on the wheel
CON 1: Mice with Cre dependent DREADD but no rg-CreEXP: Mice with activated DREADD (+ ligand) during ABAEXP 2: Activated DREADD + ligand during recoveryWT CON: No Cre, no DREADD, but underwent injection of another virus
mPFC
DS
SalB C21
Post recovery
Confocal and Light Microscopy Data
• Our data show that the majority of cells activated by C21 are mcherry Pyramidal cells (which respond to C21) which in turn excite other pyramidal neurons (mcitrine labeled)
• Not many of these pyramidal cells project onto interneurons, evidenced by the small percentage of GAD+, cFos+ cells.
• The excitatory: inhibitory ratio of cells in this region is 83:11 (~8 to 1)
Binarized sample
Isolate black pixels
Recovery
Experimental Groups
FAAFood
allowance7pm
7 am
4 pm 9 pm
Post-prandial
1 am
Food anticipatory activity
Image of mouse PFC, C21 injected ~ 1 hr before perfusion
HUMAN (AN) MOUSE (ABA)
Higher occurrence in females
Equal occurrences in male and female
• Impaired PFC activity on reversal learning task (Allen et al., 2017)
• Anxiety• Voluntary Food
restriction• hyperactivity • Adolescence
ABA = food restriction + unlimited wheel access in rodents
•Green – KORD/mcitrine (Pyr)•Red – mcherry/Gq-DREADD CAMK2 (Pyr) •Blue – GAD (glutamic acid decarboxylase) indicates GABAergic neuron•Yellow – cFos – early gene product, indicates neuronal firing
cFos+ & mcherry+ cell
GAD+, cFos- cell Axon terminals in DS
Cell bodies in PFC
KORD/mcitrine, mcherry- GAD mCherry Total
cFos+ 1.00 2.00 15.00 18.00cFos - 0.00 4.00 2 6.00
% of cFos+ 5.56 11.11 83.33
% of cFos- 0 66.66666667 33.33333333