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