Impact of prenatal nicotine exposure on
impulsivity and neural activity in medial
prefrontal cortex
Team RITALIN:
Research in Testing ADHD's Link to Impulsivity in Neuroscience
13 June 2013
Introduction
Prenatal Nicotine Exposure (PNE)

PNE is linked to many psychiatric disorders

Women who smoke during pregnancy are three times as likely to
have children diagnosed with ADHD

1 in 5 women still smoke during pregnancy

Nicotine causes changes in the development that alters
dopaminergic & noradrenergic pathways in the brain

Several studies show behavioral, neuroanatomical, &
neurochemical disturbances after PNE

Benefits of methylphenidate, a common ADHD drug, point to
PNE as a valuable animal model of impulsivity
Introduction
Attention Deficit Hyperactivity Disorder (ADHD)

Symptoms: impulsivity, hyperactivity, & inattention

Affects 5-10% of all school age children

Twentyfold increase in prescription of ADHD drugs in the past 30
years


Diagnoses based on qualitative observations

Limited research on the neurobiology of the disorder

ADHD drugs are addictive stimulants
Fetal nicotine rats and humans with ADHD have similar deficits on
behavioral tasks for hyperactivity & impulsivity
Introduction
Modeling Impulsivity

Animal model validity

Face validity

Conduct validity

Predictive validity

What areas or circuits are involved?

How can we uncover more about the neurobiology?
Introduction
Medial Prefrontal Cortex (mPFC)
Introduction
Stop Signal Task (SST)
Introduction
Research Questions
I.
Is there a correlation between neural firing in the mPFC
cortex and impulsivity in control rats?
II. Is neural firing in the mPFC cortex disrupted and impulsivity
increased in fetal nicotine rats?
III. Is there a correlation between this disrupted firing and
increased impulsivity?
Methodology
Phase 1: Rat Breeding & Selection
Acclimate dams
to nicotine in
water
Breed rats
Compare
populations
Select pups

Significant differences in water consumption & mother weights

No significant differences in pregnancy duration, pups per litter, pup
birth weight, or locomotion*

Randomly selected 8 males each from 37 PNE pups (from 3 dams)
and 39 control pups (from 3 dams)
Methodology
Phase 2: SST Training & Surgery
Task training

Between group
differences
observed
Implant
electrodes
Compare movement times and percent correct on stop and go trials
Results
Percent Correct during Training Sessions
84
79
Percent Correct
74
69
Control
64
59
Nicotine
54
49
44
1
2
3
4
5
6
7
8
9
10
Day
11
12
13
14
15
16
17
18
Results
Percent Correct during Training Sessions with Stop Trials
90
Control Go
Trials
Percent Correct
80
70
Nicotine Go
Trials
60
Control Stop
Trials
50
Nicotine
Stop Trials
40
30
1
2
3
4
Day
5
6
Results
Movement Times during Training Sessions
0.31
0.3
0.29
Time (s)
0.28
0.27
Control
0.26
Nicotine
0.25
0.24
0.23
0.22
1
2
3
4
5
6
7
8
9
Day
10
11
12
13
14
15
16
17
18
Results
Movement Time during Training Sessions with Stop Trials
0.36
Control Go
Movement
Times
0.34
Nicotine Go
Movement
Times
Time (s)
0.32
0.3
Control
Stop
Movement
Times
0.28
0.26
Nicotine
Stop
Movement
Times
0.24
0.22
1
2
3
4
Day
5
6
Results
Post-Surgery Behavior
Percent Correct Trials
p ˂ 0.05
80
Percent Correct
70
60
50
40
30
20
10
0
Control
Go trials
Stop trials
Stop Change Reaction Time
Movement Time on Trials
120
800
700
100
600
80
Time (ms)
Movement Time (ms)
p ˂ 0.05
900
Nicotine
Group
500
400
300
60
40
200
20
100
0
Control
Go trials
Group
Stop trials
Nicotine
0
Control
Group
Nicotine
Methodology
Phase 3: Neural Recording & Analysis
Neural Recording

Histology
Data Analysis
12 rats from the control and PNE groups performed 157 sessions,
over which we collected neural firing from 346 cells
Methodology
Histograms for Above/Below Baseline Firing
Results
Histograms for Preferred/Nonpreferred Stop/Go Trials
Results
Distributions for Preferred/Nonpreferred for Go Direction
Results
Histograms for Contra/Ipsi Stop/Go Trials
Results
*
legend:
go ipsi - blue
go contra - green
stop ipsi - red
stop contra - yellow
Subtraction Plots for Preferred/Nonpreferred Stop/Go Trials
Results
Discussion
Preliminary Conclusions


Behavior
PNE rats were more impulsive (as measured by SCRT)

However, they were better at basic task procedures (eg
responding to spatial cue lights)
Neural recordings

Signals from neurons which encode stopping an already initiated
movement were attenuated in PNE rats as compared to controls
Signals from neurons which encode direction towards the correct
behavioral response were also attenuated as compared to
controls
This points to a neurophysiological pathway disruption in inhibiting
impulsivity caused by PNE



Discussion
Future Directions


For my team:

Finish collecting data for additional controls

Complete data analysis

Present data at Society for Neuroscience Conference

Write & present our thesis at the Senior Thesis Conference
For someone else:

Try a different task (or SST with different parameters)

Give nicotine postnatally

Administer ADHD drugs to PNE rats and controls
My Team
Questions?
Questions?