How drug-dependence impacts decision-making Christina M. Gremel, PhD - - PowerPoint PPT Presentation

How drug-dependence impacts decision-making

Christina M. Gremel, PhD University of California, San Diego Department of Psychology and The Neurosciences Graduate Program

niaaa.nih.gov drugabuse.gov

Resources

Goldstein & Volkow, 2011, Nature Reviews Neuroscience

Dependence results in long-lasting changes to the cortex

Alcohol Use Disorder (AUD): AUD is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD can range from mild to sever, and recovery is possible regardless of severity.

• In 2010, alcohol misuse cost the United States $249.0 Billion
• In 2018, 26.45% of people ages 18+ reported that they engaged in binge

drinking in the past month; 6.6 % reported heavy alcohol use in the past month. NIAAA

Cognitive function differences in abstinent alcoholic vs. nonalcoholic groups

Trick et al, 2014, Addiction Biology

Increasing number of detoxifications decreases flexible decision-making

Disrupted decision-making in dependence- disrupted self-control and loss of behavioral flexibility

• Goal-directed; control based on consequences of behavior.

Sensitive to task demands, changing outcome value, changing relationship structure

• Habit; loss of sensitivity to consequences of behavior, i.e. choosing

appropriate strategy, changes in outcome value, changes in action-

• utcome relationship

**observed in: humans, non-human primates, rats, and mice

• Deficit in goal-directed decision-making

common in psychopathologies

• Alterations to goal-directed or model-based

control often reported

Gillan et al., 2016, eLife

However….

• Addiction pathologies also show excessive

goal-directed behaviors (drug choice, economic demand)

Disrupted goal-directed decision-making in numerous Psychopathologies

Lever press training Outcome devaluation Devalued Valued Extinction test

Dias-Ferreira et al., 2009, Science

Identifying behavioral control in decision-making

Balleine, 2019

Emergence of decision-making control over time

Long-term alcohol self-administration leads to reliance on habitual control

e.g., Corbit et al., 2012; 2014 Dickinson, 2002, Lopez et al., 2014

Question: Does alcohol dependence itself change decision- making circuits that are used in everyday life?

Inducing alcohol dependence in mice

CIE CIE CIE CIE Operant Food Training RI/RR DV 12-16 days 2 days 16 hrs EtOH vapor/day, 4 days/week, 4 weeks

increased

• withdrawal severity
• tolerance
• alcohol drinking
• alcohol seeking

Lever Food pellet Context B Random Ratio (Goal-directed) Context A Random Interval (Habitual) Lever Food pellet and

Gremel & Costa, 2013, Nature Communications

Training mice to use both goal-directed and habitual processes.

Prior alcohol dependence biases towards habits

Gremel & Costa, 2013, Nature Communications

Jahanshahi et al., 2015

Cortical-striatal-thalamic circuits

Parallel cortico-basal ganglia circuits support goal-directed versus habitual control

Voorn et al., 2004

Associative cortices & medial striatum: Goal-directed lateral striatum: Habits

Gradient of control over actions

The Orbitofrontal cortex: OFC

• e.g. decreases OFC activation in

response to fearful emotional stimuli (O’Daly et al., 2012,

Multiple detoxes associated with decreased OFC function

• e.g. decreased OFC activity associated

with impaired decision-making (Boettiger et al., 2007)

RI schedule RR schedule

• 2000
• 1000

1000 2000

• 2000
• 1000

1000 2000

Spikes/s Time from lever press (ms)

habit goal Gremel & Costa, 2013, Nature Comm

OFC neurons change activity during decision-making

Lever Food pellet Context B Random Ratio (Goal-directed) Context A Random Interval (Habitual) Lever Food pellet and

OFC damage does not prevent learning

Gremel & Costa, 2013, Nature Comm

Gremel & Costa, 2013, Nature Comm

OFC damage does prevent use of goal-directed control

How to assess the contribution of a brain area without long-term damage: DREADDs

Bryan Roth

• r stop firing.

Gremel & Costa, 2013, Nature Comm

OFC

AAV DREADD

DREADD-inhibition of OFC activity prevents goal-directed control.

How to assess the contribution of a brain area without long-term damage: Optogenetics

Normalized lever presses

OFF ON 0.0 0.5 1.0 Habit Goal-directed

OFC

AAV ChR2

Gremel & Costa, 2013, Nature Comm

Optogenetic control over OFC activity increases goal-directed control.

Normalized lever presses

• Prior alcohol dependence biases against use of

goal-directed control

• Goal-directed activity recruits neural activity in the

Orbital frontal cortex

• Damage or inhibiting the Orbital cortex disrupts

goal-directed activity Question: How does alcohol dependence change the function of the Orbitofrontal Cortex?

CIE CIE CIE CIE Electrophysiological Recordings (3-21 days) Surgery 3-4 weeks

OFC Recording electrode

Air CIE

50 100 150 200 5 10 15 20 25 Current (pA) # of spikes Air CIE

Dependence reduces OFC project neuron excitability

Renteria et al., 2018, Nature Communications,

Gerfen, 2006

OFC projects to the basal ganglia in the brain.

OFC

D1 D2

Direct pathway of the Basal Ganglia “Promotes” wanted behaviors Indirect pathway of the Basal Ganglia “Reduces” unwanted behaviors

We wanted to look at how OFC talks to the basal ganglia

= Glutamate, excitatory neurotransmitter

AAV5-CAMKII-Cre OFC Recording electrode Optical stimulation DMS DIO-ChR2 +

D1 D2

CIE CIE CIE CIE Electrophysiological Recordings (3-21 days) Surgery 3-4 weeks

We wanted to look at how OFC talks to the basal ganglia

Air CIE

50 100 150 200 250 0.5 1.0 1.5 ISI (ms) PPR (oEPSC 2/oEPSC 1) D1 Air D1 CIE

**** ** ** *

D1 Air D1 CIE 5 10 15 Frequency (Hz)

**

D1 Air D1 CIE 5 10 15 Amplitude (pA)

Air CIE

50 100 150 200 250 0.5 1.0 1.5 ISI (ms) PPR (oEPSC 2/oEPSC 1) D2 Air D2 CIE

D2 Air D2 CIE 5 10 15 Amplitude (pA) D2 Air D2 CIE 5 10 15 Frequency (Hz) Renteria et al., 2018 Nature Communications

Dependence decreases OFC communication onto the direct, but not indirect, basal ganglia output pathway

OFC

D1 D2

Alcohol dependence reduces the excitability

• f OFC neurons

Alcohol dependence reduces the release

• f transmitter onto the direct pathway of

the basal ganglia

= Glutamate, excitatory neurotransmitter

• Prior alcohol dependence reduces the activity of

OFC neurons

• Prior alcohol dependence reduces the ability of

OFC to talk to downstream Basal Ganglia

• Prior alcohol dependence disrupts use of goal-

directed control Question: Can we restore OFC activity in alcohol dependence, thereby rescuing Goal-directed control?

CIE CIE CIE CIE Surgery 1-3 weeks Operant Food Training RI/RR DV CNO/saline

B.

DIO hM3Dq or mCherry control OFC

B: 2.58 mm B: 2.80 mm B: 2.68 mm

DREADD activation of OFC in alcohol dependent mice

Renteria et al., 2018 Nature Communications

• Provide information to pre-clinical research groups
• Can use these findings to investigate molecular

mechanisms and potentially identify targets for drug therapies to aid in recovery

• Pertinent to the design of TMS studies and examining

effects of cognitive behavioral therapy Why is this useful?

Diana et al., 2017 Nature Reviews Neuroscience

Future ways to alter circuit function in humans

Thank you and I look forward to your questions!