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

Resources niaaa.nih.gov drugabuse.gov

Dependence results in long-lasting changes to the cortex Goldstein & Volkow, 2011, Nature Reviews Neuroscience

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 Increasing number of detoxifications decreases flexible decision-making Trick et al, 2014, Addiction Biology

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

Disrupted goal-directed decision-making in numerous Psychopathologies • Deficit in goal-directed decision-making common in psychopathologies • Alterations to goal-directed or model-based control often reported However … . • Addiction pathologies also show excessive goal-directed behaviors (drug choice, economic demand) Gillan et al., 2016, eLife

Identifying behavioral control in decision-making Outcome devaluation Valued Devalued Lever press training Extinction test Dias-Ferreira et al., 2009, Science

Emergence of decision-making control over time Balleine, 2019

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 12-16 days 2 days 16 hrs EtOH vapor/day, 4 days/week, 4 weeks Operant Food Training RI/RR DV CIE CIE CIE CIE increased withdrawal severity • tolerance • alcohol drinking • alcohol seeking •

Training mice to use both goal-directed and habitual processes. Context A and Context B Food pellet Food pellet Lever Lever Random Interval Random Ratio (Habitual) (Goal-directed) Gremel & Costa, 2013, Nature Communications

Prior alcohol dependence biases towards habits Gremel & Costa, 2013, Nature Communications

Cortical-striatal-thalamic circuits Jahanshahi et al., 2015

Parallel cortico-basal ganglia circuits support goal-directed versus habitual control Associative cortices & medial striatum: Goal-directed lateral striatum: Habits Gradient of control over actions Voorn et al., 2004

The Orbitofrontal cortex: OFC

Multiple detoxes associated with decreased OFC function • e.g. decreased OFC activity associated • e.g. decreases OFC activation in with impaired decision-making (Boettiger et response to fearful emotional stimuli al., 2007) (O’Daly et al., 2012,

OFC neurons change activity during decision-making RR schedule RI schedule goal habit Spikes/s -2000 -1000 0 1000 2000 -2000 -1000 0 1000 2000 Time from lever press (ms) Gremel & Costa, 2013, Nature Comm

OFC damage does not prevent learning Context A and Context B Food pellet Food pellet Lever Lever Random Interval Random Ratio (Habitual) (Goal-directed) Gremel & Costa, 2013, Nature Comm

OFC damage does prevent use of goal-directed control Gremel & Costa, 2013, Nature Comm

How to assess the contribution of a brain area without long-term damage: DREADDs or stop firing. Bryan Roth

DREADD-inhibition of OFC activity prevents goal-directed control. AAV DREADD OFC Gremel & Costa, 2013, Nature Comm

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

Optogenetic control over OFC activity increases goal-directed control. Normalized lever presses 1.0 AAV ChR2 Normalized lever presses Habit Goal-directed OFC 0.5 0.0 OFF ON Gremel & Costa, 2013, Nature Comm

• 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?

Dependence reduces OFC project neuron excitability 3-4 weeks Electrophysiological Recordings CIE CIE CIE CIE (3-21 days) Surgery 25 Air Recording CIE 20 # of spikes Air electrode 15 OFC 10 5 0 CIE 0 50 100 150 200 Current (pA) Renteria et al., 2018, Nature Communications,

OFC projects to the basal ganglia in the brain. Gerfen, 2006

We wanted to look at how OFC talks to the basal ganglia OFC = Glutamate, excitatory neurotransmitter D1 D2 Indirect pathway of the Direct pathway of the Basal Ganglia Basal Ganglia “Reduces” “Promotes” unwanted behaviors wanted behaviors

We wanted to look at how OFC talks to the basal ganglia 3-4 weeks Electrophysiological Recordings CIE CIE CIE CIE (3-21 days) Surgery AAV5-CAMKII-Cre + DIO-ChR2 Optical stimulation Recording OFC electrode DMS D1 D2

Dependence decreases OFC communication onto the direct, but not indirect, basal ganglia output pathway Air CIE PPR (oEPSC 2/oEPSC 1) 1.5 **** 15 15 ** ** Frequency (Hz) Amplitude (pA) D1 CIE * D1 Air 1.0 10 10 ** 5 5 0.5 0 0 50 100 150 200 250 D1 Air D1 CIE D1 Air D1 CIE ISI (ms) Air CIE PPR (oEPSC 2/oEPSC 1) 1.5 15 15 Frequency (Hz) D2 CIE Amplitude (pA) D2 Air 1.0 10 10 5 5 0 0 0.5 50 100 150 200 250 D2 Air D2 CIE D2 Air D2 CIE ISI (ms) Renteria et al., 2018 Nature Communications

Alcohol dependence reduces the excitability OFC of OFC neurons Alcohol dependence reduces the release of transmitter onto the direct pathway of the basal ganglia D1 D2 = 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?

DREADD activation of OFC in alcohol dependent mice CNO/saline Operant Food Training 1-3 weeks CIE CIE CIE CIE DV RI/RR Surgery DIO hM3Dq or B. mCherry control B: 2.58 mm B: 2.68 mm OFC B: 2.80 mm Renteria et al., 2018 Nature Communications

Why is this useful? • 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

Future ways to alter circuit function in humans Diana et al., 2017 Nature Reviews Neuroscience

Thank you and I look forward to your questions!