Brain Circuits Involved in Emotion processing: Cortical and dopaminergic regulation BIOS E 232

1. Brain Circuits Involved in Emotion processing: Cortical and dopaminergic regulation BIOS E 232 Sabina Berretta, MD Harvard Medical School McLean Hospital

2. Plan for today’s class • Journal club presentations and discussion: • Robert Maher Pape HC, Pare D, 2010. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90, 419-463. • Michael Gravina Savage LM, Ramos RL, 2009. Reward expectation alters learning and memory: the impact of the amygdala on appetitive-driven behaviors. Behav Brain Res 198, 1-12. • Today’s seminar: Brain circuits involved in emotion processing: cortical and dopaminergic regulation

3. Outline • Emotion processing in the forebrain: Relationships between ventral striatum, prefrontal cortex and amygdala • Reward circuits: Focus on the ventral striatum • Prefrontal cortex: Emphasis on the orbitofrontal and medial frontal networks • Modulation of these circuits by dopaminergic inputs

4. Somatosensory Inputs (unconditioned) Sensory Inputs (context) The amygdala links sensory stimuli to innate responses BLA CE Relay nuclei Midbrain Pons Medulla HPA axis autonomic response glucocorticoid motor response

5. Prefrontal cortex (PFC) (Generation of strategies, learning sets, higher order rules) Updated affective value Ventral striatum (reward mechanisms) Emotion regulation Updated affective value Primary and associative sensory cortices Amygdala Stimulus affective value Affective value drives emotional attention: enhancement of sensory processing on the basis of salience

6. Reward Mechanisms Reward is a central mechanism for driving incentive-based learning, appropriate responses to stimuli and the development of goal-directed behaviors

7. The Ventral Striatum

8. Ventral striatum connections are arranged according to a ‘limbic’ gradient In the ventral striatum, motivations derived from limbic regions interface with motor control circuitry to regulate appropriate goal-directed behavior. Together these structures form essential components of the circuitry that serves to optimize the behavioral response to rewards and conditioned associations Haber and Knutson, 2010

9. The ventral striatum responds to both primary rewards (e.g.pleasant tastes, smells, sights, sounds, and touch) and secondary, more abstract ones (e.g. monetary gain). It is capable of encoding several aspects of anticipated reward, such as probability/uncertainty, delay and effort. From Haber and Knutson, 2010

10. The Reward Circuits Ventromedial Prefrontal Cortex Orbitofrontal Cortex Anterior Cingulate Cortex Amygdala HP Ventral Striatum Substantia Nigra DA Mediodorsal nucleus of the thalamus Ventral Pallidum

11. Dopamine modulation of reward processing The dopamine system biases goal-directed behavior based on internal drives and environmental contingencies. PFC PFC Reward NO Reward Substantia Nigra Ventral Striatum Ventral Striatum DA DA Behaviors that fail to produce an expected reward decrease dopamine transmission, which favors prefrontal cortical-driven switching to new behavioral strategies. Conditions that result in reward promote phasic dopamine release, which serves to maintain ongoing behavior For review see Sesack and Grace, 2010

12. Orbital and medial prefrontal cortex (OMPFC) Price, 2007

13. The Orbital and Medial Networks of the OMPFC The orbital network is to some extent a sensory-related system. The medial network is more an output system that can modulate visceral function in relation to emotion or other factors. Price, 2007

14. The orbital network • it receives all sensory modalities • encoding of multimodal stimuli related to food is accompanied by encoding of related affective responses, and for for the presence or expectation of reward • this network may support the abstract assessment of reward • this view is supported by the observation that lesion of the orbital network results in deficits in the ability to use reward to guide behavior

15. The Medial network • It is connected to polysensory areas and provides direct inputs to the hypothalamus and periacqueductal grey, as well as to the amygdala, entorhinal cortex and hippocampus. • It is thought to regulate visceral functions, in particular visceral reactions to emotional stimuli • Lesions of the medial-ventral networks in human abolish the normal, automatic visceral responses to emotive stimuli • These individuals are debilitated in their ability to make appropriate choices, although their cognitive intelligence is intact. They do not seem to understand the long term consequences of their actions and choose in favor of immediate reward

16. Acquisition of strategies, learning sets and high-order rules Orbito-medial prefrontal network Knowledge of ordered sequences of events associative sensory cortices, hippocampus, entorhinal and perirhinal cortex Information on current affective valence of stimuli amygdala Information on characteristics of reward and success rates ventral striatum • .

17. Iowa Gambling Task: a simulation of real life choices Normal subjects eventually learn the optimal strategy, selecting from the low-risk decks to obtain long-term gains. Patients with damage to the ventromedial regions of the prefrontal cortex —encompassing the orbitofrontal cortex and ventral aspects of the anterior cingulate— display impaired decision making, making more high-risk choices

18. PhineasGage A prefrontal cortex injury profoundly altered decision making, personality His contractors, who regarded him as the most efficient and capable foreman in their employ previous to his injury, considered the change in his mind so marked that they could not give him his place again. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. In this regard, his mind was radically changed, so decidedly that his friends and acquaintances said he was "no longer Gage." John M. Harlow, 1848

19. The amygdala contribution to PFC functions: current stimulus salience Devaluation task assesses an animal’s ability to link biologically neutral stimuli with reward value. Typically, the task begins when animals consume one kind of food to satiety, thus devaluing it. Later, they choose between a stimulus associated with the devalued food and a stimulus associated with a different food. Intact rats and monkeys avoid choosing stimuli associated with the devalued food, a finding called the devaluation effect; animals with amygdala lesions fail to show this effect Murray et al., 2010

20. In other instances, the amygdala hampers PFC functions … “Serial object-reversal learning task”: the object previously rewarded no longer produces reward when chosen, but choice of the previously unrewarded object always does. “Improvement in amygdala lesioned animals occurs because the amygdala mediates a positive affective response to objects that have a prior history of reward. This positive affective response makes it harder for intact monkeys to avoid choosing the (now) incorrect object after a reversal” Murray et al., 2010

21. The ventromedial prefrontal cortex provide overall control over amygdala emotion processing, and allow behaviors to be suppressed as well as promoted. In doing so, this cortical region plays a critical role in our ability to discern the consequences of our actions (at least in part subconsciously) and make appropriate behavioral choices. Price, 2005

22. PFC BLA ITCM CE SNc/VTA dopamine BNST Excitatory Hormonal – Autonomic - Motor Inhibitory

23. however … Increased dopaminergic tone, as it may occur in the context of heightened emotional states, stress, and disease, may alter this balance

24. PFC BLA ITCM Heightened emotional state / Stress CE SNc/VTA dopamine Excitatory Inhibitory

25. A similar mechanisms may be at work in the ventral striatum

26. Dopamine effects over low/high risk choices Over discrete trials, rats choose to respond on either the certain/small lever that delivers one pellet on every press, or the large/risky lever, that may or may not deliver four pellets. The blockade of DA receptors (flupenthixol) induces risk aversion. In contrast, amphetamine significantly increases risky choice. Floresco et al., 2008