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

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

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

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

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

The Ventral Striatum

Ventral striatum connections are arranged according to a ‘limbic’ gradient Haber and Knutson, 2010 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

From Haber and Knutson, 2010 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.

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

Ventral Striatum Dopamine modulation of reward processing PFC Substantia Nigra DA The dopamine system biases goal-directed behavior based on internal drives and environmental contingencies. 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 Ventral Striatum PFC RewardNO Reward DA For review see Sesack and Grace, 2010

Orbital and medial prefrontal cortex (OMPFC) Price, 2007

The Orbital and Medial Networks of the OMPFC Price, 2007 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.

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 view is supported by the observation that lesion of the orbital network results in deficits in the ability to use reward to guide behavior this network may support the abstract assessment of reward

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

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

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

Phineas Gage 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

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 The amygdala contribution to PFC functions: current stimulus salience Murray et al., 2010

In other instances, the amygdala hampers PFC functions … Murray et al., 2010 “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”

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

PFC Excitatory Inhibitory BLA ITCMITCM SNc/VTA dopamin e CE BNST Hormonal – Autonomic - Motor

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

PFC ExcitatoryInhibitory BLA ITCMITCM Heightened emotional state / Stress SNc/VTA dopamin e CE

A similar mechanisms may be at work in the ventral striatum

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