Dopamine Modulates the Reward Experiences Elicited by Music

Post by Flora Moujaes

What's the science?

Humans experience pleasure from abstract rewards, such as music, that do not confer any direct advantage for survival. Understanding how the brain translates music, a sequence of sounds, into a pleasant rewarding experience remains a challenge. Reward can be divided into three neurobiologically distinct components: hedonic pleasure (in-the-moment liking), motivation (or wanting), and learning. The role of dopamine in motivation and learning has been widely established in the animal literature, but dopamine’s function in hedonic pleasure is more controversial. Animal literature has tended to focus on primary rewards such as food and sex, rather than abstract rewards such as music. This week in PNAS, Ferreri and colleagues used a pharmacological intervention to explore for the first time whether dopamine function is causally related to the pleasure we experience from music, and how it influences both hedonic pleasure and motivation.

How did they do it?

Researchers manipulated dopamine transmission in 27 human participants while they listened to music in three different sessions, each at least a week apart. The authors began by orally administering either levodopa (a dopamine enhancer), risperidone (a dopamine blocker), or lactose (a placebo). Participants then listened to five of their favourite musical excerpts and 10 pop songs selected by the experimenters, which included a range of artists from Antonio Orozco to Taylor Swift. Pleasure responses were measured continuously 1) by participants indicating in real-time the degree of pleasure they were experiencing and 2) by measuring electrodermal activity: changes in the electrical properties of the skin that are related to emotional arousal. Motivational responses were measured using an auction paradigm, where participants indicated how much money they were willing to part with to buy the song. Finally, participants also completed a well-validated reward control task (the Monetary Incentive Delay Task) in order to verify that any changes caused by dopamine were related to the reward system, and not more general processes.

What did they find?

Researchers predicted that if dopamine plays a causal role in music-evoked reward, enhancing dopamine through levodopa and reducing dopamine through risperidone should lead to opposite effects regarding musical pleasure and motivation. In line with their prediction, they found that administration of levodopa and risperidone led to opposite effects: levodopa led to an increase in the experience of ‘chills’ or goose bumps, a common indicator of musical pleasure, while risperidone resulted in a decrease in chills. Electrodermal activity and participants’ ratings also indicated that they experienced an increase in pleasure when listening to music following dopamine enhancement and a decrease in pleasure following dopamine impairment. In contrast to much of the animal literature, this suggests that dopamine causally influences the hedonic pleasure experienced while listening to music. Participants bid significantly more money for songs under levodopa than risperidone, indicating that dopamine is also causally involved in motivational reward responses. The dopamine-induced changes in reward responses were paralleled by those observed in the control Monetary Incentive Delay task, suggesting that the effects seen while listening to music were a result of dopamine’s modulation of the reward system rather than of more general processes.

What's the impact?

This study is the first to show that dopamine function is causally related to the pleasure we experience from music, influencing both hedonic pleasure and motivation. More broadly, these findings begin to shed light on the more complex role the human dopaminergic system plays in abstract rewards. Musical pleasure also depends on additional affective and abstract cognitive processes (e.g. episodic memory). Given these additional processes also rely on dopaminergic transmission, further research is needed to determine whether dopamine generates the hedonic and motivational responses to music or whether it interacts with other neurotransmitter systems (e.g. the opioid system) to generate such responses.

Ferreri et al. Dopamine modulates the reward experiences elicited by music. PNAS (2019). Access the original scientific publication here.

Hippocampal-Accumbens Pathway Drives Memories of Reward-Seeking Behavior

Post by Lincoln Tracy

What's the science?

Being able to recall specific memories of where to find food – a reward-seeking behavior – is a fundamental part of survival. In mammals, pyramidal cells in the dorsal hippocampus store memories of the environment around us. The nucleus accumbens (part of the ventral striatum) plays an important role in connecting memory and the motor system to process reward-driven behaviors such as eating. Research suggests suggesting a functional connection between the dorsal hippocampus and the nucleus accumbens, however, little is known about whether hippocampal pyramidal cells and nucleus accumbens neurons are connected to one another and how they interact. This week in Cell, Trouche and colleagues used in vivo electrophysiological recordings, viral vector-mediated tracing, and intersectional trans-synaptic optogenetics to understand how hippocampal pyramidal cells interact with nucleus accumbens neurons to use memories of the surrounding environment in reward-seeking behavior.

How did they do it?

The authors first used electron microscopy to investigate whether hippocampal pyramidal cells connect and interact with nucleus accumbens neurons by labelling pyramidal cells in mice with green fluorescent protein. Next, the authors investigated whether pyramidal cell activity was required for using memories of the surrounding environment in reward-seeking behavior. They used a conditioned place preference task in which mice formed memories between entering one of two different chambers and a reward (sucrose). The conditioned place preference task involved three stages: (1) a pre-test session to determine which chamber the mice preferred without any stimulus or reward present; (2) a conditioning session in which the mice explored their non-preferred chamber (using sucrose as bait) and then their preferred chamber (using water as bait); and (3) a test session where conditioned place preference memory was assessed –whether the mice spent more time in the chamber that contained sucrose or the one that contained water. The authors implanted electrodes in the CA1 region of the dorsal hippocampus to record pyramidal cell activity while the mouse completed the conditioned place preference task. They also implanted optic fibers in the dorsal hippocampus and nucleus accumbens so they could use light to turn off different cells in these brain regions (i.e., pyramidal cells and parvalbumin-expressing interneurons).

What did they find?

The authors found a direct pathway connecting hippocampal pyramidal cells to nucleus accumbens medium spiny neurons, providing the first evidence for a link between dorsal hippocampal pyramidal cells and nucleus accumbens neurons. Electrode recordings revealed patterns of dorsal hippocampal pyramidal cell activity during the pre-test component of the conditioned place preference task, representative of the mice forming memories about the different chambers. These firing patterns returned during the test phase of the conditioned place preference task, coinciding with the amount of time spent in the sucrose-containing chamber. When the dorsal hippocampal pyramidal cells were silenced via the optic fibers, the mice spent less time in the sucrose-containing chamber – and the dorsal hippocampal firing patterns decreased during the test phase of the task.

Therefore, remembering the location of sucrose – and subsequently seeking the sucrose out depended on dorsal hippocampal pyramidal cell firing. When the axon terminals of the pyramidal cells in the nucleus accumbens were silenced during the conditioned place preference test phase the mice still explored the two chambers – but they spent less time in the sucrose-containing chamber. When the authors silenced parvalbumin-expressing interneurons in the nucleus accumbens they saw the same result – the mice explored the conditioned place preference apparatus but spent less time in the sucrose-containing chamber during the test phase. These results suggest that interrupting the hippocampal-nucleus accumbens pathway prevented the ability to form and use memories of the surrounding environment in reward seeking behavior.

What's the impact?

This study provides evidence that the dorsal hippocampal – nucleus accubmens pathway represents an interaction point between memory and motor processes when recalling information about reward-seeking behavior.  Pyramidal cells from the hippocampus connect to medium spiny neurons and parvalbumin-expressing interneurons in the nucleus accumbens – and all three cell types are required in using spatial memory to drive reward seeking behavior. This study suggests that this pathway could be important in several aspects of linking memory and motor behavior.

Trouche et al. A hippocampus-accumbens tripartite neuronal motif guides appetitive memory in space. Cell (2019).Access the original scientific publication here.

Neural Circuit Underlying Long-Lasting Treatment for PTSD

Post by Deborah Joye

What's the science?

Post-traumatic stress disorder (PTSD) is a condition in which individuals experience persistent anxiety, flashbacks, and intense fear after a traumatic event. PTSD treatments vary and can include everything from exposure therapy and cognitive processing therapy to medications such as antidepressants. One current treatment for PTSD uses a process called Eye Movement Desensitization and Reprocessing (EMDR), which has patients recall a traumatic memory while they track a flashing light switching from left to right (called Alternating Bilateral Sensory Stimulation or ABS). This treatment effectively directs visual stimulation and eye movements, resulting in reduced fear responses. This method has successfully been used to treat PTSD, but how it might result in long-lasting weakening of fear responses remains a mystery. The role of eye movements and orientation in the technique suggests involvement of the superior colliculus, a region of the midbrain involved in eye movements, head orientation, and distractibility. This week in Nature, Baek and colleagues investigate the neural circuitry underlying long-lasting reduction in fear when fear extinction is paired with ABS in mice.

How did they do it?

To test the effects of visual stimulation in fear conditioned mice, the authors trained mice to associate a sound with a mild foot shock. The authors then put those mice in a cylinder with a line of LEDs installed around the wall and played the sound without the additional foot shock (fear extinction). Mice undergoing fear extinction were simultaneously exposed to one of three lighting conditions: 1) LEDs were continuously lit, 2) all LEDs flashed on and off at the same time or 3) LEDs were sequentially lit, then turned off in alternating directions (mimicking ABS). The authors then measured activity using single-unit recordings in the superior colliculus and the mediodorsal thalamus, a brain region which receives information from the superior colliculus and is also tightly linked to the prefrontal cortex and the amygdala (main regions involved in fear extinction). To test how the ABS lighting condition might be associated with reduced fear responses, the authors performed single-unit recordings in the basolateral amygdala, which has at least two distinct cell populations, one that is active during the fear state, and another that is active when fear is being extinguished. Finally, to assess whether the superior colliculus to mediodorsal thalamus (SC-MD) projection and/or the mediodorsal thalamus to basolateral amygdala (MD-BLA) projection play a causal role in the fear-attenuating effect of ABS, the authors used optogenetics. They then either inhibited or excited the two different projections (SC-MD or MD-BLA) to determine the effect on fear responses.

What did they find?

First, the authors found that pairing ABS with fear extinction resulted in an overall reduced fear response compared to all other groups. This finding was specific to the pairing of ABS with fear extinction as mice who experienced ABS when the sound wasn’t played did not show the same reduction in fear. The authors also found that the ABS fear extinction increased the number of activated cells within the superior colliculus. The magnitude of superior colliculus activation for each mouse was negatively correlated with fear response (more activation resulted in lower fear response). When the authors used optogenetics to specifically excite or inhibit the SC-MD pathway, they found that inhibition of the SC-MD pathway resulted in increased fear and stimulation of this pathway resulted in decreased fear. Single-unit recordings in the amygdala revealed that ABS paired with fear extinction increased the number of inhibited neurons in that region. The authors that inhibited cells in the amygdala were neurons that encode the fear state (versus other cells that encode the fear extinction state). They also found that the inhibitory effects of ABS paired extinction in the basolateral amygdala persisted for at least a week after extinction training. Finally, using optogenetics, the authors found that inhibition of the MD-BLA pathway completely blocked the fear-attenuating effect of ABS, suggesting that this pathway is required for fear attenuation.

What's the impact?

This study is the first to describe the neural circuitry that may underlie the therapeutic effects of eye movement desensitization and reprocessing (EMDR). Understanding the biological basis for how therapeutic treatments work can provide new ways to strengthen treatment plans resulting in better patient outcomes and efficient, targeted therapies. The findings of this study present a neural pathway consisting of the superior colliculus, mediodorsal thalamus, and the basolateral amygdala which could be a central target for the effective treatment of PTSD.

Baek et al., Neural circuits underlying a psychotherapeutic regimen for fear disorders, Nature (2019), Access the original scientific publication here.