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Murthy Lab Investigates the Formation of “Smell Memories”

Murthy Lab Investigates the Formation of “Smell Memories”

Good or bad experiences associated with smells are thought to become strongly ingrained in memory, even more so than memories associated with sights, sounds, and other senses. Where and how do these smell associations get encoded and stored in the brain, and are there notable differences between smells associated with good vs. bad experiences? Researchers from the Murthy Lab, led by postdoc Nuné Martiros, report their findings on these questions in a new paper published in the journal eLife. 

Martiros and colleagues hypothesized that an ancient, evolutionarily-conserved brain connection between the olfactory sensory neurons in the nose and the ventral striatum, an emotion and reward related region of the brain that may be involved in the formation of “smell memories.” Since this link has very few intermediate stations (only the olfactory bulb), smells may have privileged access to the ventral striatum, unlike all other senses. 

To pursue this idea, the Murthy Lab trained mice to associate some odors with positive consequences and some odors with negative consequences. At the same time, they used 2-photon microscopy to visualize the activity of neurons in a region of the ventral striatum called olfactory tubercle in living mice as they smelled the odors. Two of the odors predicted water reward for these thirsty mice; while two other scents predicted mild air-puffs to their faces, and one odor led to no outcome. 

There are two kinds of neurons in this area that have different sensors for the neurotransmitter dopamine, which is intimately involved in learning or reinforcing experiences. These two neuron types are termed D1 medium spiny neurons and D2 medium spiny neurons. Researchers from the Murthy Lab found that the activity of neurons expressing D1 receptors reflects whether the mouse is smelling a good or bad odor and does not reflect the chemical identity of the smell. So, they might respond similarly to a lemon and a vanilla odor, as long as they are both odors that are associated with a positive memory (in this case a water reward). These D1 neurons can tell apart the good and bad odors very well even when the mouse is not reacting to those odors through behaviors, suggesting that D1 neurons encode the memory itself and not the action. 

Neurons with D2 type dopamine receptors, however, don’t tell apart good and bad odors very well and respond mostly to the actual identity of the odorant. For example, they might be activated in response to a lemon smell regardless of whether it was associated with a positive or negative memory, and a vanilla smell may be encoded differently even if it predicts the same outcome as the lemon odor. The D2 neurons may, therefore, help the mouse identify what the odor actually is, while D1 neurons tell the mouse whether it was good or bad. 

Although odors have a more direct neural route to the olfactory tubercle, other sensory cues such as sounds also reach this brain region via indirect routes. The next question is whether and how neurons in the olfactory tubercle respond to different sounds (e.g. different tones) that are associated with good or bad outcomes. Martiros and her colleagues found that far fewer neurons are activated by sounds compared to odors, but nevertheless some neurons in the olfactory tubercle do respond to sound stimuli. However, the different sensory modalities–sounds and odors–are not integrated in the olfactory tubercle, since different sets of neurons respond to sound and odor cues associated with the same outcome. Such multimodal integration of cue values must happen in another downstream brain region. 

Overall, these findings implicate the olfactory tubercle and the ventral striatum in the formation of olfactory associations in mice. These findings will catalyze further mechanistic studies of how neurons and their connections in a key brain region are altered during formation of value-based associations and how they are altered in maladaptive behaviors.


(l to r) Vikrant Kapoor, Spencer Kim, Nuné Martiros, and Venki Murthy. (photo by Souvik Mandal)

(l to r) Vikrant Kapoor, Spencer Kim, Nuné Martiros, and Venki Murthy. (photo by Souvik Mandal)