Olfaction is one of the most well studied, yet often elusive sensory systems. This is because while the biochemical events facilitating odorant transduction into neural activity have been well documented, the organization of this activity into large-scale and higher-order neural representations important for cognitive appraisal is unclear. As such, this sensory system in particular represents a growing body of research with critical implications about the way in which we think, evaluate sensory information, and learn from our behaviors. Here, I will first outline what we, up to the present moment, have learned about olfaction; next, I will offer a brief analysis on the importance of these findings and the conclusions they allow us to arrive at; lastly, I will discuss the implications of these findings for real-world behavior and therapeutic intervention.
I: Understanding Olfaction
The biochemical events surrounding olfactory transduction are well established. Odorants, which are a whole host of chemical compounds from the external world, are inhaled through the nose or mouth and reach the olfactory neuroepithelium in the nasal cavity. Olfactory receptor neurons (ORNs) embedded within this neuroepithelium serve to transduce incoming chemical information into electrical activity, providing the first step in the olfactory pathway.
Three important observations must be discussed in the context of ORNs. Firstly, these are bipolar neurons, with an apical dendritic region forming cilia across the epithelial surface, and a basal axonal component projecting through the cribriform plate towards the olfactory bulb. Secondly, each ORN expresses a particular type of receptor and each receptor will only bind to odorants possessing similar molecular features, such that different odorants will bind to different kinds of ORNs (Buck & Axel 1991). Once odorants successfully bind to the receptors in the cilia of their target neuron, a biochemical cascade is initiated in which activation of a G-protein leads to an influx of Na+ and Ca2+, neuronal depolarization, and generation of action potentials ascending towards the bulb. Lastly, ORNs are located in a rather tumultuous environment, easily accessible to noxious chemicals that may degrade them, or physical traumas (like those obtained in car crashes) that may sever their axonal projection at the level of the cribriform plate.
While ORNs are one of the few types of neurons with robust regeneration capabilities due to neighboring basal cells, disruption at any of these three levels may nonetheless lead to anosmia, a partial (or in more severe cases, total) attenuation in the ability to smell. Furthermore, the olfactory system is not its own distinct system, but interacts heavily with other sensory pathways (such as the gustatory pathway). Indeed, the olfactory system receives top-down feedback from the cerebral cortex and can be modulated by attention. This process, called multisensory integration, accounts for the finding that patients with anosmia as a result of ORN damage will display symptoms like loss of taste, weight loss, appetite suppression, emotional and motivational changes, and the onset of depression.
The next step in the olfactory sensory pathway occurs when ORN axons arrive at the highly organized olfactory bulb, the first site of further odor processing. Here, the axonal projections of the ORNs synapse at circular clusters of nerve endings called glomeruli, in which information from many ORNs is converged and chemically transferred to a small number of mitral cells that carry the olfactory input to higher level brain regions. What is fascinating about this interaction is that it represents a point of massive sensory segregation where all the ORNs responding to a particular odorant converge on the same glomerulus, and as such, different glomeruli respond to information about different odors. In this way, input from a diffuse population of ORNs is converged and highly organized into a clearly identifiable map of glomerular activity (Bozza et al., 2004), with each type of odorant triggering a unique neural pattern decoded in higher olfactory centers (i.e. population coding).
There is, however, a massive gap in our current understanding of the higher-order components of olfaction. Beyond the two findings, that information from the bulb initially bypasses the thalamus in favor of the olfactory/piriform cortex, the limbic system, and several neocortical structures, and that smell is one our most primitive sensory systems, much less is known about further steps in the olfactory pathway. In particular, there is a massive gap in the literature with respect to how the brain turns glomerular information from the bulb into a perception of odor on to which meaning, value, memory, and emotional importance are superimposed – issues at the very heart of recent neuroscientific inquiry.
From our general outline of olfaction, from odorant to cortex, we can come to appreciate a few important conclusions about this sensory system. Firstly, olfaction depends upon population coding to identify the thousands of smells we can consciously perceive. This is true from the activation of specific ORNs, to the organization of the glomeruli, and even in the patterns of neural activation in the primary olfactory cortex (i.e. piriform). Population coding is of critical importance because, similarly to its role in other sensory modalities, it allows us to be sensitive to a huge spectrum of different smells and to very finely distinguish between them. Furthermore, population coding gives us highly accurate sensitivity to changes in odorant concentration and can even allow us to distinguish between enantiomers of the same chemical compound. Indeed, we owe much of the specificity and diversity of our olfactory perceptions to the role of population coding.
Another important feature of olfaction, as discussed previously, is its synchronous activity with many other sensory systems through a process called multisensory integration. Sensory perception, as our discussion of anosmia suggests, is not merely a hierarchical pyramid ascending from each sensory modality to the cortex; instead, it’s important to realize that different systems communicate with one another and receive descending inputs from the cerebrum. In a field of neuroscience in which hyper-specialization of our scientific interests is common, the relevance of our olfactory system in memory, emotion, motivation, and depression, raises the importance of understanding the brain as holistic and wholly interconnected. It is only by being mindful of how different systems can operate synergistically or antagonistically with one another can we truly appreciate the complexity of the brain’s structure and function.
Perhaps most strikingly, our olfactory system reiterates the sentiment that sensory perceptions are Kantian phenomena, such that our brains do not accurately represent the world as it exists, but instead distort it into salient representations of value. A recent body of work has identified three higher-level brain regions that are necessary for odor perception. These regions include the piriform cortex (which codes for odor identity), and then the orbitofrontal cortex (which associates odors with reward), and finally the medial prefrontal cortex (which is necessary for odor discrimination learning). Of important note is the finding, using anatomic tracing, that the piriform “…discards the spatial patterning of the bulb…” such that this brain region receives input from a seemingly random set of glomeruli, with no regard for the organized map of activity that was previously constructed in the bulb (Stettler and Axel, 2009). Because the olfactory information in the piriform is randomly arranged, this means that every individual has a differential activation of neurons, at the piriform and beyond, in response to a particular odorant. As such, our responses to most odors are not innately defined, but can only be attributed significance due to learning (Wang et al., 2020). Furthermore, our experience of odorants – indeed, our experience of the world more broadly – is subjective and uniquely personal. This has massive implications about the nature and feasibility of objective reality, encouraging us to question the biases and prejudice we may hold with respect to all our sensory perceptions.
III: Behavioral Implications
Our initial outline of the structure and function of the olfactory system allowed us to conclude three things: olfaction is specific and diverse, it is implicated in memory, emotion, and motivation, and it is developed on account of experiential learning. A massive implication of these conclusions is the diversity of behavioral responses we can expect from different odors on account of our memories. This is consistent with the idea that the smell of alcohol, for example, might allow one person to fondly remember a late night out, a second person to feel nauseous when remembering a bout of alcohol poisoning, and a third person to feel scared at the memory of almost getting pulled over for a DUI. Furthermore, while the smell of meat may be enticing to someone who is hungry (representing a large reward), it may elicit a neutral, or even aversive behavioral response in someone who is full, implying the role of internal context in olfactory-driven behaviors as well. While the odorant remains the same across participants, their episodic memories of past experiences, the emotional value they have attached to those memories, and their internal context, shapes their behavioral outcome to odorants. Next, our discussion of the shallowness of the olfactory circuit, such that it circumvents the thalamus and directly projects to limbic areas including the amygdala, suggests that the olfactory system can elicit the four F’s (fighting, fleeing, foraging, and mating), and do so without initial thalamic processing.
These findings allow us to think of many cognitive therapies and rehabilitation strategies to help those who may have odor-related phobias or suffer from obesity. Since our responses to odors are largely learned, it goes without saying that any therapeutics we may recommend for those with olfactory-related issues must be tailored to the individual. Exposure therapies over long periods of time, or reversal learning therapies where previously negative odors are subsequently rewarded, may allow for extinction of the panic and fear that certain odors may initially elicit (for instance, the smell of smoke for someone who almost died in a fire, or the smell of gunpowder for a soldier experiencing PTSD). Furthermore, since downregulation of the olfactory system (as a result of damage or inflammation) has been implicated in reduced appetite and taste, this system may also be a possible therapeutic target for those suffering from binge eating disorder or obesity. Introducing drugs that downregulate olfactory transduction, plugging one’s nose during mealtime, or associating certain unhealthy foods with nausea-inducing odors, may curb appetite and lead to behavioral changes. Furthermore, frequently exposing oneself to smells one associates with pleasurable experiences (potentially in the form of sprays or scented candles), might be a very easy way to boost mood throughout the day. Importantly, therapeutics, such as the ones mentioned above, might not only help people deal directly with their illnesses, but may also reduce the growing cost of these disorders on the global economy and healthcare system. Ultimately, since our olfactory system is highly diverse, interactive, and personal, we must express great care when trying to treat its disorders or influence particular behaviors.
Bozza, T., McGann, J.P., Mombaerts, P., and Wachowiak, M. (2004). In vivo imaging of neuronal activity by targeted expression of a genetically encoded probe in the mouse. Neuron 42, 9–21.
Buck, L., and Axel, R. (1991). A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175–187.
Stettler, D.D., and Axel, R. (2009). Representations of Odor in the Piriform Cortex. Neuron 63, 854–864.
Peter Y. Wang, Cristian Boboila, Philip Shamash, Zheng Wu, Nicole P Stein, L.F.Abbott, Richard Axel (2020). The Imposition of Value on Odor: Transient and Persistent Representations of Odor Value in Prefrontal Cortex