There is a widespread belief that olfaction, or the sense of smelling, is not something humans are particularly good at. But an emerging opinion says that human olfaction is a different kind of special: while it is true that 60 percent of our genes coding for olfactory receptors are functionless compared to only 20 percent in mice (Mombaerts, 2004), we are eight times more efficient at using the remaining 40 percent (Maresh et al., 2008). One study would even suggest that our limited lexicon for the odor world is a clear indication that “odors may interfere specifically with language and vice versa” (Lorig, 1999). Here I shed light on the recent discovery of a neurogenic process unique to the human brain (the striatum in specific) and how it might share the cellular makeup of olfactory processing in other mammals. Surprisingly, the underlying recruitment of common subtypes of neurons indicates a similar associative role in both circuits and could thus expand the endeavor of neuroscience to unravel the brain’s involvement in human decision making and therefore ultimately shed light on one aspect of consciousness.

First, imagine a brain mass the size of two walnuts stuck to the front of a human brain and you’ll have a rough idea of what a mouse brain would look like. These clumps are the olfactory bulbs (OBs), only that in humans they’re more like peas and are attached from below – this has long been the convincing answer to explain the terrible smellers that we are believed to be. What is more remarkable about the OB is that it is one of only two accepted sites in mammals that witness continuous regeneration of brain cells long beyond embryonic development (Ming and Song, 2011). In the hippocampus, adult neurogenesis also produces new neurons with a slight variation in its dynamics between humans and mice (Spalding et al., 2013) such that it arguably contributes to memory consolidation and spatial learning (Aimone et al., 2014). But while the OBs of an adult mouse receive a nonstop massive flow of neurons from the relatively distant hub of dormant stem cells (known as the subventricular zone or SVZ), the pea-shaped human OBs can barely accommodate newborn neurons (Bergmann et al., 2012). Yet, compared to adult mice, the human SVZ also maintains a robust neurogenic activity (Wang et al., 2011). So where are these neurons going?

In 2011, Nader Sanai and colleagues found that in human neonates aged 4-6 months, some SVZ migrating neurons deviate from their known route to the OB (named the Rostral Migratory Stream or RMS) to form a more inclined stream (the Medial Migratory Stream or MMS) destined to the prefrontal cortex (the ventromedial PFC in particular, sometimes called the medial Orbitofrontal Cortex mOFC) (Sanai et al., 2011). A recent follow up study further emphasized this to include extensive tangential migration to several cortical regions of the infant human frontal lobe (Paredes et al., 2016). However, these observations were limited to the first 18 months of age and therefore cannot explain the absence of SVZ migratory corridors in humans beyond that period. Yet in 2014, Aurélie Ernst and colleagues unraveled an additional site for adult neurogenesis unique to the human striatum (Ernst et al., 2014). They would later argue that a shift in Doublecortin (DCX) expression ratios (a marker of neuronal migration) can reasonably explain why the human OB would shrink in size to nearly inexistent at a time the normalized striatal volume is around three folds that of mice (Ernst and Frisén, 2015) which means that human SVZ neurons could have gone, to use Gerd Kempermann’s words, “off the beaten track” as compared to other mammals. But it remains unclear why the human striatum would possess this unique “permissiveness” in the first place to attract SVZ neurons and manage their successful integration to a new circuit (Kempermann, 2014).

This finding is not without controversy, as other studies have specifically argued against SVZ-derived striatal neurogenesis (Paredes et al., 2015). However, the story does not end here. SVZ stem cells are undifferentiated and can therefore specialize in a broad spectrum of brain cells (both neuronal and glial), but there is a reason to believe that they are slightly committed to specific differentiation programs which depend, for instance, on their spatial positioning in the SVZ (Fiorelli et al., 2015). As a result, adult-born striatal neurons might not only be derived from the SVZ but if so, they are likely to share some functional attributes with their next-of-kin OB equivalents as both subtypes got initiated in the same SVZ niche. Existing studies show that this hypothesis is not far-fetched, where an induced stroke in the mouse middle cerebral artery causes substantial SVZ proliferation and migration to the nearby damaged striatum, only to be followed by massive cell death probably due to “an unfavorable environment with lack of trophic support and connections” (Arvidsson et al., 2002). Nonetheless, one population is spared (Calretinin-expressing cells) and was found to accumulate in the striatum for longer periods after stroke (Liu et al., 2009). These cells are preferentially derived from the medial and dorsal SVZ domains, and are the main subtype to be regenerated in the adult mouse OB (Fujiwara and Cave, 2016). Remarkably, these cells are also the same subtype of neurons expressed in the adult human striatum under normal conditions (Ernst et al., 2014).

Other, though less compelling, evidence comes from the field of neuroeconomics: although it is now thought to act as a task space for outcome expectancies, the rat mOFC circuit has 25% of its neurons acting as flexible encoders in the reversal of associative information, i.e. odor discriminations in the case of rats (Schoenbaum et al., 2011). Similarly, the striatum functions to evaluate stimuli and actions (Pauli et al., 2016) and its deterioration in Huntington’s disease (HD) causes “inflexibility in adapting behavior to changing reward contingencies” (van Wouwe et al., 2016). Better yet, a decline in human striatal neurogenesis was correlated with a higher incidence of HD (Ernst et al., 2014). All this is reminiscent of the described role of adult-born neurons in the rodent OB where they act to facilitate difficult odor associative learning and olfactory memory (Alonso et al., 2012), hence mediating the circuit’s adaptation and flexibility (Lazarini and Lledo, 2011).

Thus, recent studies suggest that SVZ derived cells share a common developmental lineage and hence a functional homology across humans and mice. This finding allows modeling of olfactory disorders in mice in order to mimic cognitive ailments of the human OFC and striatum. Perhaps even more interestingly, it contributes to our understanding of how smell impairment is correlated with dysfunctional cognitive control in tobacco smokers (Vennemann et al. 2008, Fecteau et al. 2014) or how major depressive disorder (MDD) is correlated with smaller OB volumes (Schablitzky et al. 2014), especially when the complete removal of OBs in mice, an established model of depression, can reversibly damage the SVZ neurogenic activity (Keilhoff et al., 2006). Finally, the simple demarcation of conscious/unconscious olfactory processing by task-dependency (Keller, 2014) and the fact that diminished human OBs are dispensable for olfactory consciousness (Merrick et al. 2014) could implicate this neuronal rerouting in contemporary efforts to narrow down where to look for a brain circuit – consciousness interface.

 

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