To ask how dopamine might impart structure onto spontaneous behavior, we performed dLight photometry in the dorsolateral striatum in mice running around an open field, while we simultaneously identified ongoing behavioral syllables (i.e., brief 3D motifs of behavior like turning or rearing) and sequences using MoSeq.

A lot packed in the paper, but take home is that in the DLS DA fluctuates a ton during spontaneous behavior, and that these fluctuations causally structure ongoing action, even without task structure or rewards.

Importantly, DLS DA during free behavior doesn’t seem to casually determine movement kinematics or initiation, but instead appears to specify both digital aspects of behavior — which behavioral syllable to use and how much — and analog aspects of behavior — like the vigor of each syllable.

DA does this not by directly specifying which syllable to use at a given moment, but rather through reinforcement, suggesting that the same circuits/mechs that govern low-D choices in structured tasks are relevant during high-D spontaneous behavior without structure/rewards.

It is unclear what is driving the fluctuations in DLS DA during spontaneous behavior – DA could be implementing an action plan, or may be signaling some sort of action prediction error (as has been beautifully argued by Ashok Litwin-Kumar and Marcus Stephenson Jones recently).

Paper is an amazing collab with many labs (Bernardo Sabatini, Nao Uchida, Scott Linderman) and would have been impossible if not for the help of many others.

First, a recap. After COVID infection (especially with the early variants) many/most folks lost their sense of smell - for most it was transient (days-weeks) but for some others much longer (months-years). So how does SARS-CoV-2 actually attack your sense of smell?

Odors are detected by olfactory sensory neurons (OSNs) in your nose, which send information about odors to the brain. These sensory neurons are surrounded by support and stem cells, which enable OSN function and renewal of the olfactory epithelium (which gets banged up every time you breath through your nose).

At the beginning of the pandemic we (including Brad Goldstein, Darren Logan, Hiro Matsumani, John Ngai, Matt Grubb and others) hypothesized that SARS-CoV-2 infects support/stem cells but not OSNs themselves. Since then many studies have explored this issue - most are consistent with the hypothesis that support cell infection and possibly the loss of support cell function indirectly causes sensory neuron dysfunction = transient and/or long term loss of smell

Two key studies from human autopsies (from Stavros Lomvardas and Peter Mombaerts) revealed that in people the virus likely infects support cells and not OSNs, and further that after COVID there are hallmarks of inflammation that could affect OSNs. Animal models also suggested that the nose might be subject to all sorts of immune-mediated madness (see work from Ben tenOever).

But what is going on in living patients suffering from long-term smell loss?

To explore this idea, Brad's lab performed biopsies of the olfactory epithelium from patients with post-COVID smell loss (objectively documented via testing), followed by single cell sequencing to enable definitive cell type identification (side note - in the field there is a lot of confusion about how to identify cell types).

There is a lot of data in the paper, but the most important observation is the presence of an immune infiltrate comprised of T cells and myeloid cells, just camping out in the epithelium of patients with long term smell loss; there is no evidence of viral RNA, but support cells are clearly responding to immune signals. There are also fewer OSNs, there are changes in OSN gene expression, and there is evidence that stem cells may not be renewing the epithelium effectively.

These findings lead to a model in which support cell infection triggers a cascade that culminates in immune infiltration, OSN dysfunction and long-term smell loss. The data argue that persistent smell loss is immune mediated, suggesting possible new strategies for patient treatment; these results are also broadly consistent with the idea that neuroinflammation is the main way SARS-CoV-2 impacts the nervous system.

Our findings are also relevant to long COVID, which affects many other organ systems, and is also thought to be at least in part immune mediated. Many questions remain (why do some patients get their smell back quickly while others have this immune infiltrate and long term loss?). Looking forward to continuing to work on this important problem - congrats to all the authors (and thanks to the patients!)