Datta Lab

It’s always a special day when a student graduates from the lab, but in this case we have three! The amazing Maya Jay, David Brann and Win Gillis all got officially hooded today – we are all so proud of all they accomplished (you can read some of their work here, here, here, and here), with much more exciting work from these three on dopamine, behavior, aging and the molecular organization of olfaction to come in the near future. Win and David are both sticking around for a bit to finish up some exciting science, while Maya has already started an amazing new career starting companies in the life sciences space. They have all given so much to the lab, and it has been such a privilege to work with them – all of us in the Datta lab wish them all the best!

Congrats, Maya on a wonderful thesis defense! You killed it!

….well we are too! That didn’t stop Tatsuya Tsukahara and David Brann in the lab from writing this excellent review about how COVID can cost you your sense of smell. This work is evolving rapidly – as you can see from the review, there are some things we are sure about (COVID doesn’t directly infect sensory neurons but instead infects support cells), some things we are pretty skeptical about (COVID directly infects neurons in the brain), and a ton we don’t know (especially about how infection of support cells ultimately yields a loss of the sense of smell, and why smell recovers at the rate it does.). More to follow from us and colleagues, but our bet is that looking at humans is going to be more informative that what we learn from transgenic rodent models (that ectopically express e.g., the COVID receptor ACE2) going forward.

It is a *very* old commonplace: female behavior is more variable than male behavior because of hormonal variation during the estrous cycle. This pervasive belief (and the biases that come with it) has influenced the choice of rodent sex in experiments for decades, and contributed to the fact that more male mice are used to study brain function than female mice. But is it true? Dana Rubi Levy and friends address a very small slice of this big question in this recent paper, and come up with a surprising answer: at least for open field exploration, estrous seems to not matter much if at all. Instead, most of the variability in behavior observed in these experiments (in which the spontaneous behavior of mice in the open field is quantified using MoSeq) is caused by the individual identity of the mice (all of whom are 8-12 weeks old). The surprise – at least at this age, the inter-individual variability of male and female mice differs, with males actually behaving in a more variable manner (both across and within individual mice) than females. Of course, the estrous cycle is going to influence *lots* of female behaviors, especially in social contexts. But, as we show here, that is no reason to assume that female behavior is more variable in general. Check out the paper to learn more, as well as this article about the work in the NY Times!

 

Dopamine does lots of things — it signals reward prediction errors and been linked to behavioral vigor, engagement, effort and movement itself. However ,as a general matter, people think of dopamine from the perspective of experimenter-designed tasks — you train a monkey or a mouse to do a thing, and then ask how dopamine levels change in various parts of the brain as the animal learns and performs. We wondered something different: what does dopamine do in the absence of rewards or structured tasks, like during natural behavior? To see the answer, check out our paper in Nature by the terrific trio of Jeff Markowitz, Win Gillis and Maya Jay. By combining MoSeq (done with mice running around of their own accord in the open field) with careful measurements of dopamine in the dorsolateral striatum, they found something startling: that each time the mouse switched behavioral syllables (like going from a run to a rear), there was a systematic phasic fluctuation in dopamine. Syllables are fast — in the mouse the mean duration is about 300 seconds — and DLS dopamine seems fluctuate with a matched rhythm, as if there is some important relationship between dopamine in ongoing syllables. But no matter how hard they looked, Jeff and co. could not find a relationship between the actual movements the mouse was executing and the height of the associated dopamine transient…indeed for the very same syllable, sometimes dopamine went up, and other times dopamine fell. That got them thinking that maybe syllable-associated doesn’t control movements *in the moment*, but instead acts as a natural reinforcer to encourage (or discourage) the expression of syllables in the future. Through modeling and closed loop calibrated optogenetic manipulations of dopamine triggered on targeted syllables (!), they were able to demonstrate that DLS dopamine plays a key causal role in reinforcing syllables even in the absence of explicit rewards and tasks…and indeed these fluctuations determine in a given experiment and mouse how often given syllables are used and the order in which they occur. There is a ton in this paper, but what excites us the most is the idea that the very same cells, circuits and mechanisms that influence decision-making via the cortex and basal ganglia in low-dimensional tasks are recruited to help structure the high dimensional, self-directed behavior of mice. These findings raise a ton of questions – see the paper for more!

We are still writing a paper together (stay tuned!) so it feels like he hasn’t really left, but our beloved postdoc Jeff Markowitz recently decamped to start his own laboratory at Georgia Tech (https://bme.gatech.edu/bme/faculty/Jeffrey-Markowitz). We won’t even try to summarize all his many contributions to the lab and all of the great science he did (although see https://pubmed.ncbi.nlm.nih.gov/29779950/), but he is a amazing both as a scientist and a person, and he will be sorely missed. Anyone interested in a terrific mentor at Georgia Tech/Emory should check out his new lab, which will work on building better brain-machine interfaces. Pic of goodbye party below…as well as a special message from the most powerful individual in the universe.

Sara Jager (https://www.saraejager.com/) is a postdoc at King’s College, and in her spare time makes science cartoons. She liked the Brann COVID paper, and so did one about smell and the pandemic – check it out!

 

…for our two new postdocs, Dilansu Guneykaya and Kara Fulton!

This year was messed up in so many ways, but here in the Datta lab we are counting our blessings. Very few of us have gotten COVID, for the most part things are safe enough that we can work (everyone is vaxxed and masked, of course), and despite all the challenges we got some great science done in the last year. To celebrate the season (and the ending of 2021, which really needed to end) we all got a PCR test, then an antigen test, then had our holiday party (thanks Maya for hosting!!!). We did a Yankee swap with a twist – if you were the last to steal a gift, you had to sing! Embarrassing clips below. We wish everyone the best for a wonderful and safe holiday, and look forward to doing more science and having more fun in 2022.

 

 

Check out the lab’s latest paper in Cell, led by Tatsuya and David, which demonstrates that olfactory sensory neurons (OSNs) — the cells in the nose responsible for detecting smells — use regulated gene expression to flexibly make predictions about which odors are present in the environment and to dynamically adapt their odor responses (paper here, also for those of you on twitter, see tweet thread here). We are super excited about this work, in no small part because it revises basic ideas about how the olfactory system works. It has long been thought that OSNs (each of which expresses only one of the ~1000 possible odorant receptors (ORs) encoded in the genome) faithfully send information to the brain about OR-odor interactions. The brain, in this model, therefore has access to stable information about the degree to which any given OR is activated; this fixed peripheral odor code, in principle, enables the brain not only to decode odor identity and concentration, but also to make predictions about which odors are constantly present in the background, thereby enabling the brain to emphasize new information over predictable or constant stimuli. In this view, OSNs are passive cellular vehicles whose main purpose is to express a given OR and a set of signaling molecules that couple ORs to spikes — the brain listens to these spikes, and then does all the good stuff.

In contrast to this canonical model, Tatsuya and David’s amazing work (with tons of help from Greg and Stan) reveals that the nose uses a novel transcriptional mechanism to itself make odor predictions.  We’ll leave all the many surprises to the paper itself, but the work reveals that each subtype of OSN (as identified by which OR it expresses) has a unique transcriptome, that the main axis of transcriptional variation includes more that 70 genes whose function is to couple odors to spikes, that the expression of these genes systematically varies depending on the activation history of each OSN, that the environment determines OSN activation history and therefore determines OSN gene expression,  and critically, that expression levels of the 70 function-related genes actually predict how strongly each OSN responds to odors — indeed gene expression is far more predictive of the extent to which an OSN will respond to an odor than the in vitro-defined binding affinity! These results demonstrate that OSNs use dynamic gene expression to predict the presence of odors in the environment, thereby filtering out the expected to emphasize the new. This work has implications for how the brain organizes information about the chemical world, for our understanding of neuronal homeostasis, and for our interpretation of the many single cell sequencing atlases being generated of various brain regions. Getting to these discoveries involved sequencing ~2 million individual cells from the nose, and inventing a whole new way to identify which ORs are activated in vivo by any odor – huge congrats to Tatsuya, David, Stan and Greg (as well as to our collaborator Tom Bozza) on their incredible work and spectacular findings!