Seth Blackshaw

Good questions. The anteriotuberal component here is Foxg1-negative and therefore not telencephalic, so not POA. Probably corresponds to part of anterior hypothalamus. Thalamic eminence is prethalamic and dorsal to slightly more posterior hypothalamic structures.

Just doing my best cleaning up the mess. Look forward to never having to work on Ptbp1 again.

The message here is, as always, don't trust cell-based assays without also verifying your conclusions in vivo, with genetic tools where possible. Kudos to Haley Appel, Rogger Carmen,
Clayton Santiago, and Thanh Hoang. This work was supported by NEI/NIH./end

Previous studies claiming it to be a master negative regulator of neurogenesis were based on in vitro studies, and its developmental function was never closely examined owing to early lethality of Ptbp1 mutants. We avoided this by selectively deleting Ptbp1 in early-stage retinal progenitors./2

Ptbp1 is not required for retinal neurogenesis and cell fate specification. The RNA-binding protein Ptbp1 has been proposed as a master regulator of neuronal fate, repressing neurogenesis through its effects on alternative splicing and miRNA maturation. While prior studies us...

Now up, positively our lab's last word on Ptbp1. Developmental loss of function Ptbp1 turns out not to regulate neurogenesis or cell fate specification at all, but does alter splicing patterns and slightly accelerates expression of photoreceptor-specific genes./1
www.biorxiv.org/content/10.1...

Congratulations Kristen!

Postdoctoral Researcher in Single-Cell Genomics through the NORPOD program Postdoctoral Researcher in Single-Cell Genomics through the NORPOD program

Job alert ‼️ @thomasdwkim.bsky.social and I are recruiting a postdoc in single-cell genomics via the NORPOD program of the @nordicembl.bsky.social. Collaboration between @fimm-uh.bsky.social and @dandrite.bsky.social on multimodal data integration in neurodevelopment.
jobs.helsinki.fi/job/Helsinki...

Congrats Joaquin!

Congratulations Xin!

In any case, huge kudos to Sangsoo, Mark, and all the other members of Mark's lab who did the vast majority of the work here, and special thanks to @thomasdwkim.bsky.social‬ who was in our group at the time and contributed our part./end

Clearly there will other neuronal populations that relay this information to the Lhx6 ZI neurons, although since these cells receive direct projections from dozens of brain regions, there are many potential candidates./18

Second, what are the other components of this circuit, and how exactly does it modulate activity of neurons that directly regulate sleep/wake transitions? While ReN neurons are selectively activated by induced SD, Lhx6 ZI neurons are also activated by naturally occurring variation in sleep need./17

First, how is sleep pressure sensed in the first place? We still have no idea. Fos trapping combined with snRNA-Seq in ReN did not identify any molecular markers of sleep pressure-activated neurons other than Fos itself./16

This work establishes the ReN-Lhx6 ZI circuit as essential for both sensing and signaling levels of homeostatic sleep pressure, but leaves many questions unanswered./15

What's more, synaptic connections between ReN and Lhx6 ZI neurons are both physically and functionally strengthened by sleep deprivation in a CamKII-dependent manner, and these are in turn reversed by recovery sleep./14

So where do the Lhx6-positive cells fit in? It turns out that if you selectively activate ReN projections to the ZI you phenocopy the effects of whole cell activation, and if you kill the Lhx6-positive neurons you no longer observe ReN-induced sleep./13

ReN neurons are activated during sleep deprivation and silenced during recovery sleep, and are themselves necessary for recovery sleep.12

In the period between stimulation and sleep onset, mice showed sleep anticipatory behaviors such as nest building./11

Somewhat shorter delays in sleep onset were seen with ChR2-medidated activation -- roughly 45 minutes instead of several hours./10

Activation of ReN neurons robustly promoted sleep, but did so with the same delayed and prolonged kinetics that we'd previously seen with the Lhx6-positive neurons of the ZI./9

He next tested the effects of DREADD-mediated activation of glutamatergic cells in Fos trapped brain regions for their ability to promote sleep. VLPO and thalamic reuniens (ReN) came out on top./8

This leads to the current study. Sangsoo Lee in Mark Wu's lab at Hopkins ran a Fos trap experiment to find neuronal subtypes activated by NREM sleep deprivation. He identified the thalamic reuniens nucleus, as well as the zona incerta and VLPO, as strongly activated and synaptically connected./7

This implied that these neurons were signaling the need to sleep, rather than promoting sleep per se. It was unclear how this was sensed, and whether there were any other components of this sleep pressure-signaling neural circuit./6

These are GABAergic neurons that directly innervate many different subtypes of arousal-promoting neurons, but they had unusual effects on sleep. When their activity was modulated with DREADDs, they showed markedly delayed (>2hrs) and prolonged (up to 8hrs) effects on sleep./5

Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep - Nature GABAergic Lhx6+ neurons in the ventral zona incerta promote both rapid eye movement and non-rapid eye movement sleep and inhibit the activity of wake-promoting GABAergic and Hcrt+ neurons of the later...

At the time, Kai Liu, a PhD student in lab, was trying to figure out what activated Lhx6-expressing neurons in zona incerta. We had no idea of what these cells regulated, but they turned out to be activated by the need to sleep./4
www.nature.com/articles/nat...

It's basically been a mystery. It's unclear what signals drive accumulation and dissipation of homeostatic sleep pressure, or whether the neural circuitry that controls it is different from that which drives sleep/wake transitions. Our part in this began over a decade ago./3

The drive to sleep is controlled by both homeostatic and circadian processes. The homeostatic element is pretty simple – the longer you’ve been awake, the stronger the urge to sleep. Failure to fully dissipate this homeostatic need leads to a broad range of health problems. How is this controlled?/2

Sleep need–dependent plasticity of a thalamic circuit promotes homeostatic recovery sleep Prolonged wakefulness leads to persistent, deep recovery sleep (RS). However, the neuronal circuits that mediate this process remain elusive. From a circuit screen in mice, we identified a group of th...

New collaborative study out with Mark Wu’s group identifies a thalamic reuniens-zona incerta circuit as both responsive to induced sleep deprivation and essential for mediating recovery sleep. Further perspective on this work follows./1
www.science.org/doi/epdf/10....

Kudos to @thomasdwkim.bsky.social‬ and
‪@leightonhduncan.bsky.social‬ who spearheaded this, and NIMH who funded the work./end

It hasn't changed all the much from the preprint posted earlier this year. Explainer thread here./2
bsky.app/profile/seth...