1: High-pressure freezing is a preservation method that allows relatively larger biospecimens, up to 200 µm thick, to be vitrified. But it requires the sample to be stuck in a large block of ice, which requires more time for milling before it can be imaged.
One way to decrease the time required is to lift the sample out of the ice, which is called cryo-lift-out. But this is challenging because it requires cooled micromanipulator devices. Arguably, it was at one point considered “practically impossible” — the evidence that people actually thought this isn’t great, but I’m biased towards it because I love me a Lord Kelvin/Wright Brothers tale.
A new study has now accomplished cryo-lift-out. The specimen is connected to a lift-out needle with a copper block adaptor, moved to a rectangular mesh grid, and then multiple sections are sliced. There is still some sample loss during sectioning and thinning, but much less than previous approaches.
This method allows them to image the generated lamellae of C. elegans using native tissue scattering contrast:
It also allows them to identify the shapes of individual molecular complexes, including 11- and 15-protofilament microtubules, and resolving the 11-protofilament version at 13 Å:
It seems hard to argue that it would be impossible to decrease the sectioning loss and scale up this type of imaging technology to the size of a human brain one day.
2: New study uses RNA sequencing to map the expression of neurotransmitters and neuropeptides across the mouse brain, with a few findings that stuck out to me. First, most neuron types only express genes for one neurotransmitter:
Among neuron types expressing neuromodulatory neurotransmitters, cholinergic neurons have more diversity and are more widespread across the brain than dopaminergic or serotonergic neurons. This might help explain why medications affecting the cholinergic system have such broad effects:
Next, they mapped the expression of neuropeptides within these cell types and across brain regions. Many were expressed primarily in one brain region. For example, AgRP (Agouti-Related Protein), a neuropeptide that regulates appetite, is predominantly expressed in the hypothalamus (HY). But many neuropeptides are expressed in cells across multiple brain regions, not just in the hypothalamus:
Finally, to identify more genes associated with functional activity in neurons, they also find the correlation of gene expression with the intermediate early gene Fos across brain regions, and cluster cell types (x axis) into groups based on those correlations:
One take away is that we are building up very robust databases relating the molecular content of brain cells to their functional states. This will naturally lead to models where we can map a cell’s molecular contents and thereby predict its functional properties with high accuracy.
3: Recent advances now allow large scale neural recording across the full cortical depth (from the pial surface to the white matter) of the superior temporal gyrus using a Neuropixels probe:
This allows the authors to record the activity of single neurons at different depths and in response to different sentences:
4: Study using electron microscopy in ferret visual cortex finds that nearly all dendritic spines (99%) are covered with perisynaptic astrocyte processes. In large synapses, they are correlated with the reliability of visual stimuli to produce postsynaptic Ca2+ responses.
5: Tissue clearing allows the 3d visualization of human cerebral blood vessels at 7 weeks of gestation, including the complete circle of Willis:
6: Still having SfN FOMO? You can listen to or read a transcript of the Aspirational Neuroscience panel discussion, which is about the goal of decoding a non-trivial memory from a static connectome. Topics discussed: C. elegans simulation; differences between genetic and neural information storage; how an engram can be defined as the delta between your brain’s structure before and after an experience, modulo other intervening experiences and homeostatic factors; and the likelihood that expansion microscopy will take over from electron microscopy since it is cheaper and allows for easier biomolecule staining.
7: A body of psychiatric literature suggests that traumatic memories are experienced in the present moment, unlike typical “sad” memories, which are often experienced as in the past. Indirectly supporting this theory, a new fMRI study of patients with PTSD finds that while sad memories have similar neural representations in the hippocampus across individuals, traumatic memories instead tend to be unique to each individual.
8: Lest we give too much credence to this type of result, Thomas Reilly asks: have we been doing neuroimaging wrong?
9: Systematic review finds an adjusted odds ratio of 2.24 (95% CI: 1.61-3.12) of cat ownership on developing schizophrenia-related disorders.
10: Study looks at the efficacy of antidepressants in people with comorbid depression and medical illness. Finds that pulmonary and especially pain conditions are associated with a relatively lower efficacy of antidepressants. On the other hand, comorbid gastrointestinal conditions are associated with a relatively higher efficacy of antidepressants:
11: Corroborating similar reports elsewhere, a retrospective chart review of 6 patients with alcohol use disorder treated with semaglutide (aka Ozempic) for weight loss finds that they all had significant incidental reductions in alcohol use disorder symptoms (p < 0.001).
12: Retrospective study from Sweden finds that a longer cumulative duration of ADHD medication is associated with an increased risk of cardiovascular disease, most commonly hypertension. I’m somewhat skeptical, because it’s not clear to me why the odds ratio would plateau at ~3 years of use in those aged 25-64 yo if it was truly a cumulative biological effect:
However, the long-term effect of medications is one of the biggest unknowns in psychiatry, because precious few studies address this for any medications in ways that aren’t statistically confounded. So we have to make our best guesses with the available data. My current guess is that there is a small but real effect here.
13: Enough about psychopathology. It’s the holiday season. What about types of brain stimulation associated with pleasant emotions? A study from July performs a retrospective analysis of 10,106 brain stimulations during pre-surgical exploration in 329 patients with drug-resistant epilepsy. They found that 5.1% of all stimulations evoked negative valence emotions, while only 0.6% evoked pleasant emotions, which is a bit of a buzzkill ratio, but let’s ignore that. The stimulations that evoked pleasant emotions were mostly localized in the anterior insula and the amygdala:
14: Cross-tissue epigenetic age acceleration is seen in premature aging models caused by deficits in DNA repair (e.g. Ercc1 deficiency) but not others. Suggests that epigenetic age is a marker for this one hallmark of aging, but not necessarily others.
15: Partial reprogramming for glaucoma in mice, using an AAV vector that could potentially be used in humans, fully restores impaired vision after 2 months of treatment.
Feels like this could be one of the first major applications of the “stem cells” we were promised in the 2000s. An update since then is that it seems much easier to make our own cells stem-like in our bodies via genetic manipulation, rather than transplanting exogenous cells. And this may eventually also be the case for CAR-T.
Related to this, my guess is that in the upcoming decades, stimulating endogenous neurogenesis and gliogenesis is a more likely path towards cellular therapeutics in the brain than cell transplantation. Anything that doesn’t require very expensive cell manufacturing and neurosurgery is going to be much more feasible.
16: An XPRIZE competition is now offering $101 million to any group that can restore muscle, cognitive, and immune function by a minimum of 10 years in a treatment period of one year or less. Related Manifold market:
17: Progress towards molecular nanotechnology, as a team is able to move a silicon atom through a lattice of carbon atoms using the electron beam of a scanning transmission electron microscope:
18: Vitrification is necessary but not sufficient for survival of organisms in the dry state (i.e., anhydrobiosis). Why? A new study finds that organisms in desiccation-tolerant states tend to have a higher glass transition temperature and a lower fragility of glass formation:
19: As of last month, Mike Perry reports that the cryonics organization Alcor has had 20 cases this year, which is the most they've ever had in a year (they were founded in 1972, and currently have 224 people preserved).
20: Max More with a comparison of long-term preservation organizations.
21: Widely reported, amazing study finds that sperm whales communicate using vowels:
This reminds me of a classic study in whale brain preservation, Knudsen et al 2002. Whale brains are very large and they were collected on boats in Arctic waters. So this was a technically challenging procedure, involving "[t]he use of chemicals and saw on a very unstable working platform and the risk of spatters of bone splints". Absolutely metal.
(I'm like this at parties too. I relate everything back to brain preservation. It's a big problem.)
I, for one, think you'd be cool to have at parties. All these fun facts! You know how to stimulate the good 0.6% of brain sites, and steer clear of the 5.1%!
Very cool, working my way through. Is link to #8 broken or is it just me?