Fremont older open space reserve & Stevens Creek County Park trail

I found another two biking trails about 8 miles from home. One is Fremont older open space reserve on hills, the other is Stevens Creek Country Park in the valley.  They are neighbors, so it's easy to ride one time for both places. After several days in flat Silicon Valley, I had some fun on hills for the first time, even though I had to walk my steel bike on some steep roads.

Steven Creek Trail to Bay trail

I found a lovely five-mile bike trail to the bay shore, along the Stevenson creek, with two lanes, each for one direction. Trees are all the way down to the bay, and many beautiful crossing bridges make it even scenic. The speed limit is 5mph so I cannot ride fast. When I reached the end, the trail is on a narrow dam, still two lanes. I felt like flying off because of its height and the surrounding emptiness.

Family tree of neurons in the brain

Darwin built the tree of evolution, where we learn our position in the history of life on Earth. You can build your family tree with your clan pedigree books. A recent paper in Science reports building a linage tree for neurons.

Archeologists use radioactive isotopes to estimate the age of a rock or bone; biologists use DNA labels to trace cell division;  with genome sequencing, geneticists can use gene mutations to trace our ancestors to African apes. In the Science paper, Lodato et al. used whole genome sequencing of single neurons to detect the mutations with which they built a linage tree of neurons for a single person.

We know during early development, all cells divide and the mutations at that stage will be carried to the descending cells; and after the body mature, most cells stop dividing and keep the mutations from their ancestors. But new mutations will continue to appear in the after dividing cells, which could be the cause of diseases. Every neuron in the brain is different, single mutation in one neuron may becomes the seed for Alzheimer disease,  Parkinson disease, Huntington disease, and CJD......For this reason, Lodato et al. wanted to investigate the mutation pattern in single somatic neurons.

They did whole genome sequencing of 36 neurons from 3 normal adult brains, and analyzed the data on single nucleotide variants. By comparing with reference data, they found ~1500 mutations for each neuron, which are more associated with transcription regulating neuronal functions than DNA replication in cell division as in cancer cells. By comparing the mutations in each neuron, they found the neurons could be arranged into four clades clusters, each originating from the same ancestors during fetal development. The result is a beautiful tree of neurons, though the neurons are taken from a brain tissue within millimeters.

This study makes use of the new techniques to prove a concept that somatic mutations can be used to construct the linage tree of neurons, which is important to understand neurodevelopment. It also indicates somatic mutations may have more weight than germ line mutations for the neurological disorders. This method could be extended to patients' brain to search for the most possible culprit of neurological diseases. However, non-localized somatic mutation, like cancer mutation, is hard to be targeted by gene therapy.

A new therapy for memory loss?

Deep brain stimulation has been used in the treatment of several neurological diseases, such as essential tremor, Parkinson disease, dystonia, and oppressive compulsive disorder. But the exact mechanisms are unknown. A recent paper in Nature add a new disease to the catalogue.

Hao et al. reported that forniceal deep brain stimulation rescued hippocampal memory in Rett syndrome mice. Rett syndrome is a genetic disorder caused by MECP2 gene mutation, leading to a series of abnormalities including apraxia, seizure and intellectual disability. The authors studied the hippocampus-dependent memory in the mouse model of Rett syndrome, because memory deficits is the most reproducible measures in this model. One of the reasons that they use forniceal deep brain stimulation, though not mentioned in the beginning of the paper, might be that forniceal stimulation can enhance hippocampal memory in rodents. Thus their hypothesis is that forniceal stimulation can rescue the memory deficits in Rett syndrome mice.

The animals were divided into 4 groups: wild type sham, wild type stimulation, Rett syndrome sham, and Rett syndrome stimulation. They implanted the stimulation electrodes into the fibria-fornix, and recording electrodes into the dentate gyrus of the brain. Then mice in deep brain stimulation groups were treated with 130 Hz, 60 microsecond pulse for 1 hour a day for 14 days, and the mice in sham group were treated without pulsation. After 3 weeks, they performed the functional tests on these mice. They observed the changes of the fear memory, spatial learning and memory, long term potentiation, and neurogenesis. All these phenotypes were improved in stimulation group compared with sham group, not only for Rett syndrome mice but also for wild type mice. The results indicate that hippocampal neurogenesis are increased by foniceal deep brain stimulation, and thus the hippocampus-dependent memory is improved. More neurogenesis, better memory, like the treadmill experiments in mice once encourage people to run, is not new. And in this report, they may need to increase neurogenesis by another way to see if the memory tests in Rett syndrome brain are improved.

Although it's quite an interesting paper with some promise for neurological disorders that affect learning and memory, I am surprised that Nature accepted this paper.

Visible inequality causes less cooperation and wealth?

In a social network like Linkedin, would you more likely to connect with people with higher social status than you or those with lower ones than you? If you are told your coworkers earned much less than you, would you like to collaborate with them for a project? A recent paper published in Nature provides a laboratory model for questions like these.

Economic inequality exist in most human societies, whereas human have strong preference for equalities. Nishi et al. asked what may determine the inequality and what is the consequence of inequality on wealth. They displayed a networked public goods game—

1. 1462 subjects were placed in groups with a average size of 17.21.

2. Each subject was connected to an average of 5.33 neighbors.

3. The subjects were initially assigned wealth (units) to be rich, poor, or non-rich-non-poor.

4. The subjects played a cooperation game lasting 10 rounds.

5. In each round, the subjects chose to cooperate or defect with each neighbor—cooperate by reducing 50 units from their own wealth to increase their neighbors' by 100 units each; defect by doing nothing to cause no cost and benefit.

6. After the choosing cooperation or defect, the subjects were informed their neighbors' choices, they can then decide to keep or break the connection with their neighbors.

7. Some of the groups were informed the wealth situations (rich, poor, non-rich-non-poor) before the game started.

What they found—

1. Visible wealth, relative to invisible wealth, increases the inequality when the subjects knows they are unequal in the beginning.

2. Invisible wealth causes more average-wealth increase than visible wealth does.

3. Visible wealth, relative to invisible wealth, lowers overall cooperation with neighbors.

4. If the wealth are visible, the new rich in the initial equal condition are more likely to cooperate, whereas the current rich in the initial unequal condition are more likely to defect.

5. The rich keeps rich, and the poor keeps poor.

What does it mean? It means concealing wealth may increase the cooperation and reduce the inequality in the society. And initial equality, relative to initial inequality, causes more wealth increase. Are these true in the real world? It may support some phenomenons like the one mentioned in the beginning, but the real world is complicated, and there are many other factors that may affect the results. At least, it's more difficult to conceal your wealth, and go back to the initial equality now than the hunter-gather time.

On watching Steven Jobs

We watched the movie Steven Jobs today. It's a good movie with full emotional display and loyal sketch of Steven Jobs as a business creator and legendary hero.

Like it or not, Steve Jobs is adored by most human beings in the world, because he is the typical type of man representing the will of power. And most leaders in the world are among this group. Nietzsche said "Man is a rope stretched between the animal and the Overman—a rope over the abyss".  We have to admit that it's still the best explain of human existence so far. Man is not the goal but the bridge to the goals—the animal or Overman. We understand that neither goal is easy to reach. For average man, we either have the will of power, or will of no will, but in the end, we are driven by man with the will of power as a race on the Earth.

From evolutional view, it quite fits with the "Selfish gene" argued by Richard Dawkins. We are only the machines driven by genetic codes to transfer them to the next generation, for whatever purpose. Thus the will of power in itself is just the plan of genes that to expand into the whole space, like what it presents in the movie "21st century space odyssey".

The brain structure that makes mothers special

We know intuitively that women are more likely than men to pursue child care. This social task division is attributed to sexual dimorphism in the brain. The hormone difference between women and men not only forges different sexual organs, but also shapes different brain. Due to the difficulties to study human behaviors, our knowledge of sexual dimorphism is mainly based on animal experiments. In a recent Nature paper, the investigators discovered a new neural circuit that control the maternal care in mice.

Dopamine is a neurotransmitter playing essential roles in controlling voluntary movements in midbrain, short of which cause Parkinson disease; it also contributes to many behavioral processes, including mother-pup interaction. In an anatomical structure called anteroventral periventricular nucleus (AVPV) in the hypothalamus, a brain area critical in coordinating sexual dimorphism, we know that there are more dopaminergic neurons in females than males. Thus the investigators of the paper raised their hypothesis — the difference of dopaminergic neurons in AVPV of males and females may cause the sex differences in parental care.

First, they confirmed the double numbers difference of dopaminergic neurons in AVPV between male and female mice, also with more AVPV dopaminergic neurons in parental females than virgin females. Then they pharmacologically destroyed these neurons or genetically overexpressed dopamine in these neurons, or selectively activated these neurons, after which they recorded the parental behavior changes of these mice, including latency to retrieve pups and parental duration in both male and female mice, also aggressive behaviors in male mice. As expected, the ablation of AVPV dopaminergic neurons increased the pup-retrieval latency, and decreased the maternal duration, while overexpressing dopamine or activating these neurons did the opposite in female but not male mice. Unexpectedly, they found the ablation of AVPV dopaminergic neurons can increase male aggressiveness to pups, while overexpressing dopamine or activating these neurons can reduce the aggressiveness.

Next, to connect the dopaminergic neuron difference with more direct functional difference in parental behavior, they tested several possible hormones involved, including oestradiol, corticosterone, prolactin, and oxytocin. Oxytocin is the only hormone that was reduced after AVPV dopaminergic neuron ablation, which let the investigators to make their second hypothesis that AVPV dopaminergic neurons control oxytocin secretion in oxytocin-secreting neurons in paraventricular nucleus (PVN) or supraoptic nucleus (SON). By using chemical tracer and electrophysiological recording, they proved that AVPV dopaminergic neurons projected to PVN oxytocin-secreting neurons, which completes the circuit for maternal care.

These experiments used classical strategy to study anatomical and functional neural circuits, with modern molecular techniques. It could be furthered if the investigators can clarify the dopaminergic control of aggressiveness in male mice during parenting, maybe through another nucleus in amygdala.