Cell: First discovery! Social fear or social cattle, the key to see this neural pathway!

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Everyone should have seen such a scene in life or in the animal world, two small birds (or monkeys, cats, dogs, mice, etc.
) combing each other's hair, this behavior has a professional name - social modification
.

For animals with limited communication patterns between individuals, social modification is an important part of their social behavior, which is of great significance for the establishment and maintenance of social relations [1].

However, we know very little
about the neural mechanisms behind social modifications.

Recently, Arpad Dobolyi from the University of Roland and the Valery Grinevich team from the University of Heidelberg have collaborated to discover for the first time the neural circuits (posterior nucleus of the thalamic plate [PIL]→ medial preoptic region of the hypothalamus [MPOA]) in rodents that regulate socially modified behavior [2].

The researchers found that selective activation of the PIL →MPOA pathway in rats significantly increased social modification behavior among rats, while parathyroid hormone 2 (PTH2) is a key neuropeptide that mediates this regulatory action, and antagonists of PTH2 receptors significantly reduce social modification behavior in rats
.

In addition, the researchers also found that the anatomy of PIL in rats and human brains and the distribution of PTH2 receptors in MPOA are very similar, indicating that PIL → MPOA pathways in humans are likely to play a similar role
in regulating social behavior.

First page of the paper

The hypothalamus is the main regulatory center for social behavior in rodents, but social behavioral perception reaches the cerebral cortex primarily through the thalamus, and it is unclear how social behavioral instructions reach the hypothalamus [3].

For the regulation of social behavior, neuropeptides play a role
that cannot be ignored.

Neuropeptide PTH2 is expressed in the thalamus (where neuropeptides are rare) and is expressed only in PIL (Multisensory Information Processing Relay Station) [4].

There is a wealth of PTH2 nerve endings in MPOA, and based on retrograde tracing technology, PTH2 projection in MPOA mainly comes from PIL [5].

At the same time, studies have shown that PTH2 neurons in PIL are activated during social activities [6].

Based on the above background, the researchers speculate that the PIL → MPOA pathway may play an important role
in regulating socially modified behavior.

Study design schematic

To test this conjecture, the researchers first used chemical genetics to regulate
neurons in rat PIL.
Activation of PIL neurons significantly increased the duration of intersex social modification in rats compared with the control group of rats, while inhibition of PIL neurons significantly reduced
the duration of social modification.

For other social behaviors, activation and inhibition of PIL neurons does not have a significant effect (eg, anogenital sniffing, chasing, etc.
), or plays the same role (e.
g.
, non-anogenital sniffing appears significantly reduced after activation and suppression of PIL neurons).

Changes in various social behaviors after activation and inhibition of PIL neurons

The researchers then separated the two animals with a baffle to prevent them from coming into direct contact (allowing each other to sniff, listen and observe each other
).
In this case, there was no effect
on the duration of social interaction in rats after activation of PIL neurons.

In addition, the researchers have also induced cell markers (vGATE) through the genetic activity of viral transmission, combined with chemical genetics, to selectively regulate PIL neurons that are activated by social behavior
.
After activating those PIL neurons labeled by vGATE, the social modification behavior of rats increased significantly; Inhibition of neurons tagged by vGATE significantly reduced the social modification behavior of rats without significant effect on
non-direct contact social interactions.

These results suggest that PIL has a regulatory role
in the social behavior of direct contact.

Next, the researchers found that social activity led to a large number of activated neurons in the downstream regions of the four PILs, namely the submarginal region (ILC), MPOA, the medial amygdala (MeA), and the dorsal medial nucleus (DMH)
of the hypothalamus.
After stopping direct contact between rats, the number of neuronal activations in the MPOA region became similar to that of the control group, and the MPOA region had a very high density of PIL neuronal axon projections, which was also consistent
with previous conjectures.

Social activity resulted in a large number of activated neurons in the downstream regions of the 4 PILs, while almost no neurons were activated in the MOPA region of social interaction that isolated direct contact

Therefore, the researchers began to study
the PIL → MPOA pathway.

It has been found that by activating the axonal endings of PIL neurons projected to the MPOA region, the social modification behavior of rats can be significantly increased, while selective inhibition of PIL neurons projected into the MPOA region significantly reduces the social modification behavior
of rats.
This suggests that the PIL→MPOA pathway does have a regulatory effect
on social modification behavior in rats.

At the same time, the researchers also noticed that after social interactions, γ-aminobutyric acid (GABA)-capable neurons are activated in MPOA and are closely opposed to
nerve fibers containing PTH2.
There is indeed an expression of the PTH2 receptor in the MPOA, and social interaction can indeed activate the neurons in the MPOA that express the PTH2 receptor
.

GABAergic neurons in MPOA are tightly opposed to nerve fibers containing PTH2

Subsequently, the researchers further confirmed the connection between
PTH2 →GABAergic neurons in the MPOA region by acute mening-film patch-clamp technique.

The results showed that GABAergic neurons in the MPOA region of mice can be activated by PTH2, which is manifested as a transient increase in the discharge frequency and is dose-dependent, and the antagonist of the PTH2 receptor can counteract this effect
.

In addition, after injecting an antagonist of the PTH2 receptor into the rats' brain chamber, the social modification behavior of rats was significantly reduced
.
These findings suggest that axons projected by PIL neurons onto MPOA can act on GABAergic neurons in MPOA by releasing neuropeptide PTH2, thereby regulating the social modification behavior
of rodents.

Finally, by comparing human brain specimens with rodents, the researchers found that the chemical structure of PIL in the human thalamus and PIL in rats is similar, and the distribution of PTH2 receptors in MPOA is also very similar, indicating that PIL→MPOA pathways in humans may also have the effect of
regulating social behavior.

Humans and rat PILs have similar chemical structures, and the distribution of PTH2 receptors in MPOA is also very similar

Overall, the study identified for the first time neural pathways
involved in regulating socially modified behavior.
Specifically, PTH2 neurons originating from PIL are projected onto MPOA and act on GABAergic neurons in the MPOA region by releasing neuropeptide PTH2, which plays a role
in regulating social modifications.

In addition, this pathway may also play a role in regulating human social behavior, and may also be related
to autism spectrum disorder.
In addition, PTH2 and its receptors may have potential value
in the treatment of diseases with deficits in direct social interaction.

However, this study also has some limitations, such as whether the PIL → MPOA pathway can truly regulate socially modified behavior independently of the cerebral cortex, which was not addressed
in this study.

In addition, it is important to analyze the neural mechanisms behind social behavior for human social disorder-related diseases; However, the difference in human and animal social behavior, so that the neural circuits of the two must also have certain differences, how to transform the research results of animals into humans, which will be a major key
to future neuroscience research.

But research is aware of this, pointing out that the PIL → MPOA pathway may also play a corresponding role
in humans.
If the role of this pathway in human social interaction can be confirmed in future studies, the implications of this study will be even more profound
.

References

1.
Ebbesen CL, Froemke RC: Body language signals for rodent social communication.
Curr Opin Neurobiol 2021, 68:91-106.

2.
Keller D, Láng T, Cservenák M, Puska G, Barna J, Csillag V, Farkas I, Zelena D, Dóra F, Küppers S et al: A thalamo-preoptic pathway promotes social grooming in rodents.
Current Biology 2022.

3.
Zilkha N, Sofer Y, Kashash Y, Kimchi T: The social network: Neural control of sex differences in reproductive behaviors, motivation, and response to social isolation.
Curr Opin Neurobiol 2021, 68:137-151.

4.
Dobolyi A, Cservenak M, Young LJ: Thalamic integration of social stimuli regulating parental behavior and the oxytocin system.
Front Neuroendocrinol 2018, 51:102-115.

5.
Cservenak M, Szabo ER, Bodnar I, Leko A, Palkovits M, Nagy GM, Usdin TB, Dobolyi A: Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation.
Psychoneuroendocrinology 2013, 38(12):3070-3084.

6.
Cservenak M, Keller D, Kis V, Fazekas EA, Ollos H, Leko AH, Szabo ER, Renner E, Usdin TB, Palkovits M et al: A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats.
Endocrinology 2017, 158(2):335-348.

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