Nature: Why is it that moving bricks can also be happy? Chinese scientists have found key molecules linking emotions and memories

➡ Article acceptance, meeting graduation requirements, successful admission.

Ding----------------- 😁

➡ The article was rejected in seconds, and the graduation was postponed, which was harmful, let alone stayed

Forehead.

The above are parts of the daily

Who discovered this interesting effect?

Recently, a team of researchers led by Professor Kay Tye of the Salk Institute of Biology published important research in Nature, and they found that NT can regulate BLA neural pathway activity on a dose-dependent basis, is a key factor influencing our positive or negative responses, and that NT and its receptors may be potential targets for therapeutic interventions for diseases such as depression, anxiety, and addiction [1

Screenshot of the first page of the paper

In the face of the good or bad of an event, our sophisticated neural networks have their own set of coping methods, they define the positive or negative feelings produced by "good" and "bad" as "Valence", and the ability to associate this good and bad memory and feeling is called "Valence assignment"[2].

The ability to correlate temporally separated information and assign positive and negative valences to environmental cues is critical for survival [3].

In Associative learning, the brain's almond base lateral nucleus (BLA) plays a very important role
.

Researchers have previously found that neurons in different parts of the brain BLA can be activated by positive and negative titers and participate in potency allocation when learning, but it is not clear whether there is a neural signaling regulation of these effects [4].

Here's how we're going to talk about our absolute C bit today: neurotensin (NT)!

NT is a polypeptide involved in the reward and punishment process[5], and NT signaling in BLA has been shown to affect long-term enhancing effects (LTP) and fear learning, possibly involved in regulating potency distribution in BLA [6].

Kay Tye and her colleagues wanted to clarify how BLA solved the problem of potency allocation and whether NT played a role
.

Left: Corresponding author Kay Tye, CNS is publishing soft-handed Chinese scientists of post-80s descent

Right: This article is the first work

They first reverse-localized neurons that release NT into BLA and found that there were NT neurons
projected onto BLA in the medial hippocampus knee nucleus (MGN), hippocampal ventral hypotrophist, and ventral hippocampus CA1 (vHPC) and parathalamic nucleus (PVT).

Next, to explore the functional role of NT, the researchers used the CRISPR/Cas9 system to selectively knock out the NT gene (Nts) in mice MGN, vHPC, or PVT, and performed "Pavlov" conditioned reflex experiments
.

They trained the mice to associate one tone with sucrose (tone-sucrose) and another tone with an electric shock (tone-shock), with the former as a reward and the latter as punishment
.

It was found that the NTs knockout of PVTs could enhance the "tone-sucrose" correlation, but did not change the "tone-shock" correlation
.

However, after knocking out Nts in MGN or vHPC, the researchers found no similar phenomenon, suggesting that NT (PVT:NT) in PVT is involved in the reward learning process
.

Nts' cKO in PVT enhances the "tone-sucrose" correlation

However, at this time, it cannot be asserted that the NT sent out of the PVT actually directs what the BLA does (PVT-BLA:NT).


After all, consider that NT in PVT may have different functions
.

So the researchers narrowed the "search circle" and simply knocked out the NTs gene (PVT-BLA Nts-cKO) projected by PVT-BLA and examined its effect on
reward and punishment learning.

In this way, the truth surfaced— they found that PVT-BLA Nts-cKO attenuated the "tone-sucrose" correlation and enhanced the "tone-shock" correlation
.

Shocked! This effect is significantly different from the full KO effect of the Nts gene in PVT!

In other words, NT does participate in the utility allocation
.

If the NT in the PVT cannot reach the BLA, then the BLA's decision will tend to produce negative valence
.

PVT-BLA Nts-cKO attenuates the "tone-sucrose" correlation and enhances the "tone-electric shock" correlation

Next, they performed forward validation
.

Consistent with the above results, optogenetic activation of PVT:NT axon endings enhances the "tone-sucrose" correlation and weakens the "tone-shock" correlation
.

PVT: Optogenetic activation (ChR2) at the ends of NT axons enhances the "tone-sucrose" correlation and weakens the "tone-shock" correlation

At the same time, the researchers had mice perform another "Pavlov" conditioned reflex experiment, in which mice were trained to associate one tone with sucrose (tone-sucrose) and another tone with a stream of air (tone-airflow
).

This is a bit like the "guessing the lyrics link" in the variety show, guessing correctly will add points, and guessing wrong will be baptized
by dry ice madness.

During the experiment, the calcium signal
of the ends of the PVT-BLA:NT axon is detected by fiber optic photometric recording.

The researchers found that calcium responses from the ends of the PVT-BLA:NT axon to sucrose/gas flow increased after obtaining a positive association (tone-sucrose) and decreased after obtaining a negative association (tone-airflow), while there was no significant change in
the SOMA cell calcium response of MGN:NT, vHPC:NT, or PVT:NT somatic calcium responses.

These studies further support the idea
that the NT is responsible for positive potency.

Reward conditions enhance the response of PVT-BLA:NT axon terminal calcium to sucrose, while penalty conditions inhibit calcium response to gas flow

But the question arises again, how does associative learning change the NT concentration in BLA?

Therefore, in order to specifically monitor the dynamic changes of NT in BLA, the researchers developed a gene-encoded fluorescent NT sensor GRABNTS1.
0, and found that after mouse associative learning, the NT sensor's response to sucrose increased and the response to gas flow decreased, suggesting that PVT-BLA: NT neurons will adjust NT concentration according to titer during learning, increase NT after reward learning, and decrease NT
after penalizing learning.

These data suggest that the brain's default factory settings are more towards being afraid of the negative until.
.
.
The emergence of
NT.

NT is like a switch on the circuit, turning on the brain's active mode, enhancing the effect of reward/punishment learning, which is probably "profit-seeking and avoiding harm"
.

Further, the researchers compared BLA neurodynamics at the population level, where they pooled all recorded neurons for principal component analysis (PCA
).

The results of trajectory analysis showed that the total trajectory length and trajectory distance of PVT-BLA Nts-cKO neurons in the "tone-sucrose" test and the "tone-shock" test were significantly reduced, indicating that the PVT-BLA Nts-cKO mice were reduced
in BLA neurodynamics in different test types.

Significant differences in trajectory length and distance occurred between the control group and the Nts-cKO group

At the same time, the researchers found that after knocking out Nts, the valence coding principle of BLA neurons changed, and the active behavior strategy of PVT-BLA Nts-cKO mice to "seek advantage and avoid harm" disappeared, and they did not actively approach the sucrose port or actively avoid electric shocks
.

PVT-BLA Nts-cKO mice exhibited negative responses to both sucrose and electric shocks

In addition, the researchers found that temporal dynamics also play a key role in NT function, and on short, medium, and long-term scales, the role of NT leads to different behavioral outcomes
.

For example, on subsecond timescales, NT rapidly promotes information transmission to BLA in a way that is dependent on the NT receptor type 1 gene (ntsr1), and can be rewarded for stimulating excited BLA neurons (BLA-NAc); On the timescale of minutes, NT pretreatment reduces neuroplasticity projected onto BLA-NAc; On a timescale spanning weeks, CRISPR cKO in BLA Ntsr1 inhibits reward learning
.

Through this series of interesting and in-depth inquiries, the researchers confirmed that neurotensin projected from PVT to BLA is a key neuromodulation signal that can adjust the coding of positive and negative titers according to the potency (the quality of the stimulus), dose-dependent, guide the titer allocation in the BLA, promote active behavior strategies, and finally choose whether we get an experience again, or avoid an experience, whether to move bricks happily or emo to rot
.

References:

[1] Li H, Namburi P, Olson JM, et al.
Neurotensin orchestrates valence assignment in the amygdala.
Nature.
2022; 10.
1038/s41586-022-04964-y.
doi:10.
1038/s41586-022-04964-y.

[2] Tye KM.
Neural Circuit Motifs in Valence Processing.
Neuron.
2018; 100(2):436-452.
doi:10.
1016/j.
neuron.
2018.
10.
001.

[3] Namburi P, Beyeler A, Yorozu S, et al.
A circuit mechanism for differentiating positive and negative associations.
Nature.
2015; 520(7549):675-678.
doi:10.
1038/nature14366.

[4] Beyeler A, Chang CJ, Silvestre M, et al.
Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala.
Cell Rep.
2018; 22(4):905-918.
doi:10.
1016/j.
celrep.
2017.
12.
097.

[5] Steele FF 3rd, Whitehouse SC, Aday JS, Prus AJ.
Neurotensin NTS1 and NTS2 receptor agonists produce anxiolytic-like effects in the 22-kHz ultrasonic vocalization model in rats.
Brain Res.
2017; 1658:31-35.
doi:10.
1016/j.
brainres.
2017.
01.
012.

[6] McCullough KM, Choi D, Guo J, et al.
Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala.
Nat Commun.
2016; 7:13149.
Published 2016 Oct 21.
doi:10.
1038/ncomms13149.

Editor-in-charge | Eddie Zhang