Neuron: Ju Huang's team reveals neural circuit mechanisms that regulate emotions through stereotyped repetitive behavior Cell Press talks to scientists

Life Sciences

Life science

On September 6, 2022, The Huang Ju team of Shanghai Jiao Tong University School of Medicine published the research results entitled "Excitatory SST neurons in the medial paralemniscal nucleus control repetitive self-grooming and encode reward" in the Cell Press Cell Press journal Neuron

Dr.

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Figure 1: MPL^SST neurons control stereotyped repetitive behaviors in mice and encode rewards

There is a potential interaction

Huang Ju's team used repeated self-grooming behavior in rodents as a research model to explore the neural circuit mechanisms

The research paper published in Neuron by Ju Huang's team at Shanghai Jiao Tong University School of Medicine in Neurons found that excitatory SST neurons located in the MPL of the medial parapontine nucleus of the midbrain mediate self-grooming behavior in mice and encode rewards

Figure 2: Activation of MPL^SST neurons induces self-grooming behavior in mice, and calcium signaling recording shows that the activity of MPL^SST neurons is closely related to

The researchers performed spatial transcriptome sequencing analysis on brain slices containing MPL brain regions in adult mice and found that MPL enriched the expression of SST and PTH2 genes encoding neuropeptides

Figure 3: Spatial transcriptome analysis shows MPL enrichment expressing neuropeptideSST and PTH2

The input of the central amygdala CeA to MPL^SST neurons in the negative emotion-related brain region is directly involved in self-grooming behavior

Figure 4: Activating MPL^SST neurons can cause a massive release

In summary, this study reveals the neural circuit mechanism of the interaction between stereotyped repetitive behavior and emotion regulation, which provides an important theoretical basis

Author Interview

Cell Press Cell Press specially invited researcher Huang Ju, the corresponding author of the paper, to conduct an exclusive interview on behalf of the team and asked him to interpret
it in further detail.

CellPress：

Please tell us about what previous research on MML brain regions has focused on? What are your new findings on cell type and function in MPL brain regions?

Researcher Huang Ju:

The specific localization of this brain region of MPL was first proposed
by Dr.
Ustin and Dr.
Dobolyi et al.

They early found that a new member of the parathyroid hormone family, parathyroid hormone 2 (PTH2, also known as TIP39), was enriched and expressed
within the MPL.

It was found that intracranial PTH2 neuropeptides may be involved in regulating maternal behavior, pain management, oxytocin signaling pathways, and fear learning
.

A recent important study has found that PTH2 is involved in the mechanical perception
of population density.

However, the functional research of this brain region of MPL has been very limited before, and we do not know much about the types of neurons contained in the MPL nuclear cluster and their functional role
.

Previous studies have not found an association
between MPL as a brain region and stereotyped repetitive behavior and emotion regulation.

We performed spatial transcriptome analysis
on brain slides containing MML nuclei in the midbrains of adult mice.

Through dimensionality reduction and clustering and differential gene analysis, we found that MPL neurons enrich the expression of neuropeptideSST and PTH2
.

Spatial transcription also suggests that MML brain regions express marker genes
for excitatory neurons rather than inhibitory neurons.

Further, we also identified excitatory neurons
in MPL containing co-releasing neuropeptideSST and PTH2 by fluorescence in situ hybridization and brain slice electrophysiology.

CellPress：

What do mouse self-grooming behaviors have in common with stereotyped repetitive behaviors in humans? What is special about your study compared to previous work on the grooming behavior of mice?

Researcher Huang Ju:

Body-oriented stereotyped repetitive behaviors (BFRBs) are a common neuropsychiatric disorder characterized by the recurrence of non-functional behaviors that target a part of the body
.

The pleasure of BFRBs causes patients to develop addictive-like compulsive behaviors
.

Similar to humans, many animals exhibit unusually enhanced stereotyped repetitive behaviors
in the face of stress.

Self-grooming is a stereotypical repetitive behavior
that is highly conservative.

Previous studies have also found that many brain regions are associated with this behavior, such as orbitofrontal cortex OFC, ventral medial striatum VMS, medial and central amygdala MeA/CeA, ventral lateral septal nucleus LSv, ventral striatum Calleja Island (ICj), trigeminal nerve spinal tract nucleus tail Sp5C, midbrain periheteral gray matter PAG, lateral hypothalamus LHA and cerebellum
.

Compared to previous studies, our study found that MPL^SST neurons not only regulate repetitive self-grooming behavior in mice, but also form direct loop connections with the CeA brain region that controls anxiety and the VTA brain region that controls rewards
.

Therefore, MPLSST neurons become the transfer points in the brain that connect anxiety and reward, and have a direct regulatory effect
on the relief of anxiety after stress stimulation.

This finding provides an important theoretical basis
for us to understand the neural circuit mechanism between stereotyped repetitive behavior and emotion regulation.

CellPress：

How previous research interprets the emotional valence of animal self-grooming behavior, and which view does your research support?

Researcher Huang Ju:

Past studies have indeed interpreted
the emotional valence of self-grooming behavior differently.

The self-grooming behavior controlled by the paraventricular nucleus PVN projection to the ventral lateral septal nucleus LSv, a neural circuit, has a negative emotional potency; The self-grooming behavior controlled by the neural circuit of the ventral lateral septal nucleus LSv projected onto the lateral nodule nucleus of the hypothalamus, Tu, has a positive emotional potency
.

In our study, because MPL^SST neurons are directly connected to VTA^DA neurons, VTA^DA neurons, as an important part of MPL^SST-mediated hair-trimming behavior, provide positive emotional potency and coding rewards
by releasing dopamine into downstream brain regions, including NAc.

We also fully verified the positive emotional titer of the coupling of activated^{MML SST} neurons through behavioral experiments
.

By knocking down the expression of endogenous SST and PTH2 in mouse MPL brain regions by CRISPR/Cas9 technique, we found that knocking down SST instead of PTH2 impairs the ability of MPL^SST neurons to encode rewards, indicating that neuropeptide SST mediates the reward effect of MPL^SST neurons
.

About the author

Huang

researcher

doctor

Ju Huang is a researcher and doctoral supervisor at the Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, and a distinguished professor of "Oriental Scholar" in
Shanghai Universities.

Research Interests and Directions:

The Laboratory of Huang Ju has long been committed to the study
of neural circuits and molecular mechanisms of instinctive behavior and emotion regulation.

Research on neural circuits, epigenetic regulation, and function of disease-related proteins that focus on the regulation of instinctive behavior and emotion.


The results provide a new perspective
for understanding the neurobiological mechanisms behind the regulation of instinctive behavior and emotions.

Sun Jingjing

doctor

Sun Jingjing, Ph.
D.
, experimentalist
.

Research Interests and Directions:

1.
Neural circuit mechanisms and molecular mechanisms of instinctive behavior

2.
Neurobiological mechanisms of energy metabolism and balance

3.
Plasticity and neural mechanisms of brain cognitive function

Yuan Yuan

Doctoral candidate

Yuan Yuan, PhD candidate
.

Research Interests and Directions:

1.
Neural circuit mechanisms and molecular mechanisms of instinctive behavior

2.
Neural circuit mechanism of motor function regulation

Wu Xiaohua

doctor

Xiaohua Wu, Ph.
D.
, Research Assistant
.

Research Interests and Directions:

1.
Neural circuit mechanisms and molecular mechanisms of instinctive behavior

2.
Neurobiological mechanisms of body temperature regulation

Information about related papers

▌Papers:

Excitatory SST neurons in the medial paralemniscal nucleus control repetitive self-grooming and encode reward

▌Thesis URL:

▌DOI：

https://doi.
org/10.
1016/j.
neuron.
2022.
08.
010

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