Written by Tan Na

Editor in charge ︱ Wang Sizhen

Editor︱Yang Binwei

Predation behavior is the main source of food for carnivores in nature, which is an evolutionarily conserved instinctive behavior driven by appetite, which is crucial to the survival of animals [1].

On August 9, 2022, the team of Professor Zhong Chen from the School of Pharmacy, Zhejiang University, and the research team from Zhejiang University of Traditional Chinese Medicine published an online publication titled "Lateral Hypothalamus Calcium/calmodulin-dependent protein kinase II α Neurons Encode Novelty-Seeking Signals to Promote "Predatory Eating" research paper, reports the latest research results of the circuit mechanism of the lateral hypothalamus (Lateral Hypothalamus, LH) mediated predation behavior in mice

In the early stage, optogenetics, virus tracing and other technologies were used to analyze the relevant loops regulating predation behavior to a certain extent.

So the authors focused their attention on another type of LH neurons, namely CaMKIIα (Calcium/calmodulin-dependent protein kinase II α) neurons

Figure 1 LH CaMIKIIα ⁺ neurons mediate programmed predator-like behavior

(Image source: Na T, et al.

Figure 2 LH CaMIIKα ⁺ neurons bidirectionally regulate predation behavior

(Image source: Na T, et al.

It has been reported that GABAergic neurons projecting specifically to the LH of the PAG mediate predation behavior, but mice do not eat their prey after preying [8]

Figure 3 LH CaMKIIα ⁺ vGluT2 ^- neurons mediate predation behavior

(Image source: Na T, et al.
, Research, 2022)

To clarify whether the PAG nuclei, which are closely related to predation, are downstream targets of LH CaMKIIα ⁺ neurons, this study examined the expression level of Fos protein, a marker of neuronal activity within the PAG, after optogenetic activation of LH CaMKIIα ⁺ neurons.
, the results showed that LH CaMKIIα ⁺ neurons specifically projected to the ventral periaqueductal gray (vPAG) and induced the expression of a large amount of Fos protein, and the CT-B reverse tracking results also showed that vPAG received projections from LH CaMKIIα ⁺ neurons
.

Interestingly, unlike direct activation of the LH CaMKIIα ⁺ neuron soma, the activation of the CaMKIIα ^LH-vPAG loop resulted in the mice biting objects in place without moving them around, suggesting a link between LH and vPAG.
CaMKIIα ⁺ neuronal projections cause movement of the mouse craniofacial muscles but not of the whole body
.

After the activation of the CaMKIIα ^LH-vPAG circuit, the mice hardly followed the movement of the ping-pong ball but closely followed the food (Fig.
4).
The above results suggest that the mice can distinguish edible items after the activation of the CaMKIIα ^LH-vPAG circuit.
and unusable items, and mice were food-selective (Figure 4)
.

Figure 4 The CaMKIIα ^LH-vPAG loop mediates craniofacial muscle movement and food selectivity in predatory behavior

(Image source: Na T, et al.
, Research, 2022)

So, what is the source of the upstream signal input received by LH CaMKIIα ⁺ neurons? Whole-brain tracking of its upstream loop by CT-B revealed the medial preoptic area (MPOA) nucleus, which is located in the anterior side of the hypothalamus and regulates social behavior, gender differences, and rewards [15-17] ], in addition to these classical functions, the CaMKIIα ⁺ neuron-to-PAG circuit within this nucleus has recently been reported to be closely related to predation [7], and the authors speculate that its circuit to the LH may also mediate predation
.

The experimental results showed that MPOA CaMKIIα ⁺ neurons could directly excite LH CaMKIIα ⁺ neurons (Fig.
5)
.

Figure 5 LH directly receives excitatory neural projection input from MPOA

(Image source: Na T, et al.
, Research, 2022)

Next, the researchers verified the function of the CaMKIIα ^MPOA-LH circuit.
The experimental results showed that activating this circuit could induce programmed predation-like behaviors such as exploration, chase, bite, and retrieval in mice.
Predation behavior of artificial prey and real prey crickets, but did not induce feeding behavior, and mice did not ingest crickets after predation (Fig.
6)
.

These results suggest that the CaMKIIα ^MPOA-LH loop mediates a non-appetite-driven predation behavior
.

Figure 6 CaMKIIα ^MPOA-LH neural circuit mediates non-appetite-driven predatory behavior

(Image source: Na T, et al.
, Research, 2022)

MPOA-LHLH-vPAG，MPOA-LH-vPAG ， MPOA LH
。

。
（RV），TVAG CaMKIIα-CreLH，LHvPAG
。
RVTVA，vPAGLH，，
。
，vPAGLH CaMKIIα⁺MPOA CaMKIIα⁺，MPOA-LH-vPAG（7）
。

，MPOALHvPAG？，MPOA CaMKIIα⁺，LHvPAG
。
，MPOA CaMKIIα⁺，LHvPAG（ 7）
。
MPOA-LH-vPAG
。

Fig.
7 CaMKIIα ^MPOA-LH neural circuit mediates non-appetite-driven predatory behavior

(Image source: Na T, et al.
, Research, 2022)

Conclusion and discussion, inspiration and prospect In conclusion, this study is the first to discover that lateral hypothalamus (LH) CaMKIIα ⁺ neurons mediate novelty exploratory behavior in mice, as well as the role and characteristic functions of predation behavior; further analysis The upstream and downstream neural circuit basis of LH CaMKIIα ⁺ neurons mediated predation behavior was found to integrate novelty exploration information mediated by CaMKIIα ⁺ neurons in the medial preoptic area (MPOA) and through projections to the ventrolateral periaqueductal gray (vPAG) loops mediate appetite-driven predatory behavior
.

It proves the key role of the MPOA-LH-vPAG CaMKIIα ⁺ neural circuit in predation behavior, enriches the neural circuit basis of predation behavior, thereby providing a theoretical basis for better understanding of animal innate behavior, and also for the treatment of violent aggressive behavior.
Provides potential pharmacological targets with important clinical and social implications
.

Original link: https://spj.
sciencemag.
org/journals/research/2022/9802382/

The first author of the research paper is Tan Na, a doctoral student at the School of Pharmacy, Zhejiang University, and Professor Chen Zhong is the only corresponding author of this paper (now the President of Zhejiang University of Traditional Chinese Medicine, second-level professor)
.

This research was funded by the "Brain Science and Brain-like Research" program of the Ministry of Science and Technology of the People's Republic of China, and the key projects of the National Natural Science Foundation of China Regional Innovation and Development Joint Fund
.

The first author Tan Na (the ninth from the left in the third row); the corresponding author Professor Chen Zhong (the fourth from the left in the second row)

(Photo provided from: Professor Chen Zhong's laboratory)

Talent Recruitment
[1] Talent Recruitment︱ "Logical Neuroscience" Recruitment Article Interpretation/Writing Position (Online Part-time, Online Office) Selected Past Articles

【1】Cell Death Dis︱Tang Tieshan/Guo Caixia team revealed the mechanism by which TMCO1 deletion affects corpus callosum development

【2】Adv Sci︱Sui Jing’s research group and collaborators reveal the brain function mechanism of cognitive aging 【3】Nat Neurosci︱New discovery! Human brain cell-specific expression of quantitative trait loci can identify new risk genes for psychiatric and neurological diseases【4】Review of Trends Genet︱ Zhou Yubin/Huang Yun/He Lian team commented on the application of optogenetics in genetic engineering and transcriptional programming Research progress【5】Genome Biol︱Durenzana team developed a new method for single-cell multi-omics data integration 【6】J Neurosci︱The visual shape pathway has probability-dependent rapid bidirectional plasticity, which can realize “dynamic visual saliency detection”
【 7] Cereb Cortex︱Lixia Gao / Xinjian Li team revealed that the coding of sound information in the thalamus of awake marmosets is selectively regulated by the auditory cortex [8] eClinicalMedicine︱ Meta-analysis: the efficacy of repetitive transcranial magnetic stimulation on Parkinson’s disease [9] NSMB | From pharmacology, structure to ligand discovery: a systematic study of serotonin 5A subtype receptors [10] PNAS︱Xu Qi's team discovered DNA methylation biomarker BICD2 in major depression and revealed its mechanism of action [1] Metagenomics and Metabolomics R Language Analysis and Visualization Practical Workshop (August 27 Tencent Conference) Forum/Seminar Preview [1] Live Preview︱Brain Talk Academician Forum Phase III: Cerebral Ischemia and Metabolism Brain Organ [2] Forum Preview︱Brain·Machine Intelligence Fusion - Connecting the Brain to the Future, the Brain Science Theme Forum is the first landing! 【3】Bio-protocol Webinar Preview︱Focus on Single Molecule Microscopy

References (swipe up and down to read) 

[1] W.
Rosenblum, Motivation - A Biobehavioural Approach, 2000.

[2] E.
Comoli, E.
R.
Ribeiro-Barbosa, N.
Negrao, M.
Goto, N.
S.
Canteras, Functional mapping of the prosencephalic systems involved in organizing predatory behavior in rats, Neuroscience, 130 (2005) 1055-1067.

[3] E.
E.
J.
B.
Shillito, Exploratory Behaviour in the Short-Tailed Vole Microtus agrestis, 21 (1963) 145-154.

[4] S.
D.
Suarez, G.
G.
Gallup, Jr.
, Open-field behaviour in chickens: A replication revisited, Behavioural processes, 10 (1985) 333-340.

[5] Z.
D.
Zhao, Z.
Chen, X.
Xiang, M.
Hu, H.
Xie, X.
Jia, F.
Cai, Y.
Cui, Z.
Chen, L.
Qian, J.
Liu, C.
Shang, Y.
Yang, X.
Ni, W.
Sun, J.
Hu, P.
Cao, H.
Li, W.
L.
Shen, Zona incerta GABAergic neurons integrate prey-related sensory signals and induce an appetitive drive to promote hunting, Nat Neurosci, 22 (2019) 921-932.

[6] W.
Han, L.
A.
Tellez, M.
J.
Rangel, Jr.
, S.
C.
Motta, X.
Zhang, I.
O.
Perez, N.
S.
Canteras, S.
J.
Shammah-Lagnado, A.
N.
van den Pol, I.
E.
de Araujo, Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala, Cell, 168 (2017) 311-324 e318.

[7] S.
G.
Park, Y.
C.
Jeong, D.
G.
Kim, M.
H.
Lee, A.
Shin, G.
Park, J.
Ryoo, J.
Hong, S.
Bae, C.
H.
Kim, P.
S.
Lee, D.
Kim, Medial preoptic circuit induces hunting-like actions to target objects and prey, Nat Neurosci, 21 (2018) 364-372.

[8] Y.
Li, J.
Zeng, J.
Zhang, C.
Yue, W.
Zhong, Z.
Liu, Q.
Feng, M.
Luo, Hypothalamic Circuits for Predation and Evasion, Neuron, 97 (2018) 911-924 e915.

[9] D.
Rossier, V.
La Franca, T.
Salemi, S.
Natale, C.
T.
Gross, A neural circuit for competing approach and defense underlying prey capture, Proc Natl Acad Sci U S A, 118 (2021).

[10] N.
E.
Erondu, M.
B.
J.
J.
o.
N.
Kennedy, Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain, 5 (1985) 3270-3277.

[11] L.
Huang, Y.
Xi, Y.
Peng, Y.
Yang, X.
Huang, Y.
Fu, Q.
Tao, J.
Xiao, T.
Yuan, K.
An, H.
Zhao, M.
Pu, F.
Xu, T.
Xue, M.
Luo, K.
-F.
So, C.
Ren, A Visual Circuit Related to Habenula Underlies the Antidepressive Effects of Light Therapy, Neuron, 102 (2019) 128-142.
e128.

[12] G.
D.
Stuber, D.
R.
Sparta, A.
M.
Stamatakis, W.
A.
van Leeuwen, J.
E.
Hardjoprajitno, S.
Cho, K.
M.
Tye, K.
A.
Kempadoo, F.
Zhang, K.
Deisseroth, A.
Bonci, Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking, Nature, 475 (2011) 377-380.

[13] J.
H.
Jennings, R.
L.
Ung, S.
L.
Resendez, A.
M.
Stamatakis, J.
G.
Taylor, J.
Huang, K.
Veleta, P.
A.
Kantak, M.
Aita, K.
Shilling-Scrivo, C.
Ramakrishnan, K.
Deisseroth, S.
Otte, G.
D.
Stuber, Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors, Cell, 160 (2015) 516-527.

[14] J.
H.
Jennings, G.
Rizzi, A.
M.
Stamatakis, R.
L.
Ung, G.
D.
Stuber, The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding, Science, 341 (2013) 1517-1521.

[15] Z.
Wu, A.
E.
Autry, J.
F.
Bergan, M.
Watabe-Uchida, C.
G.
Dulac, Galanin neurons in the medial preoptic area govern parental behaviour, Nature, 509 (2014) 325-330.

[16] J.
M.
Dominguez, E.
M.
Hull, Dopamine, the medial preoptic area, and male sexual behavior, Physiology & behavior, 86 (2005) 356-368.

[17] RM McAllen, M.
Tanaka, Y.
Ootsuka, MJ McKinley, Multiple thermoregulatory effectors with independent central controls, European journal of applied physiology, 109 (2010) 27-33.

End of this article