Current Biology︱Chen Zhong's team made new achievements in the mechanism of histamine regulation of feeding: H2 receptor-dependent medial septal nucleus histaminergic circuit

Written by ︱Xu Lingyu Edited ︱Wang Sizhen Obesity is a disease caused by excessive accumulation of fat in the body, which can cause damage to liver and kidney function and increase the probability of type II diabetes, cardiovascular and cerebrovascular diseases, and cancer.
It poses a threat to the health of more than 600 million people worldwide and causes approximately four million deaths worldwide each year [1, 2]
.

Unfortunately, there is currently a lack of safe and effective control of food intake in clinical practice.
Drugs used to treat obesity in clinical practice can easily cause side effects such as vomiting and arrhythmia, and even affect mood and cognitive function, leading to anxiety, depression and drug dependence.
problems and poor patient compliance [3–5]
.

The neural circuits and molecular mechanisms of feeding behavior regulation have not been fully elucidated, which is an important reason for restricting the development of anti-obesity drugs
.

 On March 25, 2022, Professor Zhong Chen's team from the School of Pharmacy, Zhejiang University published a paper titled "An H2R-dependent medial septum histaminergic circuit mediates feeding behavior" in Current Biology, a sub-journal of Cell, reporting that histamine regulates feeding behavior.
The latest research results in the mechanism
.

This study used optogenetics, chemical genetics, pharmacology, combined with food-borne obesity model and genetic intervention and other technologies, and found for the first time that the direct projection of histaminergic nerves from the papillary nucleus of the hypothalamus to the medial septal nucleus can be bidirectional.
In regulating feeding behavior, histamine plays a role in inhibiting feeding and regulating body weight by activating H2 receptors on glutamatergic neurons in the medial septal nucleus
.

 Histamine is an important neurotransmitter and neuromodulator, mainly synthesized and released by histaminergic neurons
.

Histaminergic neurons originate from the tuberomammillary nucleus (TMN) of the hypothalamus, project widely to the whole brain, and play a regulatory role in various brain functions, such as sleep arousal, learning and memory, feeding behavior, etc.
[6]
.

Early studies suggest that histaminergic nerves inhibit feeding behavior mainly by acting on the ventromedial hypothalamus or the paraventricular nucleus of the hypothalamus [7–9]
.

In recent years, more and more attention has been paid to the role of brain regions other than the hypothalamus in the regulation of feeding behavior
.

Some studies have found that the food-seeking behavior of starving rats is reduced after TMN damage, and at the same time, neuronal activation in multiple regions of the cortex, ventral basal forebrain, and dorsolateral tegmental area is inhibited [10, 11]
.

However, the specific functional characteristics and neural circuit mechanisms of histaminergic neurons in regulating feeding behavior have not been fully elucidated for a long time
.

Therefore, it is very necessary to further analyze the neural circuit mechanism of histaminergic nerves in the regulation of feeding behavior and find safe and effective drug intervention targets
.

 To this end, the research group first constructed HDC-CreERT2 mice, injected AAV-CAG-Flex-ArchT-EGFP virus into the TMN of the mice, and used whole-brain microscopic optical section tomography (fMOST) to detect histaminergic Whole-brain three-dimensional reconstruction of neural projections revealed that the density of histaminergic nerve fibers was high in the medial septal nucleus
.

Recent studies have found that the medial septum (MS) plays an important role in the regulation of feeding behavior, and three types of neurons (cholinergic, glutamatergic, GABAergic, and GABAergic) in MS are regulated by optogenetics or pharmacogenetics.
Neurons) can cause significant changes in food intake [12–14], but the upstream regulatory mechanism remains unclear, and the molecular targets regulating MS function have not been reported
.

So, is there a direct functional connection between histaminergic nerves and MS and regulate feeding behavior through MS? To this end, we used in vivo calcium signal optical fiber recording combined with histamine fluorescent probe to monitor the calcium signal of TMN histaminergic neuron cell bodies and the changes of MS histamine content in real time during the feeding process of mice
.

The results showed that when the mice ate, the calcium signal of histaminergic neurons and the content of MS histamine decreased concomitantly (Figure 1)
.

Further use of optogenetics to specifically inhibit histaminergic nerve endings in MS significantly increased food intake in mice, but specific activation of histaminergic nerve endings in MS significantly inhibited food intake (Fig.
2)
.

Fig.
1 Calcium signal of histaminergic neurons and histamine content in MS decreased concomitantly when mice ingested food (Source: Xu L, et al.
, Current Biology, 2022)Fig.
2 Activation or inhibition of TMNHA-MS circuit Feeding can be regulated bidirectionally (Credit: Xu L, et al.
, Current Biology, 2022) To clarify the direct projection of histaminergic neurons to MS, this study used the immune panel after optogenetic activation of MS histaminergic nerve endings.
The expression of neuronal activity marker cfos in MS was detected by chemical analysis, and the results showed that the activated neurons in MS were mainly glutamatergic neurons after activating MS histaminergic nerve endings
.

And the results of rabies virus (RV) cross-synaptic reversal and calcium signal test results show that MS glutamatergic neurons and TMN histaminergic neurons have dual functional and structural connections
.

Furthermore, pharmacogenetic inhibition of MS glutamatergic neuron activity could reverse the inhibitory effect of activation of MS histaminergic nerve endings on feeding behavior (Fig.
3)
.

The above results suggest that there is a direct functional connection between TMN histaminergic neurons and MS glutamatergic neurons, and direct regulation of this projection can regulate feeding behavior in both directions
.

Figure 3 The main downstream projections of TMNHA-MS are MS glutamatergic neurons (Source: Xu L, et al.
, Current Biology, 2022) Then, the histaminergic neuronal projections from TMN to MS regulate feeding sub-receptors What is the type? Early studies using lateral ventricle injection or local injection of histamine H1 or H2 receptor antagonists in the hypothalamus found that only H1 receptor antagonists can promote feeding behavior in rats, so the role of histamine in regulating feeding behavior has long been considered to be a Mediated by H1 receptors, H2 receptors are not involved in the regulation of feeding behavior
.

Unexpectedly, this study is the first to show that the feeding inhibition induced by optogenetic activation of MS histaminergic nerve endings can be abrogated by H2 receptors, but not by H1 receptor antagonists (Fig.
4)
.

At the same time, antagonizing HCN channel antagonism downstream of H2 with the HCN channel (ie, hyperpolarization-activated cyclic nucleotide-gated channel) blocker ZD7288 can also reverse the inhibitory effect of activating this pathway, suggesting that histamine in MS activates H2 by activating H2.
, rather than H1 receptors that play a role in regulating feeding behavior
.

 In order to verify whether H2 receptors in MS glutamatergic neurons specifically mediate feeding behavior, in situ hybridization and immunofluorescence techniques were used to detect H2 receptors in different types of MS neurons in food-induced obese mice.
The results showed that compared with normal-weight mice, the level of H2 receptors in MS glutamatergic neurons of food-induced obese mice was significantly decreased, but the levels of MS cholinergic neurons and GABAergic neurons were significantly reduced.
There were no significant changes in H2 receptor levels (Figure 4), suggesting that H2 receptors in MS may have a cell-specific role in the regulation of feeding behavior
.

Figure 4 TMNHA-MS loop mainly regulates feeding behavior through downstream H2R receptors (Source: Xu L, et al.
, Current Biology, 2022) Further, in order to explore whether H2 receptors in MS glutamatergic neurons associated with obesity
.

In this study, Cre-Loxp technology was used to inject conditional H2 receptor knockdown virus into MS vglut2-Cre mice to specifically knock down H2 receptors in MS glutamatergic neurons.
The results also showed that: specific knockdown H2 receptors in MS glutamatergic neurons can promote weight gain in mice in a food-borne obesity model; and long-term administration of the clinical H2R agonist amthamine through the micro-pump drug delivery system can also effectively delay body weight in obese mice growth (Figure 5)
.

The above results suggest that H2 receptors in MS glutamatergic neurons can further regulate the activity of glutamatergic neurons and participate in the occurrence of obesity
.

Figure 5 Specific knockdown or activation of H2 receptors on MS glutamatergic neurons can bidirectionally regulate body weight in obese mice (Source: Xu L, et al.
, Current Biology, 2022) Conclusions and discussions of the article, inspired by In conclusion, this study is the first to find that direct projections of histaminergic nerves from the tubercular papillary nucleus (TMN) to the medial septal nucleus (MS) can bidirectionally regulate feeding behavior, and histamine activates glutamatergic neurons in MS glutamatergic neurons.
H2 receptors act to inhibit food intake and ultimately regulate body weight
.

This is the first time that H2 receptors have been reported to play an important role in the regulation of feeding and body weight in specific neural circuits, while the role of histamine receptors specific to other neuronal circuits remains to be further explored
.

This study will help to elucidate the neural circuits and molecular mechanisms of histaminergic neurons in regulating feeding behavior, provide potential new targets for drug intervention for the safe and effective regulation of feeding behavior in obese patients, and provide intervention for clinical treatment of obesity new strategy
.

Link to the original text: https://doi.
org/10.
1016/j.
cub.
2022.
03.
010 The first author of this research paper is Xu Lingyu, a doctoral student at Zhejiang University School of Pharmacy, and Lin Wenkai, a doctoral student at Zhejiang University School of Pharmacy, is the co-first author.
Prof.
Zhong is the only corresponding author of this article
.

This study was also supported and helped by Professor Li Yulong of Peking University.

.

The first author Xu Lingyu (the sixth from the left in the lower row), the co-first author Lin Wenkai (the fifth from the left in the upper row), and the corresponding author Professor Chen Zhong (the eighth from the right in the upper row) (Photo courtesy of Zhejiang University) Professor Chen Zhong's laboratory) Professor Chen Zhong's research group has long been engaged in the analysis of the pathogenesis of chronic encephalopathy and the research on new drug targets[15–19]
.

Among them, the neuropharmacological function of histaminergic neurons in the brain is one of the important directions of the research group.
A series of previous studies have found that histamine is involved in schizophrenia, ischemic brain injury and other central nervous system diseases.
Mechanism of action, published papers in well-known journals such as Nature Communications, Stem cell reports, Journal of Experimental Medicine [20–23], and was invited to write a review in the internationally renowned journal Pharmacology & Therapeutics [24], summarizing the central histamine and its effects.
The latest research progress of the body
.

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Plate making︱Wang Sizhen End of this article