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Written by ︱Tan Zhibing, editor-in-charge ︱Wang Sizhen Learning and memory is a process of cognition and access to external environmental information by humans or animals, and the hippocampus brain region plays a key role in learning and memory
.
Abnormal hippocampal structure and function can lead to impaired learning and memory
.
For example, the famous epilepsy patient HM with bilateral hippocampal resection cannot form new memory after surgery, while the Alzheimer patient with hippocampal atrophy has recent amnesia and difficulty in learning and memory [1, 2]
.
There are various types of memory, among which spatial memory enables individuals to remember where they are and the spatial relationship between objects, encoded by place cells in the hippocampus [3]
.
The amplitude and frequency of the local field potential (LFP) of the hippocampus show a very interesting correlation with the movement state of the animal in a specific space.
(including sleep) LFP showed high amplitude low frequency and irregular [4, 5]
.
Interestingly, Vanderwolf et al.
found that the hippocampal LFP occasionally appeared a large negatively oriented waveform with a duration of about 40-100 ms, called sharp waves [6]
.
O'Keefe et al.
subsequently found that sharp waves are accompanied by a brief high-frequency oscillatory event (rodents: 140-200 Hz, primates and humans: 80-140 Hz), called ripples [7]
.
Since sharp waves and ripples usually occur at the same time, they are collectively called sharp wave ripples (SW-Rs)
.
Sharp wave ripples mainly originate from the CA1 pyramidal layer of the hippocampus.
Studies have shown that neurons reflecting spatial trajectories are reactivated in a time-compressed manner during sharp wave ripples, which suggests its important role in spatial learning and memory [8]
.
When the generation of sharp wave ripples is disturbed, it will damage the formation of spatial learning and memory, and conversely, increasing the duration of sharp wave ripples will help spatial learning and memory [9, 10]
.
However, the molecular mechanism that regulates sharp-wave ripples remains unclear
.
Neuregulin 1 (NRG1, neuregulin) is an EGF domain-containing trophic factor that activates its transmembrane tyrosine kinase receptor ErbB4
.
Merlin's lab in the Department of Neuroscience at Case Western Reserve University has been studying the pathway's role in the brain for years
.
Their work found that NRG1/ErbB4 promotes the formation of GABA neural circuits during development, and maintains normal GABA release after development, thereby regulating synaptic transmission and plasticity [11, 12]
.
NRG1 is mainly expressed in excitatory neurons, and its production and secretion depend on neuronal activity
.
In contrast, NRG1 receptor ErbB4 is almost exclusively expressed in GABAergic interneurons in the hippocampus, cortex and amygdala [13]
.
When NRG1 binds to ErbB4, it activates the ErbB4 tyrosine kinase and promotes the release of the inhibitory neurotransmitter GABA, thereby inhibiting the activity of excitatory neurons and interfering with the formation of synaptic long-term potentiation (LTP).
, fear memory and attention and many other brain functions are necessary [14-17]
.
Recently, Merlin's lab in the Department of Neuroscience at Case Western Reserve University published an article entitled "Neuregulin 1 and ErbB4 kinase actively regulate sharp wave ripples in the hippocampus" in the Journal of Neuroscience, reporting that the NRG1/ErbB4 signaling pathway is involved in the Regulating the role of sharp waves in the occurrence of ripples provides a new idea for the study of learning and memory
.
The authors firstly recorded LFP in the vertebral layer of CA1 region of isolated mouse hippocampus slices in vitro
.
After obtaining a stable spike-ripple signal, 10 nM of NRG1 was added to the recording system, and the results showed that NRG1 significantly reduced the frequency of spike-ripples without affecting their duration, amplitude, and energy (Figure 1)
.
Figure 1 Frequency of NRG1-inhibited spike ripples (Source: Robinson H.
et al.
, J Neurosci, 2021) Due to the lack of ErbB4-specific blocking drugs, the author's laboratory recently used a strategy of chemical genetics Developed a transgenic mouse: T796G
.
This mouse was mutated at position 796 of the ATP-binding pocket (pocket) of ErbB4, and the bulky threonine (T) was mutated to a small-sized glycine (G), thereby expanding the ATP-binding pocket (Fig.
2A)
.
This mutation does not affect the function of ErbB4, but allows the bulky inhibitor 1NMPP1 to enter the mutated ATP-binding pocket and inhibit ErbB4
.
Previous studies have shown that inhibition of ErbB4 by 1NMPP1 can reduce GABA release, and it is worth mentioning that 1NMPP has no effect on the function of wild-type mice [17]
.
The authors found that the frequency of sharp ripples in hippocampal slices was significantly increased when 1NMPP1 was added to the recording system (Fig.
2B, C), indicating that endogenous activity of the NRG1/ErbB4 pathway is required for the generation of sharp ripples
.
1NMPP1 could also block the regulatory effect of NRG1 on sharp ripples (Fig.
2D), demonstrating that the effect of NRG1 is due to activation of ErbB4 tyrosine kinase
.
These results suggest that the NRG1/ErbB4 signaling system is involved in regulating the generation of sharp ripples
.
Figure 2 1NMPP1 blocks the NRG1/ErbB4 signaling pathway to increase the frequency of spike ripples (Source: Robinson H.
et al.
, J Neurosci,, 2021) In order to study the effect of ErbB4 kinase activity on spike ripples in vivo Influence, the authors injected 1NMPP1 into the abdominal cavity of T796G mice and found that the frequency of sharp wave ripples was significantly increased (Fig.
3 AC)
.
Interestingly, 1NMPP1 has different effects on spike ripples in non-rapid eye movement sleep (NREM) and wakefulness (wake), and the effect on spike ripples in wakefulness is stronger than that in non-REM sleep.
period of sharp ripples (Fig.
3D)
.
These results suggest that the NRG1/ErbB4 signaling pathway also regulates the generation of sharp ripples in vivo
.
Further analysis of unit neuron firing found that ErbB4 inhibition increased the activity of excitatory neurons, but had no significant effect on the activity of interneurons (Fig.
3E), suggesting that NRG1/ErbB4 regulates the activity of excitatory neurons by regulating the activity of excitatory neurons.
Generation of sharp waves and ripples
.
Figure 3 1 The enhancement effect of NMPP1 on sharp wave ripples depends on the behavioral state of animals (Source: Robinson H.
et al.
, J Neurosci, 2021) Whether the regulation of NRG1/ErbB4 signaling pathway on the generation of sharp wave ripples affects animal behavior, especially spatial Learning and memory impact? To answer this question, the authors employ a behavioral paradigm called the W-maze
.
The W-maze is named for its shape like the letter W.
It consists of a black arm in the middle and white arms on both sides.
Food-deprived mice need to learn to walk from the terminal of one arm to the terminal of the adjacent arm in order to obtain food reward (Fig.
4)
.
The process (inbound) of the rat from the side arm to the middle arm depends on the reference memory (reference memory), while the process (outbound) of the rat from the middle arm to the adjacent unvisited side arm depends on the spatial working memory (spatial working memory).
) [18]
.
The authors found that when T796G mice were intraperitoneally injected with 1NMPP1, the reference memory of the mice was not affected, while the spatial learning and memory were significantly reduced (Figure 4), thus proving that the regulation of spike ripples by the NRG1/ErbB4 signaling pathway may be involved in spatial learning and memory.
formation
.
Figure 4 1NMPP1 impairs spatial learning and memory (Source: Robinson H.
et al.
, J Neurosci, 2021) Conclusion and discussion, inspiration and prospect This work proves that NRG1/ErbB4 signaling pathway regulates excitatory nerves by up-regulating the release of GABA The activity of the element affects the generation of sharp waves and ripples, and participates in the formation of spatial learning and memory
.
The paper suggests that interneuron activity has a very important influence on the fundamental frequency of spike ripples
.
Sharp wave ripples are beneficial to spatial learning and memory.
However, simply and indiscriminately increasing the frequency of sharp wave ripples will impair the formation of spatial learning and memory, which may be related to the increase of basic noise
.
The formation mechanism of sharp wave ripples is very complex, and there is no mature theory to explain its generation process and regulation method
.
This article attempts to provide new ideas and directions for the study of sharp wave ripples from the perspective of molecular biology, and at the same time reveals a new cellular physiological mechanism of the NRG1/ErbB4 pathway
.
Link to the original text: https:// First author Heath Robinson (photo courtesy of Merlin Lab) Case West Heath Robinson, a doctoral student in the Department of Neuroscience of the University of California, is the first author of this article, Professor Mei Lin is the corresponding author, research scientist Dr.
Tan Zhibing, doctoral students Ivan Santiago-Marrero, Emily P.
Arzola and Professor Xiong Wencheng made important contributions to the article
.
This work was supported by grants from the National Institutes of Health (NIH)
.
Selected Previous Articles【1】Autophagy︱Li Xiaojiang’s team discovered new progress in the clearance of TDP-43 cytoplasmic aggregation by SQSTM1 in non-human primate models【2】Nat Neurosci︱Cao Peng’s lab found that pain sensation is a struggle for survival among species [3] Neurosci Bull︱Tong Li's research group revealed that dopaminergic neurons in the VTA-PrL neural pathway play a role in promoting wakefulness during general anesthesia with sevoflurane in rats [4] Nat Aging︱Alzheimer's disease new Discovery: A regulatory mechanism of bone marrow-derived macrophages independent of TREM2 pathway【5】Sci Transl Med︱New evidence for delayed onset of monoaminergic antidepressants: hippocampal cAMP regulates HCN channel function and affects mouse behavior and behavior Memory [6] Nat Methods︱ Peng Hanchuan's research group developed cross-modal brain registration technology, which provides important support for brain map construction and single-cell accurate whole-brain mapping research [7] Nat Commun︱ astrocytes inhibit non-human primates Infiltration of peripheral macrophages in cerebral ischemia-like injury【8】Cereb Cortex | Peng Ziwen/Chen Qi’s group reveals multimodal neuroimaging features of compulsive behavior acquisition 【9】Neurosci Bull︱Li Yunqing’s group reveals anterior cingulate Changes in neuronal plasticity in the gyrus are related to hyperalgesia and anxiety in chronic pancreatitis【10】Neuron︱Cao Peng’s laboratory discovered the closed-loop neural mechanism of repetitive stereotyped behaviors.
Recommended for high-quality scientific research training courses【1】A common experimental paradigm for cognitive control and executive function 【2】Single Cell Sequencing and Spatial Transcriptomics Data Analysis Symposium Book Donation Activities References (swipe up and down to view) [1] Milner B, Corkin S, Teuber HL.
Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of HM.
Neuropsychologia.
1968 Sep 1;6(3):215- 34.
[2] [2] Carlesimo GA, Oscar-Berman M.
Memory deficits in Alzheimer's patients:
.
Abnormal hippocampal structure and function can lead to impaired learning and memory
.
For example, the famous epilepsy patient HM with bilateral hippocampal resection cannot form new memory after surgery, while the Alzheimer patient with hippocampal atrophy has recent amnesia and difficulty in learning and memory [1, 2]
.
There are various types of memory, among which spatial memory enables individuals to remember where they are and the spatial relationship between objects, encoded by place cells in the hippocampus [3]
.
The amplitude and frequency of the local field potential (LFP) of the hippocampus show a very interesting correlation with the movement state of the animal in a specific space.
(including sleep) LFP showed high amplitude low frequency and irregular [4, 5]
.
Interestingly, Vanderwolf et al.
found that the hippocampal LFP occasionally appeared a large negatively oriented waveform with a duration of about 40-100 ms, called sharp waves [6]
.
O'Keefe et al.
subsequently found that sharp waves are accompanied by a brief high-frequency oscillatory event (rodents: 140-200 Hz, primates and humans: 80-140 Hz), called ripples [7]
.
Since sharp waves and ripples usually occur at the same time, they are collectively called sharp wave ripples (SW-Rs)
.
Sharp wave ripples mainly originate from the CA1 pyramidal layer of the hippocampus.
Studies have shown that neurons reflecting spatial trajectories are reactivated in a time-compressed manner during sharp wave ripples, which suggests its important role in spatial learning and memory [8]
.
When the generation of sharp wave ripples is disturbed, it will damage the formation of spatial learning and memory, and conversely, increasing the duration of sharp wave ripples will help spatial learning and memory [9, 10]
.
However, the molecular mechanism that regulates sharp-wave ripples remains unclear
.
Neuregulin 1 (NRG1, neuregulin) is an EGF domain-containing trophic factor that activates its transmembrane tyrosine kinase receptor ErbB4
.
Merlin's lab in the Department of Neuroscience at Case Western Reserve University has been studying the pathway's role in the brain for years
.
Their work found that NRG1/ErbB4 promotes the formation of GABA neural circuits during development, and maintains normal GABA release after development, thereby regulating synaptic transmission and plasticity [11, 12]
.
NRG1 is mainly expressed in excitatory neurons, and its production and secretion depend on neuronal activity
.
In contrast, NRG1 receptor ErbB4 is almost exclusively expressed in GABAergic interneurons in the hippocampus, cortex and amygdala [13]
.
When NRG1 binds to ErbB4, it activates the ErbB4 tyrosine kinase and promotes the release of the inhibitory neurotransmitter GABA, thereby inhibiting the activity of excitatory neurons and interfering with the formation of synaptic long-term potentiation (LTP).
, fear memory and attention and many other brain functions are necessary [14-17]
.
Recently, Merlin's lab in the Department of Neuroscience at Case Western Reserve University published an article entitled "Neuregulin 1 and ErbB4 kinase actively regulate sharp wave ripples in the hippocampus" in the Journal of Neuroscience, reporting that the NRG1/ErbB4 signaling pathway is involved in the Regulating the role of sharp waves in the occurrence of ripples provides a new idea for the study of learning and memory
.
The authors firstly recorded LFP in the vertebral layer of CA1 region of isolated mouse hippocampus slices in vitro
.
After obtaining a stable spike-ripple signal, 10 nM of NRG1 was added to the recording system, and the results showed that NRG1 significantly reduced the frequency of spike-ripples without affecting their duration, amplitude, and energy (Figure 1)
.
Figure 1 Frequency of NRG1-inhibited spike ripples (Source: Robinson H.
et al.
, J Neurosci, 2021) Due to the lack of ErbB4-specific blocking drugs, the author's laboratory recently used a strategy of chemical genetics Developed a transgenic mouse: T796G
.
This mouse was mutated at position 796 of the ATP-binding pocket (pocket) of ErbB4, and the bulky threonine (T) was mutated to a small-sized glycine (G), thereby expanding the ATP-binding pocket (Fig.
2A)
.
This mutation does not affect the function of ErbB4, but allows the bulky inhibitor 1NMPP1 to enter the mutated ATP-binding pocket and inhibit ErbB4
.
Previous studies have shown that inhibition of ErbB4 by 1NMPP1 can reduce GABA release, and it is worth mentioning that 1NMPP has no effect on the function of wild-type mice [17]
.
The authors found that the frequency of sharp ripples in hippocampal slices was significantly increased when 1NMPP1 was added to the recording system (Fig.
2B, C), indicating that endogenous activity of the NRG1/ErbB4 pathway is required for the generation of sharp ripples
.
1NMPP1 could also block the regulatory effect of NRG1 on sharp ripples (Fig.
2D), demonstrating that the effect of NRG1 is due to activation of ErbB4 tyrosine kinase
.
These results suggest that the NRG1/ErbB4 signaling system is involved in regulating the generation of sharp ripples
.
Figure 2 1NMPP1 blocks the NRG1/ErbB4 signaling pathway to increase the frequency of spike ripples (Source: Robinson H.
et al.
, J Neurosci,, 2021) In order to study the effect of ErbB4 kinase activity on spike ripples in vivo Influence, the authors injected 1NMPP1 into the abdominal cavity of T796G mice and found that the frequency of sharp wave ripples was significantly increased (Fig.
3 AC)
.
Interestingly, 1NMPP1 has different effects on spike ripples in non-rapid eye movement sleep (NREM) and wakefulness (wake), and the effect on spike ripples in wakefulness is stronger than that in non-REM sleep.
period of sharp ripples (Fig.
3D)
.
These results suggest that the NRG1/ErbB4 signaling pathway also regulates the generation of sharp ripples in vivo
.
Further analysis of unit neuron firing found that ErbB4 inhibition increased the activity of excitatory neurons, but had no significant effect on the activity of interneurons (Fig.
3E), suggesting that NRG1/ErbB4 regulates the activity of excitatory neurons by regulating the activity of excitatory neurons.
Generation of sharp waves and ripples
.
Figure 3 1 The enhancement effect of NMPP1 on sharp wave ripples depends on the behavioral state of animals (Source: Robinson H.
et al.
, J Neurosci, 2021) Whether the regulation of NRG1/ErbB4 signaling pathway on the generation of sharp wave ripples affects animal behavior, especially spatial Learning and memory impact? To answer this question, the authors employ a behavioral paradigm called the W-maze
.
The W-maze is named for its shape like the letter W.
It consists of a black arm in the middle and white arms on both sides.
Food-deprived mice need to learn to walk from the terminal of one arm to the terminal of the adjacent arm in order to obtain food reward (Fig.
4)
.
The process (inbound) of the rat from the side arm to the middle arm depends on the reference memory (reference memory), while the process (outbound) of the rat from the middle arm to the adjacent unvisited side arm depends on the spatial working memory (spatial working memory).
) [18]
.
The authors found that when T796G mice were intraperitoneally injected with 1NMPP1, the reference memory of the mice was not affected, while the spatial learning and memory were significantly reduced (Figure 4), thus proving that the regulation of spike ripples by the NRG1/ErbB4 signaling pathway may be involved in spatial learning and memory.
formation
.
Figure 4 1NMPP1 impairs spatial learning and memory (Source: Robinson H.
et al.
, J Neurosci, 2021) Conclusion and discussion, inspiration and prospect This work proves that NRG1/ErbB4 signaling pathway regulates excitatory nerves by up-regulating the release of GABA The activity of the element affects the generation of sharp waves and ripples, and participates in the formation of spatial learning and memory
.
The paper suggests that interneuron activity has a very important influence on the fundamental frequency of spike ripples
.
Sharp wave ripples are beneficial to spatial learning and memory.
However, simply and indiscriminately increasing the frequency of sharp wave ripples will impair the formation of spatial learning and memory, which may be related to the increase of basic noise
.
The formation mechanism of sharp wave ripples is very complex, and there is no mature theory to explain its generation process and regulation method
.
This article attempts to provide new ideas and directions for the study of sharp wave ripples from the perspective of molecular biology, and at the same time reveals a new cellular physiological mechanism of the NRG1/ErbB4 pathway
.
Link to the original text: https:// First author Heath Robinson (photo courtesy of Merlin Lab) Case West Heath Robinson, a doctoral student in the Department of Neuroscience of the University of California, is the first author of this article, Professor Mei Lin is the corresponding author, research scientist Dr.
Tan Zhibing, doctoral students Ivan Santiago-Marrero, Emily P.
Arzola and Professor Xiong Wencheng made important contributions to the article
.
This work was supported by grants from the National Institutes of Health (NIH)
.
Selected Previous Articles【1】Autophagy︱Li Xiaojiang’s team discovered new progress in the clearance of TDP-43 cytoplasmic aggregation by SQSTM1 in non-human primate models【2】Nat Neurosci︱Cao Peng’s lab found that pain sensation is a struggle for survival among species [3] Neurosci Bull︱Tong Li's research group revealed that dopaminergic neurons in the VTA-PrL neural pathway play a role in promoting wakefulness during general anesthesia with sevoflurane in rats [4] Nat Aging︱Alzheimer's disease new Discovery: A regulatory mechanism of bone marrow-derived macrophages independent of TREM2 pathway【5】Sci Transl Med︱New evidence for delayed onset of monoaminergic antidepressants: hippocampal cAMP regulates HCN channel function and affects mouse behavior and behavior Memory [6] Nat Methods︱ Peng Hanchuan's research group developed cross-modal brain registration technology, which provides important support for brain map construction and single-cell accurate whole-brain mapping research [7] Nat Commun︱ astrocytes inhibit non-human primates Infiltration of peripheral macrophages in cerebral ischemia-like injury【8】Cereb Cortex | Peng Ziwen/Chen Qi’s group reveals multimodal neuroimaging features of compulsive behavior acquisition 【9】Neurosci Bull︱Li Yunqing’s group reveals anterior cingulate Changes in neuronal plasticity in the gyrus are related to hyperalgesia and anxiety in chronic pancreatitis【10】Neuron︱Cao Peng’s laboratory discovered the closed-loop neural mechanism of repetitive stereotyped behaviors.
Recommended for high-quality scientific research training courses【1】A common experimental paradigm for cognitive control and executive function 【2】Single Cell Sequencing and Spatial Transcriptomics Data Analysis Symposium Book Donation Activities References (swipe up and down to view) [1] Milner B, Corkin S, Teuber HL.
Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of HM.
Neuropsychologia.
1968 Sep 1;6(3):215- 34.
[2] [2] Carlesimo GA, Oscar-Berman M.
Memory deficits in Alzheimer's patients:
