J Neurosci-Hu Bo group revealed the role of dorsal hippocampus-positive interneurons in joint motor learning and their network activity mechanisms

Written by Hu Bo, edited by Li Rongyao—edited by Wang Sizhen—Xia Ye
links two events that occur at different times to make appropriate motor behaviors, and Associative motor learning is one of the important higher functions of the brain that is vulnerable to impairment in pathological states such as aging and mental disorders [1-2].

Therefore, fully revealing the mechanism of joint motor learning is of great significance
for preventing and alleviating the impairment of this function in disease states.
Previous studies have suggested that the dorsal hippocampus plays an important role in joint motor learning[3].

For example, dorsal hippocampal pyramidal cells (PYR) have increased firing activity during combined motor learning, and inhibition of PYR discharge activity can significantly impair the occurrence of combined motor learning [4-5
].
However, it should be noted that over-excitating the hippocampal PYR can also impair combined motor learning, suggesting that there may be other factors involved in the process
.
It has recently been found that both optogenetically inhibition of hippocampal interneurons or selective knockout of the expression of hippocampal interneurons can impair the combined learning ability of mice [6,7].

Among the many types of interneurons in the hippocampus, Parvalbumin-expressing interneuron (PV-IN) can be excited by pyramidal cells and in turn inhibited and regulated by cell and proximal dendritic processes [8].

Nevertheless, the characteristics and role of the hippocampal PV-IN in the process of combined motor learning, and its underlying mechanisms, remain unclear
.

On September 27, 2022, Hu Bo's research group at the Army Medical University published a report in the Journal of Neuroscience titled "Sustained activity of hippocampal parvalbumin-expressing interneurons supports trace eyeblink conditioning in mice.
" The paper reveals the role of dorsal hippocampal PV-IN in the process of joint motor learning and its network oscillation mechanism
.
Li Rongyao, Zhang Weiwei and Zhang Jie are the co-first authors of the paper, and Professor Hu Bo and Associate Professor Chen Hao are the corresponding authors
.
The authors take Trace eyeblink conditioning (tEBC) as the joint motor learning behavior model, and comprehensively use technical methods such as in vivo multi-channel recording, optogenetic stimulation, and neural signal calculation and analysis to analyze the activity mode and change law of the dorsal hippocampal PV-IN in the process of tEBC establishment, and determine the role of PV-IN activity in the establishment of tEBC and its network oscillation mechanism
。 The findings suggest that PV-IN continuous discharge activity plays a key role in tEBC establishment, which may be involved in this process
through interaction with PYR specifically regulating dorsal hippocampal Gamma band oscillations.
(Further reading: Hu Bo's team's latest research results, see the "Logical Neuroscience" report (click to read): Neurosci Bull-Hu Bo research group revealed that the cerebellar deep nuclear neurons projected to the ventral medial thalamus specifically participate in the regulation of combined sensory-motor learning behavior)

First, the authors comprehensively used optogenetic stimulation and multi-channel recording technology to specifically mark the dorsal hippocampal PV-IN in mice under somatic conditions
。 Further, the authors investigated the activity patterns of PV-IN during tEBC establishment and their variations (Figure 1
).
The authors found that conditioned stimulus (CS) can induce enhanced PV-IN discharge activity in the hippocampus (Figure 1A-C
).
In particular, this discharge enhancement activity does not stop after the end of CS, but can continue until the unconditioned stimulus (US) begins, spanning the entire interval from CS to US in time (Figures 1A-C), thus presenting a sustained activity pattern
.
In the early stages of tEBC learning, the continuous discharge of hippocampal PV-IN in mice in the paired training group was significantly stronger than that in the pseudo-pairing training group (Figure 1D-F
).
In the late stage of tEBC learning, the continuous discharge of hippocampal PV-IN in mice in the paired training group was significantly weakened, and its intensity was comparable to that of the pseudo-paired training group (Figure 1G-I).

This suggests that during combined motor learning, hippocampal PV-IN exhibits sustained discharge activity and is most pronounced
early in learning.

Figure 1 The dorsal hippocampal PV-IN exhibits stronger continuous discharge activity in the early stages of tEBC learning (Source: Li, R.
et al.
, J Neurosci, 2022)
Next, in order to determine the role of hippocampal PV-IN continuous discharge activity in tEBC establishment, the authors used optogenetic techniques to inhibit PV-IN continuous discharge activity and observed its effect on
tEBC establishment 。 The results showed that the specific inhibition of continuous discharge activity of hippocampal PV-IN significantly inhibited the establishment of tEBC in mice (Figure 2
).
This suggests that the sustained firing activity of PV-IN is the neural activity
necessary for tEBC establishment.

Fig.
2 Continuous discharge activity of the dorsal hippocampal PV-IN is necessary for tEBC establishment (Source: Li, R.
et al.
, J Neurosci, 2022)
Further, the authors investigated the possible mechanism by
which the hippocampal PV-IN exhibits sustained discharge activity 。 By analyzing the hippocampal PYR and PV-IN peak potential times recorded by the same array electrode, the authors can calculate the probability of PV-IN emitting peak potential in the 1-3 ms time window after the PYR peak potential appears, and then evaluate the potential excitation drive effect of PYR on PV-IN (Figure 3A-B).

The authors found that in the early stages of tEBC learning, the latent driving effect of hippocampal PYR on PV-IN in mice in the paired training group was significantly stronger than that of non-paired trained animals, and the strength of this driving effect was positively correlated with tEBC (Figure 3C-E).

In contrast, in the late stages of tEBC learning, the driving effect of the paired training group mouse hippocampal PYR on PV-IN was comparable to that of unpaired trained animals, and there was no significant correlation with tEBC establishment (Figure 3F-H).

Since a large number of hippocampal PYRs are enhanced by continuous release early in the establishment of tEBC [4-6], this suggests that the excitatory drive effect of PYR on PV-IN may be involved in learning the generation of sustained PV-IN discharge activity in the early stages
.

Fig.
3 The early presentation of a stronger PYR-IN excitation drive effect on tEBC learning (Source: Li, R.
et al.
, J Neurosci, 2022)
Further, the authors investigated the effect of
optogenetic inhibition of PV-IN continuous discharge activity on PYR-PVIN interaction 。 The results showed that optogenetic inhibition of continuous discharge activity of PV-IN did not significantly affect the average discharge frequency of PYR and PV-IN (Figure 4A-D), but significantly reduced the excitation-driven effect of PYR on PV-IN (Figure 4E).

This suggests that optogenetic inhibition of PV-IN continuous discharge activity may be an effective way
to interfere with PYR-PV-IN interactions.

Fig.
4 Optogenetics inhibits the interaction between PV-IN continuous discharge activity and damages PYR-PVIN (Source: Li, R.
et al.
, J Neurosci, 2022)
Next, the authors further investigate the effect on
the oscillation of the dorsal hippocampal network by inhibiting PV-IN continuous discharge activity and interfering with PYR-PVIN interaction 。 The results showed that tEBC learning enhanced the Gamma band (35-85 Hz) oscillation activity at CS-US interval, while inhibiting PV-IN continuous discharge activity significantly reduced the Gamma band oscillation enhancement on which tEBC learning depended (Figure 5A-B).

It is important to note that the effect of inhibiting PV-IN continuous discharge activity on hippocampal oscillations at CS-US interval occurs only in the Gamma band and not in the Theta (5-12 Hz) band (Figure 5A-B).

In addition, inhibiting PV-IN continuous discharge activity does not significantly impair hippocampal gamma and theta band oscillation activity during the US period (Figure 5C
).
These results suggest that PV-IN continuous discharge activity is associated with enhanced
gamma band oscillation activity associated with joint motor learning.

To further clarify whether enhanced gamma band oscillation activity is beneficial for tEBC establishment, the authors excite PV-IN at a frequency of 40 Hz and artificially induce the generation of dorsal hippocampal Gamma band oscillation activity, observing its effect on tEBC establishment (Figure 6A-C)
。 The results showed that on days 1 and 2 of tEBC learning, optogenetic excitation of PV-IN and artificial inducement of oscillation activities in the dorsal hippocampal gamma band significantly promoted the establishment of tEBC in the later stages of learning (Figure 6D).

The above results suggest that the continuous discharge activity of PV-IN is involved in enhancing the oscillation of the dorsal hippocampal Gamma band during the combined motor learning, and the enhancement of the gamma oscillation activity can promote the establishment of
tEBC.

Fig.
5 Optogenetic inhibition of continuous discharge activity of PV-IN impairs Gamma instead of Theta band oscillation activity (Source: Li, R.
et al.
, J Neurosci, 2022)
Figure 6 Excitation of PV-IN induced Gamma band oscillation promotes tEBC establishment (Source: Li, R.
et al.
, J Neurosci, 2022).

Conclusion and discussion, inspiration and prospects

In summary, the researchers used in vivo multichannel recording, optogenetic stimulation technology, combined with neural calculation and other analytical methods to find that the dorsal hippocampal PV-IN will show continuous discharge activity
in the combined motor learning process represented by tEBC.
In particular, PV-IN continuous discharge activity is most significant in the early stages of tEBC learning, and its generation may stem in part from the excitatory driving effect
of PYR on PV-IN.
Functionally, PV-IN continuous discharge activity is necessary for tEBC establishment, and it may function by regulating the oscillating activity of the dorsal hippocampal Gamma band
.
Together, the study provides a new understanding
of the mechanisms of cellular and network activity in which the dorsal hippocampus participates in joint motor learning.
Of course, there are still some unresolved issues in
the study.
For example, it is possible to infer that the source of the PV-IN continuous discharge activity signal is limited only by means of a method of computational analysis of neural signals
.
Theoretically, knocking out the receptors at the synaptic site of PYR-PVIN, specifically reducing the driving effect of PYR on PV-IN, would be a critical and more credible method for
determining the source of sustained PV-IN discharge activity.

Original link: Professor Hu Bo and Associate Professor Chen Hao designed this study as a whole, with Li Rongyao, Zhang Weiwei and Zhang Jie as the first authors, and Zhang Haibo and Chen Hui participating in the research of this project.
Professors Hu Zhi'an and Yao Zhongxiang guided
the project development and thesis writing.
The project research has been funded
by the National Natural Science Foundation of China Innovation Group Project, the National Natural Science Foundation of China and Youth Project, the Chongqing Municipal Education Commission Key Laboratory of Colleges and Universities, and the Special Project for Improving the Scientific and Technological Innovation Ability of the Army Military Medical University.

Corresponding authors: Hu Bo (first from left), Hao Chen (second from left), first author: Li Rongyao (first from right), Zhang Weiwei (second from right) (Photo courtesy of: Hu Bo Laboratory)

About the Author:

Hu Bo, deputy director, professor and doctoral supervisor of the Department of Physiology of the Basic Medical College of the Army Military Medical University, focuses on the research
of (1) the physiological mechanism of sleep promoting memory consolidation and (2) the neural circuit mechanism of cerebellar non-motor function.
It has won 4 National Natural Science Foundation of China, 1 sub-project of key military logistics scientific research, 1 project of National Defense Innovation Special Zone of the Science and Technology Commission of the Central Military Commission, and 1 project of Chongqing Natural Science Foundation
.
Authorized 2 national invention patents
.
He has published papers
in Nature Neuroscience, Neuron, Journal of Neuroscience, Cerebral Cortex, Neuroscience & Biobehavioral Reviews, Neuroscience Bulletin, Cerebellum and other journals.

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[4] Adv Sci-Chai Renjie's team made important progress in the regeneration of functional hair cells in cochlear organs

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