Dynamics of Lateral Habenula–Ventral Tegmental Area Microcircuit on Pain-Related Cognitive Dysfunctions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review 'Dynamics of lateral habenula-ventral tegmental area microcircuit on pain-related cognitive dysfunctions' provides a detailed overview of the LHb-VTA network and its potential involvement in cognitive deficits associated with depression/chronic pain syndromes. The manuscript is well written and easily understandable. The figure and table are helpful in understanding the text. As an observation, also in relation to the aims of the Journal, I would suggest to  include in the review studies carried out in humans (e.g. by means of functional MRI) on the topic, if available, in order to provide a clinical and translational relevance to the extensive preclinical evidence discussed by the Authors.

Author Response

RESPONSE TO REVIEWER #1:

Reviewer #1: The review 'Dynamics of lateral habenula-ventral tegmental area microcircuit on pain-related cognitive dysfunctions' provides a detailed overview of the LHb-VTA network and its potential involvement in cognitive deficits associated with depression/chronic pain syndromes. The manuscript is well written and easily understandable. The figure and table are helpful in understanding the text. As an observation, also in relation to the aims of the Journal, I would suggest to include in the review studies carried out in humans (e.g. by means of functional MRI) on the topic, if available, in order to provide a clinical and translational relevance to the extensive preclinical evidence discussed by the Authors.

Author’s response: Thank you for pointing it out. We have included several references and sentences highlighting clinical findings. Please see for example: on page 4, lines 128-144; on page 4, lines 154-156). Thank you for your careful revision.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In the manuscript "Dynamics of lateral habenula-ventral tegmental area microcircuit on pain-related cognitive dysfunctions", authors - Drs. Ana Raquel Pereira et al - touched on a very important topic. A large amount of material was reviewed, and the review is excellent to read, the text is very informative. Therefore, I have no objections on the merits, I only have some questions and additions.

There is some evidence of norepinephrine projections to the lateral habenula from the locus coeruleus. These norepinephrine connections are likely involved in the mechanisms of stress and anxiety, and it is also believed that such regulation may influence pain regulation and cognitive mechanisms:

Purvis et al, Lateral Habenular Norepinephrine Contributes to States of Arousal and Anxiety in Male Rats; Behav Brain Res. 2018 ; 16; 347: 108–115; doi: 10.1016/j.bbr.2018.03.012

Guo et al; Dissecting the Neural Circuitry for Pain Modulation and Chronic Pain: Insights from Optogenetics; Neurosci Bull. 2022 Apr; 38(4): 440–452; doi: 10.1007/s12264-022-00835-8

The role of this influence is not limited to the regulation of chronic pain; it is also key in the regulation of consciousness and cognitive functions:

Tsytsarev et al; Methodological aspects of studying the mechanisms of consciousness. Behav Brain Res. 2022 Feb 15;419:113684. doi: 10.1016/j.bbr.2021.113684.

I would suggest the authors to devote at least a few sentences to this issue, using these, and perhaps some other publications of recent years

As well known, animal experiments have demonstrated that the medial prefrontal cortex (mPFC), involved in chronic pain mechanisms, is activated through dopamine (DA) inputs from the ventral tegmentum (VTA). Is there data regarding the specificity of dopamine receptors in these neural circuits? This issue is directly related to the pharmacological therapy of chronic pain, so the opinion of the authors would be very interesting for everyone working in this field.

Minor criticisms: It might be a good idea to indicate whether the connections shown in Figure 1 are intrahemispheric and/or interhemispheric.

The manuscript is organized well, and written clearly, I was impressed very much. I will be happy to recommend the manuscript for the publication after minor corrections, suggested before.

Author Response

RESPONSE TO REVIEWER #2:

Reviewer #2: In the manuscript "Dynamics of lateral habenula-ventral tegmental area microcircuit on pain-related cognitive dysfunctions", authors - Drs. Ana Raquel Pereira et al - touched on a very important topic. A large amount of material was reviewed, and the review is excellent to read, the text is very informative. Therefore, I have no objections on the merits, I only have some questions and additions.

There is some evidence of norepinephrine projections to the lateral habenula from the locus coeruleus. These norepinephrine connections are likely involved in the mechanisms of stress and anxiety, and it is also believed that such regulation may influence pain regulation and cognitive mechanisms:

Purvis et al, Lateral Habenular Norepinephrine Contributes to States of Arousal and Anxiety in Male Rats; Behav Brain Res. 2018 ; 16; 347: 108–115; doi: 10.1016/j.bbr.2018.03.012

Guo et al; Dissecting the Neural Circuitry for Pain Modulation and Chronic Pain: Insights from Optogenetics; Neurosci Bull. 2022 Apr; 38(4): 440–452; doi: 10.1007/s12264-022-00835-8

The role of this influence is not limited to the regulation of chronic pain; it is also key in the regulation of consciousness and cognitive functions:

Tsytsarev et al; Methodological aspects of studying the mechanisms of consciousness. Behav Brain Res. 2022 Feb 15;419:113684. doi: 10.1016/j.bbr.2021.113684.

I would suggest the authors to devote at least a few sentences to this issue, using these, and perhaps some other publications of recent years

Author’s response: We agree. A sentence was included on page 4, lines 121-127.

Reviewer #2: As well known, animal experiments have demonstrated that the medial prefrontal cortex (mPFC), involved in chronic pain mechanisms, is activated through dopamine (DA) inputs from the ventral tegmentum (VTA). Is there data regarding the specificity of dopamine receptors in these neural circuits? This issue is directly related to the pharmacological therapy of chronic pain, so the opinion of the authors would be very interesting for everyone working in this field.

Author’s response: Pharmacological therapy for chronic pain often involves targeting DA receptors and other neuromodulatory systems. For example, opioids, which are commonly used to manage chronic pain, act on the mu-opioid receptors within the brain’s reward and pain circuits. These receptors interact with DA systems and can influence both pain perception and reward processes. In the case of the mPFC, D1r are expressed in all mPFC layers, whereas D2r is expressed mainly in deeper layers. The modulation of these receptors has been shown to provide a specific strategy to modulate pain sensation, changing neuronal excitability and synaptic transmission. Two comprehensive reviews on the topic can be found in Huang et al (2022, Neurosci Lett) and Jarcho et al. (2012, Pain). A sentence was included in page 5, lines 185-187 of the manuscript.   

Reviewer #2: Minor criticisms: It might be a good idea to indicate whether the connections shown in Figure 1 are intrahemispheric and/or interhemispheric.

Author’s response: Thanks for the observation. The legend of Fig. 1 was edited.

Reviewer #2: The manuscript is organized well, and written clearly, I was impressed very much. I will be happy to recommend the manuscript for the publication after minor corrections, suggested before.

Author’s response: Once again, thank you for your careful revision, and we hope that this version of the manuscript has solved all concerns.

 

 

Author Response File: Author Response.pdf