Stress induces divergent gene expression among lateral habenula efferent pathways

Levinstein, Marjorie R.; Coffey, Kevin R.; Marx, Russell G.; Lesiak, Atom J.; Neumaier, John F.

doi:10.1101/2020.05.15.098319

Cited by 3 publications

(6 citation statements)

References 51 publications

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“…On the other hand, the loser-promoting dHbM projects to the ventral IPN, which then projects to the median raphe nucleus 27 . The mammalian LHb sends major afferent projections to the VTA and rostromedial tegmental area (RMTg) in addition to the DRN, and some studies have shown that LHb neurons respond to stress differently depending on its projection area 31,32 . Thus, it is likely that depending on the neural projection target, activation of LHb neurons can have different effects on aggressive behavior.…”

Section: Discussionmentioning

confidence: 99%

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

et al. 2022

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The dorsal raphe nucleus (DRN) is known to control aggressive behavior in mice. Here, we found that glutamatergic projections from the lateral habenula (LHb) to the DRN were activated in male mice that experienced pre-exposure to a rival male mouse (“social instigation”) resulting in heightened intermale aggression. Both chemogenetic and optogenetic suppression of the LHb-DRN projection blocked heightened aggression after social instigation in male mice. In contrast, inhibition of this pathway did not affect basal levels of aggressive behavior, suggesting that the activity of the LHb-DRN projection is not necessary for the expression of species-typical aggressive behavior, but required for the increase of aggressive behavior resulting from social instigation. Anatomical analysis showed that LHb neurons synapse on non-serotonergic DRN neurons that project to the ventral tegmental area (VTA), and optogenetic activation of the DRN-VTA projection increased aggressive behaviors. Our results demonstrate that the LHb glutamatergic inputs to the DRN promote aggressive arousal induced by social instigation, which contributes to aggressive behavior by activating VTA-projecting non-serotonergic DRN neurons as one of its potential targets.

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Section: Discussionmentioning

confidence: 99%

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

et al. 2022

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“…Future studies need to be designed to record LHb firing rates prior to each 24-hr ethanol access period in the IAE paradigm to understand how LHb activity changes over time with chronic ethanol intake. It needs to be mentioned that our study was focused on individual differences in outbred rats with no other prior stress experience; and the next step would be to determine how baseline LHb neuronal activity and ethanol intake differs in rat with depression-like symptoms that have undergone stress [48][49][50] compared with normal rats.…”

Section: Discussionmentioning

confidence: 99%

Baseline Lateral Habenula Firing Rate Negatively Correlates with Increase in Ethanol Intake over Days in Adult Long Evans Rats

Tandon

2021

Preprint

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While many adults consume alcohol, yet only some individuals are at a risk to develop alcohol use disorder (AUD). Variability in the risk for alcohol abuse is multifactorial and includes differences in behavioral and neuronal traits. The lateral habenula (LHb) has been shown to mediate aversive state-related behavioral responses. Interestingly, in both humans and rodents, depression-like symptoms are associated with high LHb activity. Additionally, there is a high co-morbidity between major depressive disorder and AUD. However, LHb lesions in rodents increase ethanol intake over time. Thus, we wanted to determine how baseline LHb activity correlates with ethanol intake over days. Specifically, we wanted to test whether individual variation in baseline LHb activity in ethanol-naive rats is related to home-cage ethanol drinking patterns. Hence, in this study, we determined the correlation between individual variability in baseline LHb neural activity, the negative-affective state-related ultrasonic vocalizations (USVs; 22-28 kHz), and the extent of ethanol intake over days. We first surgically implanted a unilateral 16-wire electrode array in the LHb of adult male Long Evans rats (n=11). Following recovery from surgery, rats were placed in sound-insulated chambers for two hours, where they were free to explore while we simultaneously recorded neuronal signals from their LHb and the USVs emitted by them. Next, these rats underwent an intermittent access to ethanol (IAE) paradigm, where they received 20% ethanol for 24 hours on alternate days (Monday-Wednesday-Friday) and ad-libitum water in their home cages for four weeks. The change in ethanol intake over days differed between rats, with some rats escalating their ethanol intake in the four weeks, while other rats showing no meaningful change in ethanol intake over days as compared to the first session. We found a significant negative correlation between average baseline LHb firing rates in rats and the changes in ethanol intake in the first week of IAE. Specifically, rats with higher baseline LHb firing rats, unlike rats with lower baseline firing rates, did not escalate their ethanol intake from the first session to the second and fourth ethanol sessions of the IAE paradigm. We also found a moderate positive correlation between the number of 22-28 kHz USVs and the average LHb firing rates of these rats. These results indicate that higher baseline LHb neuronal activity in normal adult ethanol naive rats is associated with decreased motivation to seek and consume ethanol during the early stages of ethanol consumption.

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“…RiboTag-associated RNA extraction as previously described. 30,46,47 The LHb was extracted using a midline 3 mm punch and homogenized After the final wash, HSB was removed and beads were re-suspended in 400 μL supplemented RLT buffer (10 μL β-mercaptoethanol/10 mL RLT Buffer) from the RNeasy Plus Micro Kit (Qiagen, Hilden, Germany) and vortexed vigorously. These samples were then placed back on the magnet and the RLT buffer was removed from the magnetic beads prior to RNA extraction.…”

Section: Ribotag Extractionmentioning

confidence: 99%

“…3,[25][26][27][28][29] Using intersectional expression of RiboTag to immunopurify ribosome-associated mRNAs selectively from each of these pathways in rats, we previously identified only small differences in gene expression between the neurons comprising these three pathways, suggesting that the regional target of LHb neurons is not defined by distinctions in neuronal phenotype. 30 LHb neurons are mostly glutamatergic, but numerous neuropeptides are also expressed in these neurons and these may be important in generating different patterns of output activity. 31 Recent gene array and single cell RNA sequencing studies in mice identified several clusters of similar neurons within LHb.…”

Section: Introductionmentioning

confidence: 99%

“…First, LHb neurons that project to three primary targets, DRN, VTA, and RMTg are highly segregated with minimal collateral branching 3,25–29 . Using intersectional expression of RiboTag to immunopurify ribosome‐associated mRNAs selectively from each of these pathways in rats, we previously identified only small differences in gene expression between the neurons comprising these three pathways, suggesting that the regional target of LHb neurons is not defined by distinctions in neuronal phenotype 30 . LHb neurons are mostly glutamatergic, but numerous neuropeptides are also expressed in these neurons and these may be important in generating different patterns of output activity 31 .…”

Section: Introductionmentioning

confidence: 99%

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PACAP‐expressing neurons in the lateral habenula diminish negative emotional valence

Levinstein

Bergkamp

Lewis

et al. 2022

Genes Brain and Behavior

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The lateral habenula (LHb) is a small, bilateral, epithalamic nucleus which processes aversive information. While primarily glutamatergic, LHb neurons express genes coding for many neuropeptides, such as Adcyap1 the gene encoding pituitary adenylate cyclase‐activating polypeptide (PACAP), which itself has been associated with anxiety and stress disorders. Using Cre‐dependent viral vectors, we targeted and characterized these neurons based on their anatomical projections and found that they projected to both the raphe and rostromedial tegmentum but only weakly to ventral tegmental area. Using RiboTag to capture ribosomal‐associated mRNA from these neurons and reanalysis of existing single cell RNA sequencing data, we did not identify a unique molecular phenotype that characterized these PACAP‐expressing neurons in LHb. In order to understand the function of these neurons, we conditionally expressed hM3Dq DREADD selectively in LHb PACAP‐expressing neurons and chemogenetically excited these neurons during behavioral testing in the open field test, contextual fear conditioning, sucrose preference, novelty suppressed feeding, and conditioned place preference. We found that Gq activation of these neurons produce behaviors opposite to what is expected from the LHb as a whole—they decreased anxiety‐like and fear behavior and produced a conditioned place preference. In conclusion, PACAP‐expressing neurons in LHb represents a molecularly diverse population of cells that oppose the actions of the remainder of LHb neurons by being rewarding or diminishing the negative consequences of aversive events.

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Stress induces divergent gene expression among lateral habenula efferent pathways

Cited by 3 publications

References 51 publications

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

Baseline Lateral Habenula Firing Rate Negatively Correlates with Increase in Ethanol Intake over Days in Adult Long Evans Rats

PACAP‐expressing neurons in the lateral habenula diminish negative emotional valence

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