Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model

Abulseoud, Osama A.; Camsari, Ulas M.; Ruby, Christina L.; Mohamed, Khalid; Gawad, Noha Abdel; Kasasbeh, Aimen; Yüksel, Mehmet Y.; Choi, Doo Sup

doi:10.1186/s40345-014-0007-8

Cited by 20 publications

(17 citation statements)

References 60 publications

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“…Our results on hyperactivity produced by disinhibiting LH circuits are consistent with previous findings. In rats, repeated delivery of subthreshold stimuli (kindling) to the LH induces manialike behavior 45 . Indeed, the LH promotes physical activity and motivated behavior 46 ; LH lesions in rodents and people produce a state of wakefulness with no motion 47 .…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Zhao

et al. 2019

Preprint

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The ventral tegmental area (VTA), an important source of dopamine, regulates goal-and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTA Vgat ) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTA Vgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleepdeprived baseline, suggesting that the sleep homeostasis process was bypassed. The manialike behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect.The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTA Vgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTA Vgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTA Vgat neurons are centrally positioned to help set an animal's (and human's) level of mental and physical activity. Inputs that inhibit VTA Vgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival.Taken to the extreme, however, decreased or failed inhibition from VTA Vgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).

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Section: Discussionmentioning

confidence: 99%

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Zhao

et al. 2019

Preprint

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“…Although hyperactivity is the most frequently used measure of manic-like behavior in animals [17,24,36], hyperactivity only represents one facet of mania. Tests involving enhanced sexual behavior, socially aggressive behavior, increased reward-seeking behavior and disrupted circadian rhythmicity have also been used to measure manic-like behaviors in animals [1,13,16,20].…”

Section: Introductionmentioning

confidence: 99%

Chronic treatment with mood stabilizer lithium inhibits amphetamine-induced risk-taking manic-like behaviors

Zhu

Wang

Tan

et al. 2015

Neuroscience Letters

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“…These effects may indicate an increased copulatory performance in BACHD rats. Increased sexual performance has only been described in a few animal models and different studies using these models defined sexual behavior on the base of different parameters [ 35 – 37 ] making it difficult to compare our results to previous findings and understand the underlying mechanisms. Brain lesioning studies suggest the involvement of septal and hypothalamic areas in increasing sexual behavior [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Sexual behavior and testis morphology in the BACHD rat model

et al. 2018

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BackgroundHuntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, which results in brain neurodegeneration and peripheral pathology affecting different organs including testis. Patients with HD suffer from motor and cognitive impairment, and multiple psychiatric symptoms. Among behavioral abnormalities in HD, sexual disturbances have often been reported, but scarcely investigated in animal models. The BACHD rat model of HD carries the human full-length mutated HTT (mHTT) genomic sequence with 97 CAG-CAA repeats and displays HD-like alterations at neuropathological and behavioral level.ObjectiveThis study aims to phenotype the BACHD rats’ sexual behavior and performance as well as testis morphology because alterations in these aspects have been associated to HD.MethodsTwo rat cohorts at the age of 3 and 7 months were subjected to mating tests to assess different parameters of sexual behavior. Histological analyses for testis morphology were performed in different rat cohorts at 1.5, 7 and 12 months of age whereas immunohistochemical analyses were carried out at 7 and 12 months of age to visualize the presence of mHTT in testicular tissue. Furthermore, western blot analyses were used to assess HTT and mHTT expression levels in striatum and testis at three months of age.ResultsAt 3 months, BACHD rats showed a decreased time exploring the female anogenital area (AGA), decreased latency to mount, increased number of intromissions and ejaculations and enhanced hit rate. At 7 months, all sexual parameters were comparable between genotypes with the exception that BACHD rats explored the AGA less than wild type rats. Testis analyses did not reveal any morphological alteration at any of the examined ages, but showed presence of mHTT limited to Sertoli cells in transgenic rats at both 7 and 12 months. BACHD rat HTT and mHTT expression levels in testis were lower than striatum at 3 months of age.ConclusionsThe testis phenotype in the BACHD rat model does not mimic the changes observed in human HD testis. The altered sexual behavior in BACHD rats at three months of age could be to a certain extent representative of and share common underlying pathways with some of the sexual disturbances in HD patients. Further investigating the biological causes of the sexual phenotype in BACHD rats may therefore contribute to clarifying the mechanisms at the base of sexual behavior changes in HD.

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Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model

Cited by 20 publications

References 60 publications

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Chronic treatment with mood stabilizer lithium inhibits amphetamine-induced risk-taking manic-like behaviors

Sexual behavior and testis morphology in the BACHD rat model

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