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

Abstract

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).

Natural VTA activity during NREM sleep influences future exploratory behavior

“…However, acute opto-inhibition during wake, did affect consummatory licking behavior similarly to what has been previously described for Vgat ( Van Zessen et al., 2012 ) and Dat ( Hughes et al., 2020 ; Lee et al., 2020 ) neurons ( Figure S4 ). In addition, chronic opto-inhibition of each population during rest (laser on continuously for 4 h, beginning in quiet wake) did alter sleep architecture in drastically opposing ways, consistent with chemogenetic and sustained opto-manipulation results from previous studies ( Eban-Rothschild et al., 2016 ; Yu et al., 2019a , b ; Figure S5 ).

Figure 4 Sleep was not disrupted by state-specific opto-silencing in the VTA (A) Light delivery during NREM sleep did not affect the amount of time spent in different vigilance states for Vgat-cre -ArchT (orange) or Dat-cre -ArchT (purple) mice (student’s t -tests did not reveal any significant difference between groups for any vigilance state).

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“…Because it has been shown that VTA populations play a role in transitions between sleep and wakefulness, we wanted to ensure that our optogenetic approach did not directly disrupt sleep architecture; therefore, we avoided optogenetic activation because previous work has demonstrated that for both the dopaminergic ( Eban-Rothschild et al., 2016 ) and GABAergic ( Yu et al., 2019a , b ) populations, this causes sleep state transitions within seconds of stimulation. With our unilateral opto-inhibition approach, we found that state-specific optical manipulation did not alter the time spent in each arousal state, compared to wild-type no-laser controls or non-opsin controls, which received the same laser treatment ( Figures 4 A and 4B).…”

“…It is possible that sleep propels the VTA into a different activity regime not coupled to ongoing behavior, with the effect of temporally separating neural processing from action as proposed for other brain areas ( Kaufman et al., 2014 ). Interestingly, strong silencing of these populations (optogenetically: our Figure S5 ; Chowdhury et al., 2019 ; and chemogenetically: Eban-Rothschild et al., 2016 ; Yu et al., 2019a , b ) does lead to different effects on sleep architecture, suggesting perhaps that these populations are differentially connected with sleep/wake centers of the brain (e.g., the LH: Yu et al., 2019a ). Disrupting sleep architecture itself makes it impossible to examine the contribution of these different populations on future behavior, which is why we kept our optogenetic manipulation below the threshold of sleep disruption.…”

“…Recently, it was revealed that the VTA also mediates transitions between sleep and wake states. Dopaminergic and glutamatergic neurons in the VTA are necessary for the maintenance of wakefulness ( Eban-Rothschild et al., 2016 ; Oishi et al., 2017 ; Yu et al., 2019a ), whereas VTA GABAergic neurons are necessary for transition to sleep ( Yang et al., 2018 ; Yu et al., 2019a , 2019b , Chowdhury et al., 2019 ).…”

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice

“… 1 GABAergic VTA neurons communicate locally within the VTA but also give rise to prominent projections to other parts of the brain 2 , 3 and regulate sleep, mania-like behavior, and innate defensive responses. 4–6 In 2005, Perrotti et al found that chronic administration of psychostimulants, such as cocaine and amphetamine, to rats could induce the expression of the transcription factor Delta FosB within a group of GABAergic neurons in the posterior VTA, but no expression was observed in the anterior VTA, the traditional VTA area. 7 Jhou et al also reported GABAergic neurons lateral to the median raphe nucleus and caudal to the VTA regulate freezing and other passive aversive responses via projections to midbrain DAergic neurons.…”